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Secondary brain damage caused by the innate immune response and subsequent proinflammatory factor production is a major factor contributing to the high mortality of intracerebral haemorrhage (ICH).,Nucleotide-binding oligomerization domain 1 (NOD1)/receptor-interacting protein 2 (RIP2) signalling has been reported to participate in the innate immune response and inflammatory response.,Therefore, we investigated the role of NOD1/RIP2 signalling in mice with collagenase-induced ICH and in cultured primary microglia challenged with hemin.,Adult male C57BL/6 mice were subjected to collagenase for induction of ICH model in vivo.,Cultured primary microglia and BV2 microglial cells (microglial cell line) challenged with hemin aimed to simulate the ICH model in vitro.,We first defined the expression of NOD1 and RIP2 in vivo and in vitro using an ICH model by western blotting.,The effect of NOD1/RIP2 signalling on ICH-induced brain injury volume, neurological deficits, brain oedema, and microglial activation were assessed following intraventricular injection of either ML130 (a NOD1 inhibitor) or GSK583 (a RIP2 inhibitor).,In addition, levels of JNK/P38 MAPK, IκBα, and inflammatory factors, including tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, and inducible nitric oxide synthase (iNOS) expression, were analysed in ICH-challenged brain and hemin-exposed cultured primary microglia by western blotting.,Finally, we investigated whether the inflammatory factors could undergo crosstalk with NOD1 and RIP2.,The levels of NOD1 and its adaptor RIP2 were significantly elevated in the brains of mice in response to ICH and in cultured primary microglia, BV2 cells challenged with hemin.,Administration of either a NOD1 or RIP2 inhibitor in mice with ICH prevented microglial activation and neuroinflammation, followed by alleviation of ICH-induced brain damage.,Interestingly, the inflammatory factors interleukin (IL)-1β and tumour necrosis factor-α (TNF-α), which were enhanced by NOD1/RIP2 signalling, were found to contribute to the NOD1 and RIP2 upregulation in our study.,NOD1/RIP2 signalling played an important role in the regulation of the inflammatory response during ICH.,In addition, a vicious feedback cycle was observed between NOD1/RIP2 and IL-1β/TNF-α, which could to some extent result in sustained brain damage during ICH.,Hence, our study highlights NOD1/RIP2 signalling as a potential therapeutic target to protect the brain against secondary brain damage during ICH.,The online version contains supplementary material available at 10.1186/s12974-020-02015-9. | Inflammasomes are involved in diverse inflammatory diseases.,Previous study reported that the neurotransmitter dopamine inhibited NLRP3 inflammasome activation via dopamine D1 receptor (DRD1).,The present study aims to investigate the role of DRD1 on neuroinflammation in intracerebral hemorrhage (ICH) mice and the potential mechanism mediated by NLRP3 inhibition.,One hundred and six male CD-1 mice were subjected to intrastriatal injection of bacterial collagenase or PBS.,A68930 (DRD1 specific agonist) was administered by subcutaneous injection at 1 h after collagenase injection.,Behavioral deficits and brain water content were assayed.,The expression of Iba 1 and MPO levels were measured by immunofluorescence staining.,The expressions of proteins in the DRD1/interferon-beta (IFN-beta)/NLRP3 signaling pathway were evaluated by western blotting.,Activation of the DRD1 by A68930 decreased brain edema and improved behavior at 24 and 72 h of ICH.,A68930 inhibited partly the activation of microglia and the neutrophil infiltration after 24 h of ICH.,IFN-beta, p-STAT1 increased while NLRP3, caspase 1, and IL-1beta decreased after A68930 administration in ICH mice.,DRD1 antagonist and IFN-beta siRNA reversed effects of A68930 on neurological outcome and brain edema.,DRD1 antagonist and IFN-beta siRNA blocked not only A68930-mediated increases of IFN-beta, p-STAT1 but also A68930-mediated decreases of NLRP3, caspase 1, and IL-1beta.,DRD1 activation by A68930 improves neurological outcome through inhibition of NLRP3-mediated inflammation in ICH mice.,The online version of this article (10.1186/s12974-017-1039-7) contains supplementary material, which is available to authorized users. | 1 |
Coronary artery disease (CAD) has substantial heritability and a polygenic architecture.,However, the potential of genomic risk scores to help predict CAD outcomes has not been evaluated comprehensively, because available studies have involved limited genomic scope and limited sample sizes.,This study sought to construct a genomic risk score for CAD and to estimate its potential as a screening tool for primary prevention.,Using a meta-analytic approach to combine large-scale, genome-wide, and targeted genetic association data, we developed a new genomic risk score for CAD (metaGRS) consisting of 1.7 million genetic variants.,We externally tested metaGRS, both by itself and in combination with available data on conventional risk factors, in 22,242 CAD cases and 460,387 noncases from the UK Biobank.,The hazard ratio (HR) for CAD was 1.71 (95% confidence interval [CI]: 1.68 to 1.73) per SD increase in metaGRS, an association larger than any other externally tested genetic risk score previously published.,The metaGRS stratified individuals into significantly different life course trajectories of CAD risk, with those in the top 20% of metaGRS distribution having an HR of 4.17 (95% CI: 3.97 to 4.38) compared with those in the bottom 20%.,The corresponding HR was 2.83 (95% CI: 2.61 to 3.07) among individuals on lipid-lowering or antihypertensive medications.,The metaGRS had a higher C-index (C = 0.623; 95% CI: 0.615 to 0.631) for incident CAD than any of 6 conventional factors (smoking, diabetes, hypertension, body mass index, self-reported high cholesterol, and family history).,For men in the top 20% of metaGRS with >2 conventional factors, 10% cumulative risk of CAD was reached by 48 years of age.,The genomic score developed and evaluated here substantially advances the concept of using genomic information to stratify individuals with different trajectories of CAD risk and highlights the potential for genomic screening in early life to complement conventional risk prediction. | Supplemental Digital Content is available in the text.,Coronary artery disease (CAD) is a complex phenotype driven by genetic and environmental factors.,Ninety-seven genetic risk loci have been identified to date, but the identification of additional susceptibility loci might be important to enhance our understanding of the genetic architecture of CAD.,To expand the number of genome-wide significant loci, catalog functional insights, and enhance our understanding of the genetic architecture of CAD.,We performed a genome-wide association study in 34 541 CAD cases and 261 984 controls of UK Biobank resource followed by replication in 88 192 cases and 162 544 controls from CARDIoGRAMplusC4D.,We identified 75 loci that replicated and were genome-wide significant (P<5×10−8) in meta-analysis, 13 of which had not been reported previously.,Next, to further identify novel loci, we identified all promising (P<0.0001) loci in the CARDIoGRAMplusC4D data and performed reciprocal replication and meta-analyses with UK Biobank.,This led to the identification of 21 additional novel loci reaching genome-wide significance (P<5×10−8) in meta-analysis.,Finally, we performed a genome-wide meta-analysis of all available data revealing 30 additional novel loci (P<5×10−8) without further replication.,The increase in sample size by UK Biobank raised the number of reconstituted gene sets from 4.2% to 13.9% of all gene sets to be involved in CAD.,For the 64 novel loci, 155 candidate causal genes were prioritized, many without an obvious connection to CAD.,Fine mapping of the 161 CAD loci generated lists of credible sets of single causal variants and genes for functional follow-up.,Genetic risk variants of CAD were linked to development of atrial fibrillation, heart failure, and death.,We identified 64 novel genetic risk loci for CAD and performed fine mapping of all 161 risk loci to obtain a credible set of causal variants.,The large expansion of reconstituted gene sets argues in favor of an expanded omnigenic model view on the genetic architecture of CAD. | 1 |
Despite evidence that therapeutic hypothermia improves patient outcomes for out-of-hospital cardiac arrest, use of this therapy remains low.,To determine whether the use of therapeutic hypothermia and patient outcomes have changed after publication of the Targeted Temperature Management trial on December 5, 2013, which supported more lenient temperature management for out-of-hospital cardiac arrest.,A retrospective cohort was conducted between January 1, 2013, and December 31, 2016, of 45 935 US patients in the Cardiac Arrest Registry to Enhance Survival who experienced out-of-hospital cardiac arrest and survived to hospital admission.,Calendar time by quarter year.,Use of therapeutic hypothermia and patient survival to hospital discharge.,Among 45 935 patients (17 515 women and 28 420 men; mean [SD] age, 59.3 [18.3] years) who experienced out-of-hospital cardiac arrest and survived to admission at 649 US hospitals, overall use of therapeutic hypothermia during the study period was 46.4%.,In unadjusted analyses, the use of therapeutic hypothermia dropped from 52.5% in the last quarter of 2013 to 46.0% in the first quarter of 2014 after the December 2013 publication of the Targeted Temperature Management trial.,Use of therapeutic hypothermia remained at or below 46.5% through 2016.,In segmented hierarchical logistic regression analysis, the risk-adjusted odds of use of therapeutic hypothermia was 18% lower in the first quarter of 2014 compared with the last quarter of 2013 (odds ratio, 0.82; 95% CI, 0.71-0.94; P = .006).,Similar point-estimate changes over time were observed in analyses stratified by presenting rhythm of ventricular tachycardia or ventricular fibrillation (odds ratio, 0.89; 95% CI, 0.71-1.13, P = .35) and pulseless electrical activity or asystole (odds ratio, 0.75; 95% CI, 0.63-0.89; P = .001).,Overall risk-adjusted patient survival was 36.9% in 2013, 37.5% in 2014, 34.8% in 2015, and 34.3% in 2016 (P < .001 for trend).,In mediation analysis, temporal trends in use of hypothermia did not consistently explain trends in patient survival.,In a US registry of patients who experienced out-of-hospital cardiac arrest, the use of guideline-recommended therapeutic hypothermia decreased after publication of the Targeted Temperature Management trial, which supported more lenient temperature thresholds.,Concurrent with this change, survival among patients admitted to the hospital decreased, but was not mediated by use of hypothermia.,This cohort study examines whether the use of therapeutic hypothermia and patient survival have changed after publication of the Targeted Temperature Management trial, which supported more lenient temperature management for out-of-hospital cardiac arrest.,Did the use of therapeutic hypothermia for out-of-hospital cardiac arrest change after publication of a trial that supported more lenient temperature goals?,In a cohort study of 45 935 US patients who experienced out-of-hospital cardiac arrest and survived to hospital admission, the risk-adjusted odds of the use of therapeutic hypothermia decreased 18% in the first quarter of 2014 after publication of the Targeted Temperature Management trial, compared with the last quarter of 2013.,Risk-adjusted patient survival also decreased during the study period, but was not mediated by trends in hypothermia use.,In a US registry of patients who experienced out-of-hospital cardiac arrest, the use of guideline-recommended active cooling decreased after publication of the Targeted Temperature Management trial. | We assessed the effects of targeting low-normal or high-normal arterial carbon dioxide tension (PaCO2) and normoxia or moderate hyperoxia after out-of-hospital cardiac arrest (OHCA) on markers of cerebral and cardiac injury.,Using a 23 factorial design, we randomly assigned 123 patients resuscitated from OHCA to low-normal (4.5-4.7 kPa) or high-normal (5.8-6.0 kPa) PaCO2 and to normoxia (arterial oxygen tension [PaO2] 10-15 kPa) or moderate hyperoxia (PaO2 20-25 kPa) and to low-normal or high-normal mean arterial pressure during the first 36 h in the intensive care unit.,Here we report the results of the low-normal vs. high-normal PaCO2 and normoxia vs. moderate hyperoxia comparisons.,The primary endpoint was the serum concentration of neuron-specific enolase (NSE) 48 h after cardiac arrest.,Secondary endpoints included S100B protein and cardiac troponin concentrations, continuous electroencephalography (EEG) and near-infrared spectroscopy (NIRS) results and neurologic outcome at 6 months.,In total 120 patients were included in the analyses.,There was a clear separation in PaCO2 (p < 0.001) and PaO2 (p < 0.001) between the groups.,The median (interquartile range) NSE concentration at 48 h was 18.8 µg/l (13.9-28.3 µg/l) in the low-normal PaCO2 group and 22.5 µg/l (14.2-34.9 µg/l) in the high-normal PaCO2 group, p = 0.400; and 22.3 µg/l (14.8-27.8 µg/l) in the normoxia group and 20.6 µg/l (14.2-34.9 µg/l) in the moderate hyperoxia group, p = 0.594).,High-normal PaCO2 and moderate hyperoxia increased NIRS values.,There were no differences in other secondary outcomes.,Both high-normal PaCO2 and moderate hyperoxia increased NIRS values, but the NSE concentration was unaffected.,ClinicalTrials.gov, NCT02698917.,Registered on January 26, 2016.,The online version of this article (10.1007/s00134-018-5453-9) contains supplementary material, which is available to authorized users. | 1 |
Multiple myeloma is a malignancy of antibody-secreting plasma cells.,Most patients benefit from current therapies, however, 20% of patients relapse or die within two years and are deemed high risk.,Here we analyze structural variants from 795 newly-diagnosed patients as part of the CoMMpass study.,We report translocations involving the immunoglobulin lambda (IgL) locus are present in 10% of patients, and indicative of poor prognosis.,This is particularly true for IgL-MYC translocations, which coincide with focal amplifications of enhancers at both loci.,Importantly, 78% of IgL-MYC translocations co-occur with hyperdiploid disease, a marker of standard risk, suggesting that IgL-MYC-translocated myeloma is being misclassified.,Patients with IgL-translocations fail to benefit from IMiDs, which target IKZF1, a transcription factor that binds the IgL enhancer at some of the highest levels in the myeloma epigenome.,These data implicate IgL translocation as a driver of poor prognosis which may be due to IMiD resistance.,Multiple myeloma is frequently characterised by translocation of genes next to the immunoglobulin heavy chain locus.,In this study, the authors sequence a large cohort of high risk myeloma samples and find translocations of cMyc to the immunoglobulin heavy chain locus and this is associated with poor prognosis. | Fluorescence in situ hybridization evaluation is essential for initial risk stratification in multiple myeloma.,While the presence of specific cytogenetic high-risk abnormalities (HRA) is known to confer a poor prognosis, less is known about the cumulative effect of multiple HRA.,We studied 1181 patients with newly diagnosed multiple myeloma who received novel agents as first-line therapy.,High-risk abnormalities were defined as t(4;14), t(14;16), t(14;20) and del(17p).,There were 884 patients (75%) without any HRA and 297 patients (25%) with HRA, including 262 (22%) with one HRA and 35 (3%) with two HRA.,The presence of one HRA (versus zero, hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.32-2.05, p<0.001) and the presence of two HRA (versus zero, HR 3.15, 95% CI 2.00-4.96, p<0.001) were of prognostic significance after adjusting for other prognostic factors.,Abnormalities of chromosome 13 were of prognostic significance independent of the established HRA: Monosomy 13 (HR 1.27, 95% CI 1.04-1.56, P=0.022) and del(13q) (HR 0.48, 95% CI 0.28-0.81, P=0.006) with opposite effects.,Patients with HRA experienced worse overall survival suggesting a cumulative adverse effect of multiple HRA.,Abnormalities of chromosome 13 were of prognostic significance after adjusting for other prognostic factors. | 1 |
The etiology of myocarditis often remains undetermined.,A large variety of infectious agents, systemic diseases, drugs, and toxins can cause the disease.,We report the case of a 19-year-old man who developed myocarditis three days after Pfizer-BioNTech COVID-19 booster vaccination.,A 19-year-old man, presenting with troponin-positive acute chest pain, was referred to our department.,He had received the Pfizer-BioNTech COVID-19 vaccine three days prior to his admission.,The diagnosis of acute myocarditis was confirmed by cardiovascular magnetic resonance imaging.,Patient hemodynamic status remained stable during hospitalization.,The left ventricular ejection fraction was preserved during hospital stay and at one-month follow-up.,We found no evidence for another infectious or autoimmune etiology.,Although imputability of the vaccine cannot be formally established on the basis of this case report, the findings raise the possibility of an association between mRNA COVID-19 vaccination and acute myocarditis. | Immune-mediated myocardial injury following Severe Acute Respiratory Syndrome Coronavirys-2 (SARS-CoV2) infection has been described in adults and children.,Cases of myocarditis following immunization for SARS-CoV2 have recently been documented, mostly associated with mild severity and spontaneous recovery.,We herein report two cases of fulminant myocarditis following BNT162b2 mRNA Covid-19 vaccination associated with systemic hyperinflammatory syndrome and refractory shock requiring support with veno-arterial extracorporeal membrane oxygenation. | 1 |
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also referred to as COVID-19, was declared a pandemic by the World Health Organization in March 2020.,The manifestations of COVID-19 are widely variable and range from asymptomatic infection to multi-organ failure and death.,Like other viral illnesses, acute myocarditis has been reported to be associated with COVID-19 infection.,However, guidelines for the diagnosis of COVID-19 myocarditis have not been established.,Using a combination of search terms in the PubMed/Medline, Ovid Medline and the Cochrane Library databases and manual searches on Google Scholar and the bibliographies of articles identified, we reviewed all cases reported in the English language citing myocarditis associated with COVID-19 infection.,Fourteen records comprising a total of fourteen cases that report myocarditis/myopericarditis secondary to COVID-19 infection were identified.,There was a male predominance (58%), with the median age of the cases described being 50.4 years.,The majority of patients did not have a previously identified comorbid condition (50%), but of those with a past medical history, hypertension was most prevalent (33%).,Electrocardiogram findings were variable, and troponin was elevated in 91% of cases.,Echocardiography was performed in 83% of cases reduced function was identified in 60%.,Endotracheal intubation was performed in the majority of cases.,Glucocorticoids were most commonly used in treatment of myocarditis (58%).,Majority of patients survived to discharge (81%) and 85% of those that received steroids survived to discharge.,Guidelines for diagnosis and management of COVID-19 myocarditis have not been established and our knowledge on management is rapidly changing.,The use of glucocorticoids and other agents including IL-6 inhibitors, IVIG and colchicine in COVID-19 myocarditis is debatable.,In our review, there appears to be favorable outcomes related to myocarditis treated with steroid therapy.,However, until larger scale studies are conducted, treatment approaches have to be made on an individualized case-by-case basis. | To investigate the characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019 (COVID-19).,We enrolled 671 eligible hospitalized patients with severe COVID-19 from 1 January to 23 February 2020, with a median age of 63 years.,Clinical, laboratory, and treatment data were collected and compared between patients who died and survivors.,Risk factors of death and myocardial injury were analysed using multivariable regression models.,A total of 62 patients (9.2%) died, who more often had myocardial injury (75.8% vs.,9.7%; P < 0.001) than survivors.,The area under the receiver operating characteristic curve of initial cardiac troponin I (cTnI) for predicting in-hospital mortality was 0.92 [95% confidence interval (CI), 0.87-0.96; sensitivity, 0.86; specificity, 0.86; P < 0.001].,The single cut-off point and high level of cTnI predicted risk of in-hospital death, hazard ratio (HR) was 4.56 (95% CI, 1.28-16.28; P = 0.019) and 1.25 (95% CI, 1.07-1.46; P = 0.004), respectively.,In multivariable logistic regression, senior age, comorbidities (e.g. hypertension, coronary heart disease, chronic renal failure, and chronic obstructive pulmonary disease), and high level of C-reactive protein were predictors of myocardial injury.,The risk of in-hospital death among patients with severe COVID-19 can be predicted by markers of myocardial injury, and was significantly associated with senior age, inflammatory response, and cardiovascular comorbidities. | 1 |
Throughout 2020, the COVID-19 pandemic has had a major impact on the care of non-communicable diseases across the world and diabetes is no exception.,Whereas many branches of medicine have adapted to telemedicine, this is difficult and challenging for the diabetic foot which often requires “hands on” treatment.,This review covers the challenges that have faced clinicians across the world in the management of complex diabetic foot problems and also includes some illustrative case vignettes which show how it is possible to manage foot ulcers without the usual access to laboratory and radiological testing.,There is no doubt that the COVID-19 experience when handling diabetic foot problems will likely transform our approach to the management of diabetic foot disease especially in the areas of digital health and smart technology. | COVID‐19 pandemia began in Wuhan, China, in December 2019.,A total of 1 878 489 people were infected and 119 044 people were lost because of the disease and its complications by 15 April.,Severe morbidity and mortality complications are mostly seen in elderly and patients having comorbidities.,Diabetic foot ulcers (DFUs) are one of severe complications of diabetes mellitus and it may require urgent surgical interventions.,In this paper, we aimed to create a management algorithm to prevent the unexpected complications that may occur in the patients and health care workers during the evaluation of COVID‐19 in DFU patients who require urgent surgical intervention.,We advise the use of thorax computerised tomography for preoperative screening in all DFU patients with severe signs of infection and especially those requiring urgent surgery for both the detection of the possible undiagnosed COVID‐19 in the patient for the need for close follow‐up and protection of the surgical and anaesthesiology team. | 1 |
Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).,Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described.,In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020.,Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors.,We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death.,191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients).,Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03-1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61-12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64-128·55; p=0·0033) on admission.,Median duration of viral shedding was 20·0 days (IQR 17·0-24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors.,The longest observed duration of viral shedding in survivors was 37 days.,The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage.,Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future.,Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development. | We describe the first case of acute cardiac injury directly linked to myocardial localization of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in a 69‐year‐old patient with flu‐like symptoms rapidly degenerating into respiratory distress, hypotension, and cardiogenic shock.,The patient was successfully treated with venous‐arterial extracorporeal membrane oxygenation (ECMO) and mechanical ventilation.,Cardiac function fully recovered in 5 days and ECMO was removed.,Endomyocardial biopsy demonstrated low‐grade myocardial inflammation and viral particles in the myocardium suggesting either a viraemic phase or, alternatively, infected macrophage migration from the lung. | 1 |
The new coronavirus disease outbreak in 2019 (COVID-19) represents a dramatic challenge for healthcare systems worldwide.,As to viral tropism, lungs are not the only COVID-19 target but also the heart may be involved in a not negligible percentage of the infected patients.,Myocarditis-related cardiac dysfunction and potentially life-threatening arrhythmias are the main aftermaths.,A few studies showed that myocardial injury in adult patients is often linked with a fatal outcome.,Conversely, scientific evidence in children is sparse, although several reports were published with the description of a cardiac involvement in COVID-19 paediatric patients.,In these young subjects, a background of surgically treated congenital heart disease seems to be a predisposing factor.,Conclusion: This systematic review is aimed at summarizing all COVID-19 cases with a cardiac involvement published in paediatric age and trying to explain the underlying mechanisms responsible for COVID-19-related myocardial damage.What is Known:• Coronaviruses proved to be able to jump from animals to humans.,• The outbreak of COVID-19 started from China (Dec 2019) and became pandemic.What is New:• Even in childhood, COVID-19 is not without the risk of cardiac involvement.,• Myocarditis, heart failure, and arrhythmias are among the possible manifestations.,What is Known:,• Coronaviruses proved to be able to jump from animals to humans.,• The outbreak of COVID-19 started from China (Dec 2019) and became pandemic.,What is New:,• Even in childhood, COVID-19 is not without the risk of cardiac involvement.,• Myocarditis, heart failure, and arrhythmias are among the possible manifestations. | This case series study evaluates the association of underlying cardiovascular disease and myocardial injury on fatal outcomes in patients with coronavirus disease 2019 (COVID-19).,What is the impact of underlying cardiovascular disease (CVD) and myocardial injury on fatal outcomes in patients with coronavirus disease 2019 (COVID-19)?,In this case series study of 187 patients with COVID-19, 27.8% of patients had myocardial injury, which resulted in cardiac dysfunction and arrhythmias.,Myocardial injury has a significant association with fatal outcome of COVID-19, while the prognosis of patients with underlying CVD but without myocardial injury were relatively favorable.,It is reasonable to triage patients with COVID-19 according to the presence of underlying CVD and evidence of myocardial injury for prioritized treatment and even more aggressive strategies.,Increasing numbers of confirmed cases and mortality rates of coronavirus disease 2019 (COVID-19) are occurring in several countries and continents.,Information regarding the impact of cardiovascular complication on fatal outcome is scarce.,To evaluate the association of underlying cardiovascular disease (CVD) and myocardial injury with fatal outcomes in patients with COVID-19.,This retrospective single-center case series analyzed patients with COVID-19 at the Seventh Hospital of Wuhan City, China, from January 23, 2020, to February 23, 2020.,Analysis began February 25, 2020.,Demographic data, laboratory findings, comorbidities, and treatments were collected and analyzed in patients with and without elevation of troponin T (TnT) levels.,Among 187 patients with confirmed COVID-19, 144 patients (77%) were discharged and 43 patients (23%) died.,The mean (SD) age was 58.50 (14.66) years.,Overall, 66 (35.3%) had underlying CVD including hypertension, coronary heart disease, and cardiomyopathy, and 52 (27.8%) exhibited myocardial injury as indicated by elevated TnT levels.,The mortality during hospitalization was 7.62% (8 of 105) for patients without underlying CVD and normal TnT levels, 13.33% (4 of 30) for those with underlying CVD and normal TnT levels, 37.50% (6 of 16) for those without underlying CVD but elevated TnT levels, and 69.44% (25 of 36) for those with underlying CVD and elevated TnTs.,Patients with underlying CVD were more likely to exhibit elevation of TnT levels compared with the patients without CVD (36 [54.5%] vs 16 [13.2%]).,Plasma TnT levels demonstrated a high and significantly positive linear correlation with plasma high-sensitivity C-reactive protein levels (β = 0.530, P < .001) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (β = 0.613, P < .001).,Plasma TnT and NT-proBNP levels during hospitalization (median [interquartile range (IQR)], 0.307 [0.094-0.600]; 1902.00 [728.35-8100.00]) and impending death (median [IQR], 0.141 [0.058-0.860]; 5375 [1179.50-25695.25]) increased significantly compared with admission values (median [IQR], 0.0355 [0.015-0.102]; 796.90 [401.93-1742.25]) in patients who died (P = .001; P < .001), while no significant dynamic changes of TnT (median [IQR], 0.010 [0.007-0.019]; 0.013 [0.007-0.022]; 0.011 [0.007-0.016]) and NT-proBNP (median [IQR], 352.20 [174.70-636.70]; 433.80 [155.80-1272.60]; 145.40 [63.4-526.50]) was observed in survivors (P = .96; P = .16).,During hospitalization, patients with elevated TnT levels had more frequent malignant arrhythmias, and the use of glucocorticoid therapy (37 [71.2%] vs 69 [51.1%]) and mechanical ventilation (31 [59.6%] vs 14 [10.4%]) were higher compared with patients with normal TnT levels.,The mortality rates of patients with and without use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers was 36.8% (7 of 19) and 21.4% (36 of 168) (P = .13).,Myocardial injury is significantly associated with fatal outcome of COVID-19, while the prognosis of patients with underlying CVD but without myocardial injury is relatively favorable.,Myocardial injury is associated with cardiac dysfunction and arrhythmias.,Inflammation may be a potential mechanism for myocardial injury.,Aggressive treatment may be considered for patients at high risk of myocardial injury. | 1 |
The COVID-19 pandemic has disrupted established care paths worldwide.,Patient awareness of the pandemic and executive limitations imposed on public life have changed the perception of when to seek care for acute conditions in some cases.,We sought to study whether there is a delay in presentation for acute ischemic stroke patients in the first month of the pandemic in the US.,The interval between last-known-well (LKW) time and presentation of 710 consecutive patients presenting with acute ischemic strokes to 12 stroke centers across the US were extracted from a prospectively maintained quality database.,We analyzed the timing and severity of the presentation in the baseline period from February to March 2019 and compared results with the timeframe of February and March 2020.,There were 320 patients in the 2-month baseline period in 2019, there was a marked decrease in patients from February to March of 2020 (227 patients in February, and 163 patients in March).,There was no difference in the severity of the presentation between groups and no difference in age between the baseline and the COVID period.,The mean interval from LKW to the presentation was significantly longer in the COVID period (603±1035 min) compared with the baseline period (442±435 min, P<0.02).,We present data supporting an association between public awareness and limitations imposed on public life during the COVID-19 pandemic in the US and a delay in presentation for acute ischemic stroke patients to a stroke center. | Higher rates of strokes have been observed in patients with coronavirus disease 2019 (COVID-19), but data regarding the outcomes of COVID-19 patients suffering from acute ischemic stroke due to large vessel occlusion (LVO) are lacking.,We report our initial experience in the treatment of acute ischemic stroke with LVO in patients with COVID-19.,All consecutive patients with COVID-19 with acute ischemic stroke due to LVO treated in our institution during the 6 first weeks of the COVID-19 outbreak were included.,Baseline clinical and radiological findings, treatment, and short-term outcomes are reported.,We identified 10 patients with confirmed COVID-19 treated for an acute ischemic stroke due to LVO.,Eight were men, with a median age of 59.5 years.,Seven had none or mild symptoms of COVID-19 at stroke onset.,Median time from COVID-19 symptoms to stroke onset was 6 days.,All patients had brain imaging within 3 hours from symptoms onset.,Five patients had multi-territory LVO.,Five received intravenous alteplase.,All patients had mechanical thrombectomy.,Nine patients achieved successful recanalization (mTICI2B-3), none experienced early neurological improvement, 4 had early cerebral reocclusion, and a total of 6 patients (60%) died in the hospital.,Best medical care including early intravenous thrombolysis, and successful and prompt recanalization achieved with mechanical thrombectomy, resulted in poor outcomes in patients with COVID-19.,Although our results require further confirmation, a different pharmacological approach (antiplatelet or other) should be investigated to take in account inflammatory and coagulation disorders associated with COVID-19. | 1 |
Coronavirus disease 2019 (COVID‐19) can lead to systemic coagulation activation and thrombotic complications.,To investigate the incidence of objectively confirmed venous thromboembolism (VTE) in hospitalized patients with COVID‐19.,Single‐center cohort study of 198 hospitalized patients with COVID‐19.,Seventy‐five patients (38%) were admitted to the intensive care unit (ICU).,At time of data collection, 16 (8%) were still hospitalized and 19% had died.,During a median follow‐up of 7 days (IQR, 3‐13), 39 patients (20%) were diagnosed with VTE of whom 25 (13%) had symptomatic VTE, despite routine thrombosis prophylaxis.,The cumulative incidences of VTE at 7, 14 and 21 days were 16% (95% CI, 10‐22), 33% (95% CI, 23‐43) and 42% (95% CI 30‐54) respectively.,For symptomatic VTE, these were 10% (95% CI, 5.8‐16), 21% (95% CI, 14‐30) and 25% (95% CI 16‐36).,VTE appeared to be associated with death (adjusted HR, 2.4; 95% CI, 1.02‐5.5).,The cumulative incidence of VTE was higher in the ICU (26% (95% CI, 17‐37), 47% (95% CI, 34‐58), and 59% (95% CI, 42‐72) at 7, 14 and 21 days) than on the wards (any VTE and symptomatic VTE 5.8% (95% CI, 1.4‐15), 9.2% (95% CI, 2.6‐21), and 9.2% (2.6‐21) at 7, 14, and 21 days).,The observed risk for VTE in COVID‐19 is high, particularly in ICU patients, which should lead to a high level of clinical suspicion and low threshold for diagnostic imaging for DVT or PE.,Future research should focus on optimal diagnostic and prophylactic strategies to prevent VTE and potentially improve survival. | Coagulopathy is a common abnormality in patients with COVID‐19.,However, the exact incidence of venous thromboembolic event is unknown in anticoagulated, severe COVID‐19 patients.,Systematic assessment of venous thromboembolism (VTE) using complete duplex ultrasound (CDU) in anticoagulated COVID‐19 patients.,We performed a retrospective study in 2 French intensive care units (ICU) where CDU is performed as a standard of care.,A CDU from thigh to ankle at selected sites with Doppler waveforms and images was performed early during ICU stay in patients admitted with COVID‐19.,Anticoagulation dose was left to the discretion of the treating physician based on the individual risk of thrombosis.,Patients were classified as treated with prophylactic anticoagulation or therapeutic anticoagulation.,Pulmonary embolism was systematically searched in patients with persistent hypoxemia or secondary deterioration.,From March 19 to April 11, 2020, 26 consecutive patients with severe COVID‐19 were screened for VTE.,Eight patients (31%) were treated with prophylactic anticoagulation, whereas 18 patients (69%) were treated with therapeutic anticoagulation.,The overall rate of VTE in patients was 69%.,The proportion of VTE was significantly higher in patients treated with prophylactic anticoagulation when compared with the other group (100% vs 56%, respectively, P = .03).,Surprisingly, we found a high rate of thromboembolic events in COVID‐19 patients treated with therapeutic anticoagulation, with 56% of VTE and 6 pulmonary embolisms.,Our results suggest considering both systematic screening of VTE and early therapeutic anticoagulation in severe ICU COVID‐19 patients. | 1 |
Venous thromboembolism (VTE) may complicate the course of Coronavirus Disease 2019 (COVID-19).,To evaluate the incidence of VTE in patients with COVID-19.,MEDLINE, EMBASE, and PubMed were searched up to 24th June 2020 for studies that evaluated the incidence of VTE, including pulmonary embolism (PE) and/or deep vein thrombosis (DVT), in patients with COVID-19.,Pooled proportions with corresponding 95% confidence intervals (CI) and prediction intervals (PI) were calculated by random-effect meta-analysis.,3487 patients from 30 studies were included.,Based on very low-quality evidence due to heterogeneity and risk of bias, the incidence of VTE was 26% (95% PI, 6%-66%).,PE with or without DVT occurred in 12% of patients (95% PI, 2%-46%) and DVT alone in 14% (95% PI, 1%-75%).,Studies using standard algorithms for clinically suspected VTE reported PE in 13% of patients (95% PI, 2%-57%) and DVT in 6% (95% PI, 0%-60%), compared to 11% (95% PI, 2%-46%) and 24% (95% PI, 2%-85%) in studies using other diagnostic strategies or patient sampling.,In patients admitted to intensive care units, VTE occurred in 24% (95% PI, 5%-66%), PE in 19% (95% PI, 6%-47%), and DVT alone in 7% (95% PI, 0%-69%).,Corresponding values in general wards were respectively 9% (95% PI, 0%-94%), 4% (95% PI, 0%-100%), and 7% (95% CI, 1%-49%).,VTE represents a frequent complication in hospitalized COVID-19 patients and often occurs as PE.,The threshold for clinical suspicion should be low to trigger prompt diagnostic testing.,•Incidence of venous thromboembolism (VTE) in Coronavirus Disease-2019 (COVID-19) is unclear.,•A total of 3487 patients with COVID-19 were included in 30 observational studies.,•VTE incidence varied due to differences in diagnostic protocols and hospital setting.,•VTE risk was higher in intensive care units, but seemed also substantial in general wards despite prophylaxis.,Incidence of venous thromboembolism (VTE) in Coronavirus Disease-2019 (COVID-19) is unclear.,A total of 3487 patients with COVID-19 were included in 30 observational studies.,VTE incidence varied due to differences in diagnostic protocols and hospital setting.,VTE risk was higher in intensive care units, but seemed also substantial in general wards despite prophylaxis. | COVID-19 predisposes patients to a prothrombotic state with demonstrated microvascular involvement.,The degree of hypercoagulability appears to correlate with outcomes; however, optimal criteria to assess for the highest-risk patients for thrombotic events remain unclear; we hypothesized that deranged thromboelastography measurements of coagulation would correlate with thromboembolic events.,Patients admitted to an ICU with COVID-19 diagnoses who had thromboelastography analyses performed were studied.,Conventional coagulation assays, d-dimer levels, and viscoelastic measurements were analyzed using a receiver operating characteristic curve to predict thromboembolic outcomes and new-onset renal failure.,Forty-four patients with COVID-19 were included in the analysis.,Derangements in coagulation laboratory values, including elevated d-dimer, fibrinogen, prothrombin time, and partial thromboplastin time, were confirmed; viscoelastic measurements showed an elevated maximum amplitude and low lysis of clot at 30 minutes.,A complete lack of lysis of clot at 30 minutes was seen in 57% of patients and predicted venous thromboembolic events with an area under the receiver operating characteristic curve of 0.742 (p = 0.021).,A d-dimer cutoff of 2,600 ng/mL predicted need for dialysis with an area under the receiver operating characteristic curve of 0.779 (p = 0.005).,Overall, patients with no lysis of clot at 30 minutes and a d-dimer > 2,600 ng/mL had a venous thromboembolic event rate of 50% compared with 0% for patients with neither risk factor (p = 0.008), and had a hemodialysis rate of 80% compared with 14% (p = 0.004).,Fibrinolysis shutdown, as evidenced by elevated d-dimer and complete failure of clot lysis at 30 minutes on thromboelastography predicts thromboembolic events and need for hemodialysis in critically ill patients with COVID-19.,Additional clinical trials are required to ascertain the need for early therapeutic anticoagulation or fibrinolytic therapy to address this state of fibrinolysis shutdown. | 1 |
The outbreak of a novel coronavirus since December 2019, became an emergency of major international concern.,As of June 21, 2020, the SARS-CoV-2 pandemic has caused 8,769,844 confirmed infections with 463,745 fatal cases worldwide.,The SARS-CoV-2 outbreak is a major challenge for clinicians.,In our clinic, we found a rare case that a COVID-19 patient combined with ischemic stroke.,A 79-year-old man was admitted to the Hubei Provincial Hospital of Traditional Chinese Medicine due to right limb weakness for 1 day and slight cough for 1 week.,At presentation, his oxygen saturation was 94.2% on room air and body temperature was 37.3 °C (99.0 °F) with some moist rales.,Neurological examination showed right limb weakness, and the limb muscle strength was grade 4.,The left leg and arms were unaffected.,In addition, runs of speech were not fluent enough with tongue deviation.,Laboratory studies showed lymphopenia and eosinophilic granulocytopenia.,Chest CT revealed bilateral pulmonary parenchymal ground-glass and consolidative pulmonary opacities, with a peripheral lung distribution.,Real-time polymerase chain reaction (RT-PCR) from throat swab sample was positive for SARS-CoV-2 nucleic acid.,This patient was treated with antiviral drugs and anti-inflammatory drugs with supportive care until his discharge.,Clopidogrel (75 mg) and atorvastatin (20 mg) were administered orally to treat acute ischemic stroke.,After 12 days of treatment, he can walk normally and communicate with near fluent language.,We report an even more unusual case, a patient who was hospitalized for right limb weakness and was later diagnosed with COVID-19.,Here, SARS-CoV-2 infection caused hypoxemia and excessive secretion of inflammatory cytokines, which contribute to the occurrence and development of ischemic stroke.,Once COVID-19 patients show acute ischemic stroke, neurologists should cooperate with infectious disease doctors to help patients. | Acute stroke remains a medical emergency even during the COVID-19 pandemic.,Most patients with COVID-19 infection present with constitutional and respiratory symptoms; while others present with atypical gastrointestinal, cardiovascular, or neurological manifestations.,Here we present a series of four patients with COVID-19 that presented with acute stroke.,We searched the hospital databases for patients that presented with acute stroke and concomitant features of suspected COVID-19 infection.,All patients who had radiographic evidence of stroke and PCR-confirmed COVID-19 infection were included in the study.,Patients admitted to the hospital with PCR- confirmed COVID-19 disease whose hospital course was complicated with acute stroke while inpatient were excluded from the study.,Retrospective patient data were obtained from electronic medical records.,Informed consent was obtained.,We identified four patients who presented with radiographic confirmation of acute stroke and PCR-confirmed SARS-CoV-2 infection.,We elucidate the clinical characteristics, imaging findings, and the clinical course.,Timely assessment and hyperacute treatment is the key to minimize mortality and morbidity of patients with acute stroke.,Stroke teams should be wary of the fact that COVID-19 patients can present with cerebrovascular accidents and should don appropriate personal protective equipment in every suspected patient.,Further studies are urgently needed to improve current understandings of neurological pathology in the setting of COVID-19 infection. | 1 |
Supplemental Digital Content is available in the text.,Information on the cardiac manifestations of coronavirus disease 2019 (COVID-19) is scarce.,We performed a systematic and comprehensive echocardiographic evaluation of consecutive patients hospitalized with COVID-19 infection.,One hundred consecutive patients diagnosed with COVID-19 infection underwent complete echocardiographic evaluation within 24 hours of admission and were compared with reference values.,Echocardiographic studies included left ventricular (LV) systolic and diastolic function and valve hemodynamics and right ventricular (RV) assessment, as well as lung ultrasound.,A second examination was performed in case of clinical deterioration.,Thirty-two patients (32%) had a normal echocardiogram at baseline.,The most common cardiac pathology was RV dilatation and dysfunction (observed in 39% of patients), followed by LV diastolic dysfunction (16%) and LV systolic dysfunction (10%).,Patients with elevated troponin (20%) or worse clinical condition did not demonstrate any significant difference in LV systolic function compared with patients with normal troponin or better clinical condition, but they had worse RV function.,Clinical deterioration occurred in 20% of patients.,In these patients, the most common echocardiographic abnormality at follow-up was RV function deterioration (12 patients), followed by LV systolic and diastolic deterioration (in 5 patients).,Femoral deep vein thrombosis was diagnosed in 5 of 12 patients with RV failure.,In COVID-19 infection, LV systolic function is preserved in the majority of patients, but LV diastolic function and RV function are impaired.,Elevated troponin and poorer clinical grade are associated with worse RV function.,In patients presenting with clinical deterioration at follow-up, acute RV dysfunction, with or without deep vein thrombosis, is more common, but acute LV systolic dysfunction was noted in ≈20%. | A novel coronavirus disease (COVID-19) in Wuhan has caused an outbreak and become a major public health issue in China and great concern from international community.,Myocarditis and myocardial injury were suspected and may even be considered as one of the leading causes for death of COVID-19 patients.,Therefore, we focused on the condition of the heart, and sought to provide firsthand evidence for whether myocarditis and myocardial injury were caused by COVID-19.,We enrolled patients with confirmed diagnosis of COVID-19 retrospectively and collected heart-related clinical data, mainly including cardiac imaging findings, laboratory results and clinical outcomes.,Serial tests of cardiac markers were traced for the analysis of potential myocardial injury/myocarditis.,112 COVID-19 patients were enrolled in our study.,There was evidence of myocardial injury in COVID-19 patients and 14 (12.5%) patients had presented abnormalities similar to myocarditis.,Most of patients had normal levels of troponin at admission, that in 42 (37.5%) patients increased during hospitalization, especially in those that died.,Troponin levels were significantly increased in the week preceding the death.,15 (13.4%) patients have presented signs of pulmonary hypertension.,Typical signs of myocarditis were absent on echocardiography and electrocardiogram.,The clinical evidence in our study suggested that myocardial injury is more likely related to systemic consequences rather than direct damage by the 2019 novel coronavirus.,The elevation in cardiac markers was probably due to secondary and systemic consequences and can be considered as the warning sign for recent adverse clinical outcomes of the patients.,•The evidence from clinical standpoint and front-line data in Wuhan for COVID-19.,•The novel coronavirus in COVID-19 less likely caused myocardial injury directly.,•Elevation in cardiac markers is the warning sign of adverse outcomes for COVID-19.,The evidence from clinical standpoint and front-line data in Wuhan for COVID-19.,The novel coronavirus in COVID-19 less likely caused myocardial injury directly.,Elevation in cardiac markers is the warning sign of adverse outcomes for COVID-19. | 1 |
Extracellular vesicles (EVs)-particularly exosomes and microvesicles (MVs)-are attracting considerable interest in the cardiovascular field as the wide range of their functions is recognized.,These capabilities include transporting regulatory molecules including different RNA species, lipids, and proteins through the extracellular space including blood and delivering these cargos to recipient cells to modify cellular activity.,EVs powerfully stimulate angiogenesis, and can protect the heart against myocardial infarction.,They also appear to mediate some of the paracrine effects of cells, and have therefore been proposed as a potential alternative to cell-based regenerative therapies.,Moreover, EVs of different sources may be useful biomarkers of cardiovascular disease identities.,However, the methods used for the detection and isolation of EVs have several limitations and vary widely between studies, leading to uncertainties regarding the exact population of EVs studied and how to interpret the data.,The number of publications in the exosome and MV field has been increasing exponentially in recent years and, therefore, in this ESC Working Group Position Paper, the overall objective is to provide a set of recommendations for the analysis and translational application of EVs focussing on the diagnosis and therapy of the ischaemic heart.,This should help to ensure that the data from emerging studies are robust and repeatable, and optimize the pathway towards the diagnostic and therapeutic use of EVs in clinical studies for patient benefit. | The burden of cardiovascular diseases (CVDs) remains unclear in many regions of the world.,The GBD (Global Burden of Disease) 2015 study integrated data on disease incidence, prevalence, and mortality to produce consistent, up-to-date estimates for cardiovascular burden.,CVD mortality was estimated from vital registration and verbal autopsy data.,CVD prevalence was estimated using modeling software and data from health surveys, prospective cohorts, health system administrative data, and registries.,Years lived with disability (YLD) were estimated by multiplying prevalence by disability weights.,Years of life lost (YLL) were estimated by multiplying age-specific CVD deaths by a reference life expectancy.,A sociodemographic index (SDI) was created for each location based on income per capita, educational attainment, and fertility.,In 2015, there were an estimated 422.7 million cases of CVD (95% uncertainty interval: 415.53 to 427.87 million cases) and 17.92 million CVD deaths (95% uncertainty interval: 17.59 to 18.28 million CVD deaths).,Declines in the age-standardized CVD death rate occurred between 1990 and 2015 in all high-income and some middle-income countries.,Ischemic heart disease was the leading cause of CVD health lost globally, as well as in each world region, followed by stroke.,As SDI increased beyond 0.25, the highest CVD mortality shifted from women to men.,CVD mortality decreased sharply for both sexes in countries with an SDI >0.75.,CVDs remain a major cause of health loss for all regions of the world.,Sociodemographic change over the past 25 years has been associated with dramatic declines in CVD in regions with very high SDI, but only a gradual decrease or no change in most regions.,Future updates of the GBD study can be used to guide policymakers who are focused on reducing the overall burden of noncommunicable disease and achieving specific global health targets for CVD. | 1 |
The triglyceride-glucose index (TyG index) has been proposed as a simple and reliable alternative insulin resistance (IR) marker, while the homeostasis model assessment for IR (HOMA-IR) is the most frequently used index.,Few studies have evaluated the role of IR assessed by the TyG index and HOMA-IR on arterial stiffness in a type 2 diabetes (T2D) population with a high risk of increased arterial stiffness.,We aimed to investigate the association of the TyG index and HOMA-IR with arterial stiffness in patients with T2D.,We recruited 3185 patients with T2D, who underwent brachial-ankle pulse wave velocity (baPWV), an indicator of arterial stiffness, but without previous cardiovascular disease.,Increased arterial stiffness was defined as a baPWV value greater than the 75th percentile (18.15 m/s) in the present study.,The TyG index was determined as ln(fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2), and the HOMA-IR was calculated as (fasting insulin [μIU/mL] × fasting glucose [mmol/L])/22.5.,The mean age of the study participants was 54.6 ± 12.0 years, and 1954 (61.4%) were men.,Seemingly unrelated regression estimation analysis demonstrated that the TyG index had stronger associations with baPWV than the HOMA-IR (all P < 0.001).,In the multivariable logistic analyses, each one-unit increase in the TyG index was associated with a 1.40-fold (95% CI 1.16-1.70, P < 0.001) higher prevalence of increased arterial stiffness, but the prominent association of the HOMA-IR with the prevalence of increased arterial stiffness was not observed.,Subgroup analyses showed that a more significant association between the TyG index and the prevalence of increased arterial stiffness was detected in older patients with a longer duration of diabetes and poor glycaemic control (all P < 0.05).,Compared with the HOMA-IR, the TyG index is independently and more strongly associated with arterial stiffness in patients with T2D.,The online version contains supplementary material available at 10.1186/s12933-021-01274-x. | Data on the relationship between the triglyceride glucose (TyG) index and coronary artery calcification (CAC) progression is limited.,This longitudinal study evaluated the association of TyG index with CAC progression in asymptomatic adults.,We enrolled 12,326 asymptomatic Korean adults who had at least two CAC evaluations.,The TyG index was determined using ln (fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2).,CAC progression was defined as a difference ≥ 2.5 between the square roots (√) of the baseline and follow-up coronary artery calcium score (CACS) (Δ√transformed CACS).,Annualized Δ√transformed CACS was defined as Δ√transformed CACS divided by the inter-scan period.,During a mean 3.3 years, the overall incidence of CAC progression was 30.6%.,The incidence of CAC progression (group I [lowest]: 22.7% versus [vs.] group II: 31.7% vs. group III [highest]: 37.5%, P < 0.001) and annualized Δ√transformed CACS (group I: 0.46 ± 1.44 vs. group II: 0.71 ± 2.02 vs. group III: 0.87 ± 1.75, P < 0.001) were markedly elevated with increasing TyG index tertiles.,Multivariate linear regression analysis showed that TyG index was associated with annualized Δ√transformed CACS (β = 0.066, P = 0.036).,In multivariate logistic regression analysis, the TyG index was significantly associated with CAC progression in baseline CACS ≤ 100.,The TyG index is an independent predictor of CAC progression, especially in adults without heavy baseline CAC. | 1 |
The hypothesis that been set forward that use of Renin Angiotensin Aldosterone System (RAAS) inhibitors is associated with COVID−19 severity.,We set-up a multicenter Italian collaboration (CORIST Project, ClinicalTrials.gov ID: NCT04318418) to retrospectively investigate the relationship between RAAS inhibitors and COVID−19 in-hospital mortality.,We also carried out an updated meta-analysis on the relevant studies.,We analyzed 4069 unselected patients with laboratory-confirmed SARS-CoV-2 infection and hospitalized in 34 clinical centers in Italy from February 19, 2020 to May 23, 2020.,The primary end-point in a time-to event analysis was in-hospital death, comparing patients who received angiotensin-converting-enzyme inhibitors (ACE-I) or angiotensin-receptor blockers (ARB) with patients who did not.,Articles for the meta-analysis were retrieved until July 13th, 2020 by searching in web-based libraries, and data were combined using the general variance-based method.,Out of 4069 COVID−19 patients, 13.5% and 13.3% received ACE-I or ARB, respectively.,Use of neither ACE-I nor ARB was associated with mortality (multivariable hazard ratio (HR) adjusted also for COVID−19 treatments: 0.96, 95% confidence interval 0.77-1.20 and HR = 0.89, 0.67-1.19 for ACE-I and ARB, respectively).,Findings were similar restricting the analysis to hypertensive (N = 2057) patients (HR = 1.00, 0.78-1.26 and HR = 0.88, 0.65-1.20) or when ACE-I or ARB were considered as a single group.,Results from the meta-analysis (19 studies, 29,057 COVID−19 adult patients, 9700 with hypertension) confirmed the absence of association.,In this observational study and meta-analysis of the literature, ACE-I or ARB use was not associated with severity or in-hospital mortality in COVID−19 patients. | Whether pulmonary artery (PA) dimension and coronary artery calcium (CAC) score, as assessed by chest computed tomography (CT), are associated with myocardial injury in patients with coronavirus disease 2019 (COVID-19) is not known.,The aim of this study was to explore the risk factors for myocardial injury and death and to investigate whether myocardial injury has an independent association with all-cause mortality in patients with COVID-19.,This is a single-centre cohort study including consecutive patients with laboratory-confirmed COVID-19 undergoing chest CT on admission.,Myocardial injury was defined as high-sensitivity troponin I >20 ng/L on admission.,A total of 332 patients with a median follow-up of 12 days were included.,There were 68 (20.5%) deaths; 123 (37%) patients had myocardial injury.,PA diameter was higher in patients with myocardial injury compared with patients without myocardial injury [29.0 (25th-75th percentile, 27-32) mm vs.,27.7 (25-30) mm, P < 0.001).,PA diameter was independently associated with an increased risk of myocardial injury [adjusted odds ratio 1.10, 95% confidence interval (CI) 1.02-1.19, P = 0.01] and death [adjusted hazard ratio (HR) 1.09, 95% CI 1.02-1.17, P = 0.01].,Compared with patients without myocardial injury, patients with myocardial injury had a lower prevalence of a CAC score of zero (25% vs.,55%, P < 0.001); however, the CAC score did not emerge as a predictor of myocardial injury by multivariable logistic regression.,Myocardial injury was independently associated with an increased risk of death by multivariable Cox regression (adjusted HR 2.25, 95% CI 1.27-3.96, P = 0.005).,Older age, lower estimated glomerular filtration rate, and lower PaO2/FiO2 ratio on admission were other independent predictors for both myocardial injury and death.,An increased PA diameter, as assessed by chest CT, is an independent risk factor for myocardial injury and mortality in patients with COVID-19.,Myocardial injury is independently associated with an approximately two-fold increased risk of death. | 1 |
Introduction: The Coronavirus disease 2019 (COVID-19) outbreak is a whole Earth health emergency related to a highly pathogenic human coronavirus responsible for severe acute respiratory syndrome (SARS-CoV-2).,Despite the fact that the majority of infected patients were managed in outpatient settings, little is known about the clinical characteristics of COVID-19 patients not requiring hospitalization.,The aim of our study was to describe the clinical comorbidity and the pharmacological therapies of COVID-19 patients managed in outpatient settings.,Materials and Methods: We performed an observational, retrospective analysis of laboratory-confirmed COVID-19 patients managed in outpatient settings in Naples, Italy between 9 March and 1 May 2020.,Data were sourced from the prospectively maintained Health Search (HS)/Thales database, shared by 128 primary care physicians (PCPs) in Naples, Italy.,The clinical features and pharmacological therapies of COVID-19 patients not requiring hospitalization and managed in outpatient settings have been described.,Results: A total of 351 laboratory-confirmed COVID-19 patients (mean age 54 ± 17 years; 193 males) with outpatient management were evaluated.,Hypertension was the most prevalent comorbidity (35%).,The distribution of cardiovascular comorbidities showed no gender-related differences.,A total of 201 patients (57.3%) were treated with at least one experimental drug for COVID-19.,Azithromycin, alone (42.78%) or in combination (27.44%), was the most widely used experimental anti-COVID drug in outpatient settings.,Low Molecular Weight Heparin and Cortisone were prescribed in 24.87% and 19.4% of the study population, respectively.,At multivariate regression model, diabetes (risk ratio (RR): 3.74; 95% CI 1.05 to 13.34; p = 0.04) and hypertension (RR: 1.69; 95% CI 1.05 to 2.7; p = 0.03) were significantly associated with the experimental anti-COVID drug administration.,Moreover, only diabetes (RR: 2.43; 95% CI 1.01 to 5.8; p = 0.03) was significantly associated with heparin administration.,Conclusions: Our data show a high prevalence of hypertension, more likely treated with renin-angiotensin-aldosterone system (RASS) inhibitors, among COVID-19 patients not requiring hospitalization.,Experimental COVID-19 therapies have been prescribed to COVID-19 patients considered at risk for increased venous thromboembolism based on concomitant comorbidities, in particular diabetes and hypertension. | Coronavirus disease-2019 (COVID-19), a viral respiratory illness caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), may predispose patients to thrombotic disease, both in the venous and arterial circulations, because of excessive inflammation, platelet activation, endothelial dysfunction, and stasis.,In addition, many patients receiving antithrombotic therapy for thrombotic disease may develop COVID-19, which can have implications for choice, dosing, and laboratory monitoring of antithrombotic therapy.,Moreover, during a time with much focus on COVID-19, it is critical to consider how to optimize the available technology to care for patients without COVID-19 who have thrombotic disease.,Herein, the authors review the current understanding of the pathogenesis, epidemiology, management, and outcomes of patients with COVID-19 who develop venous or arterial thrombosis, of those with pre-existing thrombotic disease who develop COVID-19, or those who need prevention or care for their thrombotic disease during the COVID-19 pandemic.,•COVID-19 may predispose patients to arterial and venous thrombosis.,•Initial series suggest the common occurrence of venous thromboembolic disease in patients with severe COVID-19.,The optimal preventive strategy warrants further investigation.,•Drug-drug interactions between antiplatelet agents and anticoagulants with investigational COVID-19 therapies should be considered.,•The available technology should be used optimally to care for patients without COVID-19 who have thrombotic disease during the pandemic.,COVID-19 may predispose patients to arterial and venous thrombosis.,Initial series suggest the common occurrence of venous thromboembolic disease in patients with severe COVID-19.,The optimal preventive strategy warrants further investigation.,Drug-drug interactions between antiplatelet agents and anticoagulants with investigational COVID-19 therapies should be considered.,The available technology should be used optimally to care for patients without COVID-19 who have thrombotic disease during the pandemic. | 1 |
Coronavirus disease 2019 (COVID‐19) is associated with coagulopathy but the optimal prophylactic anticoagulation therapy remains uncertain and may depend on COVID‐19 severity.,To compare outcomes in hospitalized adults with severe COVID‐19 treated with standard prophylactic versus intermediate dose enoxaparin.,We conducted a multi‐center, open‐label, randomized controlled trial comparing standard prophylactic dose versus intermediate dose enoxaparin in adults who were hospitalized with COVID‐19 and admitted to an intensive care unit (ICU) and/or had laboratory evidence of coagulopathy.,Patients were randomly assigned in a 1:1 ratio to receive standard prophylactic dose enoxaparin or intermediate weight‐adjusted dose enoxaparin.,The primary outcome was all‐cause mortality at 30 days.,Secondary outcomes included arterial or venous thromboembolism and major bleeding.,A total of 176 patients (99 males and 77 females) underwent randomization.,In the intention‐to‐treat population, all‐cause mortality at 30 days was 15% for intermediate dose enoxaparin and 21% for standard prophylactic dose enoxaparin (odds ratio, 0.66; 95% confidence interval, 0.30-1.45; P = .31 by Chi‐square test).,Unadjusted Cox proportional hazards modeling demonstrated no significant difference in mortality between intermediate and standard dose enoxaparin (hazard ratio, 0.67; 95% confidence interval, 0.33-1.37; P = .28).,Arterial or venous thrombosis occurred in 13% of patients assigned to intermediate dose enoxaparin and 9% of patients assigned to standard dose enoxaparin.,Major bleeding occurred in 2% of patients in each arm.,In hospitalized adults with severe COVID‐19, standard prophylactic dose and intermediate dose enoxaparin did not differ significantly in preventing death or thrombosis at 30 days. | Individual studies have reported widely variable rates for VTE and bleeding among hospitalized patients with coronavirus disease 2019 (COVID-19).,What is the incidence of VTE and bleeding among hospitalized patients with COVID-19?,In this systematic review and meta-analysis, 15 standard sources and COVID-19-specific sources were searched between January 1, 2020, and July 31, 2020, with no restriction according to language.,Incidence estimates were pooled by using random effects meta-analyses.,Heterogeneity was evaluated by using the I2 statistic, and publication bias was assessed by using the Begg and Egger tests.,The pooled incidence was 17.0% (95% CI, 13.4-20.9) for VTE, 12.1% (95% CI, 8.4-16.4) for DVT, 7.1% (95% CI, 5.3-9.1) for pulmonary embolism (PE), 7.8% (95% CI, 2.6-15.3) for bleeding, and 3.9% (95% CI, 1.2-7.9) for major bleeding.,In subgroup meta-analyses, the incidence of VTE was higher when assessed according to screening (33.1% vs 9.8% by clinical diagnosis), among patients in the ICU (27.9% vs 7.1% in the ward), in prospective studies (25.5% vs 12.4% in retrospective studies), and with the inclusion of catheter-associated thrombosis/isolated distal DVTs and isolated subsegmental PEs.,The highest pooled incidence estimate of bleeding was reported for patients receiving intermediate- or full-dose anticoagulation (21.4%) and the lowest in the only prospective study that assessed bleeding events (2.7%).,Among hospitalized patients with COVID-19, the overall estimated pooled incidence of VTE was 17.0%, with higher rates with routine screening, inclusion of distal DVT, and subsegmental PE, in critically ill patients and in prospective studies.,Bleeding events were observed in 7.8% of patients and were sensitive to use of escalated doses of anticoagulants and nature of data collection.,Additional studies are required to ascertain the significance of various thrombotic events and to identify strategies to improve patient outcomes.,PROSPERO; No.: CRD42020198864; URL: https://www.crd.york.ac.uk/prospero/. | 1 |
The clinical expert consensus statement on takotsubo syndrome (TTS) part II focuses on the diagnostic workup, outcome, and management.,The recommendations are based on interpretation of the limited clinical trial data currently available and experience of international TTS experts.,It summarizes the diagnostic approach, which may facilitate correct and timely diagnosis.,Furthermore, the document covers areas where controversies still exist in risk stratification and management of TTS.,Based on available data the document provides recommendations on optimal care of such patients for practising physicians. | Left ventricular (LV) thrombi during Takotsubo syndrome represent a potential complication and can be associated with cerebrovascular embolic events.,The aim of this study was to evaluate the exact incidence, predictors, and management strategies of LV thrombi in patients with Takotsubo syndrome.,We enrolled 541 consecutive patients in a multicenter international registry.,Clinical features and echocardiographic data at admission, during hospitalization, and after 3 months were evaluated.,Survival rates for long‐term follow‐up (mean 984±908 days) were recorded.,Twelve Takotsubo syndrome patients (2.2%) developed LV thrombi (all female presenting with apical ballooning pattern).,All patients with LV thrombi were treated with oral anticoagulation therapy; however, 2 (17%) had a stroke before treatment initiation.,These patients were characterized by a higher prevalence of ST‐elevation (56% versus 16%; P<0.001) and higher troponin I levels (10.8±18.3 ng/mL versus 3.5±4.3 ng/mL; P=0.001) as compared with those without LV thrombi.,At multivariate analysis including age, sex, LV ejection fraction, ST‐elevation at admission, and apical ballooning pattern, troponin I level >10 ng/mL was the only predictor for LV thrombosis (hazard ratio 6.6, confidence interval, 1.01-40.0; P=0.04).,After 3 months all LV thrombi disappeared.,Oral anticoagulation therapy was interrupted in all patients except 1.,At long‐term follow‐up, the survival rate was not different between patients with and without LV thrombi (84% versus 85%; P=0.99).,LV thrombi have a relatively low incidence among patients with Takotsubo syndrome and were detected in female patients with apical ballooning pattern and increased troponin levels.,Oral anticoagulation therapy for 3 months seems reasonable in these high‐risk patients. | 1 |
The current coronavirus disease 2019 (COVID-19) pandemic represents a global public health crisis, disrupting emergency healthcare services.,We determined whether COVID-19 has resulted in delays in stroke presentation and affected the delivery of acute stroke services in a comprehensive stroke center in Hong Kong.,We retrospectively reviewed all patients with transient ischemic attack and stroke admitted via the acute stroke pathway of Queen Mary Hospital, Hong Kong, during the first 60 days since the first diagnosed COVID-19 case in Hong Kong (COVID-19: January 23, 2020-March 24, 2020).,We compared the stroke onset to hospital arrival (onset-to-door) time and timings of inpatient stroke pathways with patients admitted during the same period in 2019 (pre-COVID-19: January 23, 2019-March 24, 2019).,Seventy-three patients in COVID-19 were compared with 89 patients in pre-COVID-19.,There were no significant differences in age, sex, vascular risk factors, nor stroke severity between the 2 groups (P>0.05).,The median stroke onset-to-door time was ≈1-hour longer in COVID-19 compared with pre-COVID-19 (154 versus 95 minutes, P=0.12), and the proportion of individuals with onset-to-door time within 4.5 hours was significantly lower (55% versus 72%, P=0.024).,Significantly fewer cases of transient ischemic attack presented to the hospital during COVID-19 (4% versus 16%, P=0.016), despite no increase in referrals to the transient ischemic attack clinic.,Inpatient stroke pathways and treatment time metrics nevertheless did not differ between the 2 groups (P>0.05 for all comparisons).,During the early containment phase of COVID-19, we noted a prolongation in stroke onset to hospital arrival time and a significant reduction in individuals arriving at the hospital within 4.5 hours and presenting with transient ischemic attack.,Public education about stroke should continue to be reinforced during the COVID-19 pandemic. | The purpose of the study is to analyze how the coronavirus disease 2019 (COVID-19) pandemic affected acute stroke care in a Comprehensive Stroke Center.,On February 28, 2020, contingency plans were implemented at Hospital Clinic of Barcelona to contain the COVID-19 pandemic.,Among them, the decision to refrain from reallocating the Stroke Team and Stroke Unit to the care of patients with COVID-19.,From March 1 to March 31, 2020, we measured the number of emergency calls to the Emergency Medical System in Catalonia (7.5 million inhabitants), and the Stroke Codes dispatched to Hospital Clinic of Barcelona.,We recorded all stroke admissions, and the adequacy of acute care measures, including the number of thrombectomies, workflow metrics, angiographic results, and clinical outcomes.,Data were compared with March 2019 using parametric or nonparametric methods as appropriate.,At Hospital Clinic of Barcelona, 1232 patients with COVID-19 were admitted in March 2020, demanding 60% of the hospital bed capacity.,Relative to March 2019, the Emergency Medical System had a 330% mean increment in the number of calls (158 005 versus 679 569), but fewer Stroke Code activations (517 versus 426).,Stroke admissions (108 versus 83) and the number of thrombectomies (21 versus 16) declined at Hospital Clinic of Barcelona, particularly after lockdown of the population.,Younger age was found in stroke admissions during the pandemic (median [interquartile range] 69 [64-73] versus 75 [73-80] years, P=0.009).,In-hospital, there were no differences in workflow metrics, angiographic results, complications, or outcomes at discharge.,The COVID-19 pandemic reduced by a quarter the stroke admissions and thrombectomies performed at a Comprehensive Stroke Center but did not affect the quality of care metrics.,During the lockdown, there was an overload of emergency calls but fewer Stroke Code activations, particularly in elderly patients.,Hospital contingency plans, patient transport systems, and population-targeted alerts must act concertedly to better protect the chain of stroke care in times of pandemic. | 1 |
Previous studies demonstrated that Bailcalin (BAI) prevented cardiac injuries under different disease models.,Whether BAI protected against type 2 diabetes mellitus- (T2DM-) associated cardiomyopathy was investigated in this study.,T2DM was established by the combination of streptozotocin injection and high-fat diet in mice.,BAI was administered daily for 6 months.,After evaluating cardiac functions, mice hearts were removed and processed for morphological, biochemical, and molecular mechanism analyses.,Neonatal rat cardiomyocytes (NRCM) were isolated and treated with high glucose and palmitate (HG/Pal) for in vitro investigation.,BAI significantly ameliorated T2DM-induced cardiomyocyte hypertrophy, interstitial fibrosis, and lipid accumulation accompanied by markedly improved cardiac functions in diabetic mice.,Mechanically, BAI restored decreased phosphorylation of AMPK and enhanced expression and nuclei translocation of Nrf2.,In in vitro experiments, BAI also prevented NRCM from HG/Pal-induced apoptosis and oxidative stress injuries by increasing p-AMPK and Nrf2 accumulation.,The means by which BAI restored p-AMPK seemed to be related to the antioxidative effects of Nrf2 after silencing AMPK or Nrf2 in NRCM.,Furthermore, BAI regulated Nrf2 by inhibiting Nrf2 ubiquitination and consequent degradation mediated by Keap1.,This study showed that BAI alleviated diabetes-associated cardiac dysfunction and cardiomyocyte injuries in vivo and in vitro via Keap1/Nrf2/AMPK-mediated antioxidation and lipid-lowering effects.,BAI might be a potential adjuvant drug for diabetes cardiomyopathy treatment. | Andrographolide (Andro), a major bioactive component obtained from Andrographis paniculata Nees, has exerted wide antioxidant as well as cytoprotective properties.,However, whether Andro treatment could retard the progress of diabetic cardiomyopathy (DCM) remains unknown.,In this study, we evaluated the effects of Andro against diabetes-induced myocardial dysfunction and explored the underlying mechanism in STZ-induced diabetic mice.,As a result, treatment with Andro dose dependently suppressed cardiac inflammation and oxidative stress, accompanied by decreasing cardiac apoptosis, which subsequently ameliorated cardiac fibrosis and cardiac hypertrophy.,Further, Andro blocked hyperglycemia-triggered reactive oxygen species (ROS) generation by suppressing NADPH oxidase (NOX) activation and augmenting nuclear factor erythroid 2-related factor 2 (Nrf2) expression both in vitro and in vivo.,Our results suggest that the cardioprotective effects afforded by Andro treatment involve the modulation of NOX/Nrf2-mediated oxidative stress and NF-κB-mediated inflammation.,The present study unravels the therapeutic potential of Andro in the treatment of DCM by attenuating oxidative stress, inflammation, and apoptosis. | 1 |
The coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 that has significant implications for the cardiovascular care of patients.,First, those with COVID-19 and pre-existing cardiovascular disease have an increased risk of severe disease and death.,Second, infection has been associated with multiple direct and indirect cardiovascular complications including acute myocardial injury, myocarditis, arrhythmias, and venous thromboembolism.,Third, therapies under investigation for COVID-19 may have cardiovascular side effects.,Fourth, the response to COVID-19 can compromise the rapid triage of non-COVID-19 patients with cardiovascular conditions.,Finally, the provision of cardiovascular care may place health care workers in a position of vulnerability as they become hosts or vectors of virus transmission.,We hereby review the peer-reviewed and pre-print reports pertaining to cardiovascular considerations related to COVID-19 and highlight gaps in knowledge that require further study pertinent to patients, health care workers, and health systems.,•Patients with pre-existing CVD appear to have worse outcomes with COVID-19.,•CV complications include biomarker elevations, myocarditis, heart failure, and venous thromboembolism, which may be exacerbated by delays in care.,•Therapies under investigation for COVID-19 may have significant drug-drug interactions with CV medications.,•Health care workers and health systems should take measures to ensure safety while providing high-quality care for COVID-19 patients.,Patients with pre-existing CVD appear to have worse outcomes with COVID-19.,CV complications include biomarker elevations, myocarditis, heart failure, and venous thromboembolism, which may be exacerbated by delays in care.,Therapies under investigation for COVID-19 may have significant drug-drug interactions with CV medications.,Health care workers and health systems should take measures to ensure safety while providing high-quality care for COVID-19 patients. | The current COVID-19 pandemic started several months ago and is still exponentially growing in most parts of the world - this is the most recent and alarming update.,COVID-19 requires the collaboration of nearly 200 countries to curb the spread of SARS-CoV-2 while gaining time to explore and improve treatment options especially for cardiovascular disease (CVD) and immunocompromised patients, who appear to be at high-risk to die from cardiopulmonary failure.,Currently unanswered questions are why elderly people, particularly those with pre-existing comorbidities seem to exhibit higher mortality rates after SARS-CoV-2 infection and whether intensive care becomes indispensable for these patients to prevent multi-organ failure and sudden death.,To face these challenges, we here summarize the molecular insights into viral infection mechanisms and implications for cardiovascular disease.,Since the infection starts in the upper respiratory system, first flu-like symptoms develop that spread throughout the body.,The wide range of affected organs is presumably based on the common expression of the major SARS-CoV-2 entry-receptor angiotensin-converting enzyme 2 (ACE2).,Physiologically, ACE2 degrades angiotensin II, the master regulator of the renin-angiotensin-aldosterone system (RAAS), thereby converting it into vasodilatory molecules, which have well-documented cardio-protective effects.,Thus, RAAS inhibitors, which may increase the expression levels of ACE2, are commonly used for the treatment of hypertension and CVD.,This, and the fact that SARS-CoV-2 hijacks ACE2 for cell-entry, have spurred controversial discussions on the role of ACE2 in COVID-19 patients.,In this review, we highlight the state-of-the-art knowledge on SARS-CoV-2-dependent mechanisms and the potential interaction with ACE2 expression and cell surface localization.,We aim to provide a list of potential treatment options and a better understanding of why CVD is a high risk factor for COVID-19 susceptibility and further discuss the acute as well as long-term cardiac consequences.,Unlabelled Image,•COVID-19 patients with underlying CVD have drastically increased risks of mortality.,•SARS-CoV2 uses ACE2 as cell entry receptor.,•Current and novel COVID-19 drugs may act on the SARS-CoV-2 receptor ACE2.,•ACE-I and ARB may interfere with COVID-19 susceptibility and effects on the heart.,COVID-19 patients with underlying CVD have drastically increased risks of mortality.,SARS-CoV2 uses ACE2 as cell entry receptor.,Current and novel COVID-19 drugs may act on the SARS-CoV-2 receptor ACE2.,ACE-I and ARB may interfere with COVID-19 susceptibility and effects on the heart. | 1 |
Patients with pre-existing heart failure (HF) are likely at higher risk for adverse outcomes in coronavirus disease-2019 (COVID-19), but data on this population are sparse.,This study described the clinical profile and associated outcomes among patients with HF hospitalized with COVID-19.,This study conducted a retrospective analysis of 6,439 patients admitted for COVID-19 at 1 of 5 Mount Sinai Health System hospitals in New York City between February 27 and June 26, 2020.,Clinical characteristics and outcomes (length of stay, need for intensive care unit, mechanical ventilation, and in-hospital mortality) were captured from electronic health records.,For patients identified as having a history of HF by International Classification of Diseases-9th and/or 10th Revisions codes, manual chart abstraction informed etiology, functional class, and left ventricular ejection fraction (LVEF).,Mean age was 63.5 years, and 45% were women.,Compared with patients without HF, those with previous HF experienced longer length of stay (8 days vs. 6 days; p < 0.001), increased risk of mechanical ventilation (22.8% vs.,11.9%; adjusted odds ratio: 3.64; 95% confidence interval: 2.56 to 5.16; p < 0.001), and mortality (40.0% vs.,24.9%; adjusted odds ratio: 1.88; 95% confidence interval: 1.27 to 2.78; p = 0.002).,Outcomes among patients with HF were similar, regardless of LVEF or renin-angiotensin-aldosterone inhibitor use.,History of HF was associated with higher risk of mechanical ventilation and mortality among patients hospitalized for COVID-19, regardless of LVEF. | A global outbreak of coronavirus disease (COVID‐19), caused by severe acute respiratory coronavirus 2 (SARS‐CoV‐2), has emerged since December 2019, in Wuhan, China.,However, electrocardiograhic (ECG) manifestations of patients with COVID‐19 have not been fully described.,We aim to investigate ECG characteristics in COVID‐19 patients and risk factors of intensive care unit (ICU) admission.,This retrospective observational study included the patients with COVID‐19 at the Wuhan Asia General hospital between February 10, and 26, 2020.,Demographic, clinical, and ECG characteristics were collected, and comparisons were made between the ICU and non‐ICU admission groups.,Logistic regression was used to identify risk factors of ICU admission.,Among 135 included patients (median age: 64 years [interquartile range: 48-72]), ST‐T abnormalities (40%) were the most common ECG feature, followed by arrhythmias (38%).,Cardiovascular disease (CVD) was presented in 48% of the patients.,Six (4.4%) died during hospitalization, and 23 (17.0%) were admitted to the ICU.,Compared with non‐ICU group, the ICU group showed higher heart rate (p = .019) and P‐wave duration (p = .039) and was more frequently associated with CVD (p < .001), ST‐T abnormalities (p = .007), arrhythmias (p = .003), QTc interval prolongation (p = .003), and pathological Q waves (p < .001).,Twenty‐seven patients were re‐examined ECG during admission, and 17 of them presented new findings compared with their initial ECG presentations.,ST‐T abnormalities (p = .040) and history of CVD (p = .0047) were associated with increased risk of ICU hospitalization.,COVID‐19 is frequently related to cardiovascular manifestations including ECG abnormalities and cardiovascular comorbidities.,ST‐T abnormalities and CVD at admission were associated with increased odds of ICU admission. | 1 |
Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have enormous potential for the study of human cardiac disorders.,However, their physiological immaturity severely limits their utility as a model system and their adoption for drug discovery.,Here, we describe maturation media designed to provide oxidative substrates adapted to the metabolic needs of human iPSC (hiPSC)-CMs.,Compared with conventionally cultured hiPSC-CMs, metabolically matured hiPSC-CMs contract with greater force and show an increased reliance on cardiac sodium (Na+) channels and sarcoplasmic reticulum calcium (Ca2+) cycling.,The media enhance the function, long-term survival, and sarcomere structures in engineered heart tissues.,Use of the maturation media made it possible to reliably model two genetic cardiac diseases: long QT syndrome type 3 due to a mutation in the cardiac Na+ channel SCN5A and dilated cardiomyopathy due to a mutation in the RNA splicing factor RBM20.,The maturation media should increase the fidelity of hiPSC-CMs as disease models. | Human induced pluripotent stem cells (iPSCs) have emerged as an effective platform for regenerative therapy, disease modeling, and drug discovery. iPSCs allow for the production of limitless supply of patient-specific somatic cells that enable advancement in cardiovascular precision medicine.,Over the past decade, researchers have developed protocols to differentiate iPSCs to multiple cardiovascular lineages, as well as to enhance the maturity and functionality of these cells.,Despite significant advances, drug therapy and discovery for cardiovascular disease have lagged behind other fields such as oncology.,We speculate that this paucity of drug discovery is due to a previous lack of efficient, reproducible, and translational model systems.,Notably, existing drug discovery and testing platforms rely on animal studies and clinical trials, but investigations in animal models have inherent limitations due to interspecies differences.,Moreover, clinical trials are inherently flawed by assuming that all individuals with a disease will respond identically to a therapy, ignoring the genetic and epigenomic variations that define our individuality.,With ever-improving differentiation and phenotyping methods, patient-specific iPSC-derived cardiovascular cells allow unprecedented opportunities to discover new drug targets and screen compounds for cardiovascular disease.,Imbued with the genetic information of an individual, iPSCs will vastly improve our ability to test drugs efficiently, as well as tailor and titrate drug therapy for each patient. | 1 |
This study sought to explore the spectrum of cardiac abnormalities in student athletes who returned to university campus in July 2020 with uncomplicated coronavirus disease 2019 (COVID-19).,There is limited information on cardiovascular involvement in young individuals with mild or asymptomatic COVID-19.,Screening echocardiograms were performed in 54 consecutive student athletes (mean age 19 years; 85% male) who had positive results of reverse transcription polymerase chain reaction nasal swab testing of the upper respiratory tract or immunoglobulin G antibodies against severe acute respiratory syndrome coronavirus type 2.,Sequential cardiac magnetic resonance imaging was performed in 48 (89%) subjects.,A total of 16 (30%) athletes were asymptomatic, whereas 36 (66%) and 2 (4%) athletes reported mild and moderate COVID-19 related symptoms, respectively.,For the 48 athletes completing both imaging studies, abnormal findings were identified in 27 (56.3%) individuals.,This included 19 (39.5%) athletes with pericardial late enhancements with associated pericardial effusion.,Of the individuals with pericardial enhancements, 6 (12.5%) had reduced global longitudinal strain and/or an increased native T1.,One patient showed myocardial enhancement, and reduced left ventricular ejection fraction or reduced global longitudinal strain with or without increased native T1 values was also identified in an additional 7 (14.6%) individuals.,Native T2 findings were normal in all subjects, and no specific imaging features of myocardial inflammation were identified.,Hierarchical clustering of left ventricular regional strain identified 3 unique myopericardial phenotypes that showed significant association with the cardiac magnetic resonance findings (p = 0.03).,More than 1 in 3 previously healthy college athletes recovering from COVID-19 infection showed imaging features of a resolving pericardial inflammation.,Although subtle changes in myocardial structure and function were identified, no athlete showed specific imaging features to suggest an ongoing myocarditis.,Further studies are needed to understand the clinical implications and long-term evolution of these abnormalities in uncomplicated COVID-19. | This study evaluated cardiac involvement in patients recovered from coronavirus disease-2019 (COVID-19) using cardiac magnetic resonance (CMR).,Myocardial injury caused by COVID-19 was previously reported in hospitalized patients.,It is unknown if there is sustained cardiac involvement after patients’ recovery from COVID-19.,Twenty-six patients recovered from COVID-19 who reported cardiac symptoms and underwent CMR examinations were retrospectively included.,CMR protocols consisted of conventional sequences (cine, T2-weighted imaging, and late gadolinium enhancement [LGE]) and quantitative mapping sequences (T1, T2, and extracellular volume [ECV] mapping).,Edema ratio and LGE were assessed in post-COVID-19 patients.,Cardiac function, native T1/T2, and ECV were quantitatively evaluated and compared with controls.,Fifteen patients (58%) had abnormal CMR findings on conventional CMR sequences: myocardial edema was found in 14 (54%) patients and LGE was found in 8 (31%) patients.,Decreased right ventricle functional parameters including ejection fraction, cardiac index, and stroke volume/body surface area were found in patients with positive conventional CMR findings.,Using quantitative mapping, global native T1, T2, and ECV were all found to be significantly elevated in patients with positive conventional CMR findings, compared with patients without positive findings and controls (median [interquartile range]: native T1 1,271 ms [1,243 to 1,298 ms] vs. 1,237 ms [1,216 to 1,262 ms] vs. 1,224 ms [1,217 to 1,245 ms]; mean ± SD: T2 42.7 ± 3.1 ms vs.,38.1 ms ± 2.4 vs.,39.1 ms ± 3.1; median [interquartile range]: 28.2% [24.8% to 36.2%] vs.,24.8% [23.1% to 25.4%] vs.,23.7% [22.2% to 25.2%]; p = 0.002; p < 0.001, and p = 0.002, respectively).,Cardiac involvement was found in a proportion of patients recovered from COVID-19.,CMR manifestation included myocardial edema, fibrosis, and impaired right ventricle function.,Attention should be paid to the possible myocardial involvement in patients recovered from COVID-19 with cardiac symptoms. | 1 |
Early studies suggest that coronavirus disease 2019 (COVID-19) is associated with a high incidence of cardiac arrhythmias.,Severe acute respiratory syndrome coronavirus 2 infection may cause injury to cardiac myocytes and increase arrhythmia risk.,The purpose of this study was to evaluate the risk of cardiac arrest and arrhythmias including incident atrial fibrillation (AF), bradyarrhythmias, and nonsustained ventricular tachycardia (NSVT) in a large urban population hospitalized for COVID-19.,We also evaluated correlations between the presence of these arrhythmias and mortality.,We reviewed the characteristics of all patients with COVID-19 admitted to our center over a 9-week period.,Throughout hospitalization, we evaluated the incidence of cardiac arrests, arrhythmias, and inpatient mortality.,We also used logistic regression to evaluate age, sex, race, body mass index, prevalent cardiovascular disease, diabetes, hypertension, chronic kidney disease, and intensive care unit (ICU) status as potential risk factors for each arrhythmia.,Among 700 patients (mean age 50 ± 18 years; 45% men; 71% African American; 11% received ICU care), there were 9 cardiac arrests, 25 incident AF events, 9 clinically significant bradyarrhythmias, and 10 NSVTs.,All cardiac arrests occurred in patients admitted to the ICU.,In addition, admission to the ICU was associated with incident AF (odds ratio [OR] 4.68; 95% confidence interval [CI] 1.66-13.18) and NSVT (OR 8.92; 95% CI 1.73-46.06) after multivariable adjustment.,Also, age and incident AF (OR 1.05; 95% CI 1.02-1.09) and prevalent heart failure and bradyarrhythmias (OR 9.75; 95% CI 1.95-48.65) were independently associated.,Only cardiac arrests were associated with acute in-hospital mortality.,Cardiac arrests and arrhythmias are likely the consequence of systemic illness and not solely the direct effects of COVID-19 infection. | The coronavirus disease-2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) that has significant potential cardiovascular implications for patients.,These include myocarditis, acute coronary syndromes, cardiac arrhythmias, cardiomyopathies with heart failure and cardiogenic shock, and venous thromboembolic events.,We describe a Caribbean-Black gentleman with COVID-19 infection presenting with atrial arrhythmias, namely, atrial flutter and atrial fibrillation, which resolved with rate and rhythm control strategies, and supportive care. | 1 |
Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19).,We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19.,In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care.,The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge.,The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation.,Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis).,The median value for organ support-free days was 1 (interquartile range, −1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, −1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%).,The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11).,Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis.,In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis.,(REMAP-CAP, ACTIV-4a, and ATTACC ClinicalTrials.gov numbers, NCT02735707, NCT04505774, NCT04359277, and NCT04372589.) | Patients with COVID-19 have a coagulopathy and high thrombotic risk.,In a cohort of 69 intensive care unit (ICU) patients we investigated for evidence of heparin resistance in those that have received therapeutic anticoagulation. 15 of the patients have received therapeutic anticoagulation with either unfractionated heparin (UFH) or low molecular weight heparin (LMWH), of which full information was available on 14 patients.,Heparin resistance to UFH was documented in 8/10 (80%) patients and sub-optimal peak anti-Xa following therapeutic LMWH in 5/5 (100%) patients where this was measured (some patients received both anticoagulants sequentially).,Spiking plasma from 12 COVID-19 ICU patient samples demonstrated decreased in-vitro recovery of anti-Xa compared to normal pooled plasma.,In conclusion, we have found evidence of heparin resistance in critically unwell COVID-19 patients.,Further studies investigating this are required to determine the optimal thromboprophylaxis in COVID-19 and management of thrombotic episodes. | 1 |
Supplemental Digital Content is available in the text.,Coronavirus disease 2019 (COVID-19) evolved quickly into a global pandemic with myriad systemic complications, including stroke.,We report the largest case series to date of cerebrovascular complications of COVID-19 and compare with stroke patients without infection.,Retrospective case series of COVID-19 patients with imaging-confirmed stroke, treated at 11 hospitals in New York, between March 14 and April 26, 2020.,Demographic, clinical, laboratory, imaging, and outcome data were collected, and cases were compared with date-matched controls without COVID-19 from 1 year prior.,Eighty-six COVID-19-positive stroke cases were identified (mean age, 67.4 years; 44.2% women).,Ischemic stroke (83.7%) and nonfocal neurological presentations (67.4%) predominated, commonly involving multivascular distributions (45.8%) with associated hemorrhage (20.8%).,Compared with controls (n=499), COVID-19 was associated with in-hospital stroke onset (47.7% versus 5.0%; P<0.001), mortality (29.1% versus 9.0%; P<0.001), and Black/multiracial race (58.1% versus 36.9%; P=0.001).,COVID-19 was the strongest independent risk factor for in-hospital stroke (odds ratio, 20.9 [95% CI, 10.4-42.2]; P<0.001), whereas COVID-19, older age, and intracranial hemorrhage independently predicted mortality.,COVID-19 is an independent risk factor for stroke in hospitalized patients and mortality, and stroke presentations are frequently atypical. | Italy is one of the most affected countries by the coronavirus disease 2019 (COVID-19).,The responsible pathogen is named severe acute respiratory syndrome coronavirus (SARS-CoV-2).,The clinical spectrum ranges from asymptomatic infection to severe pneumonia, leading to intensive care unit admission.,Evidence of cerebrovascular complications associated with SARS-CoV-2 is limited.,We herein report six patients who developed acute stroke during COVID-19 infection.,A retrospective case series of patients diagnosed with COVID-19 using reverse-transcriptase polymerase chain reaction (RT-PCR) on nasopharyngeal swabs, who developed clinical and neuroimaging evidence of acute stroke during SARS-CoV-2 infection.,Six patients were identified (5 men); median age was 69 years (range 57-82).,Stroke subtypes were ischemic (4, 67%) and hemorrhagic (2, 33%).,All patients but one had pre-existing vascular risk factors.,One patient developed encephalopathy prior to stroke, characterized by focal seizures and behavioral abnormalities.,COVID-19-related pneumonia was severe (i.e., requiring critical care support) in 5/6 cases (83%).,Liver enzyme alteration and lactate dehydrogenase (LDH) elevation were registered in all cases.,Four patients (67%) manifested acute kidney failure prior to stroke.,Four patients (67%) had abnormal coagulation tests.,The outcome was poor in the majority of the patients: five died (83%) and the remaining one (17%) remained severely neurologically affected (mRS: 4).,Both ischemic and hemorrhagic stroke can complicate the course of COVI-19 infection.,In our series, stroke developed mostly in patients with severe pneumonia and multiorgan failure, liver enzymes and LDH were markedly increased in all cases, and the outcome was poor. | 1 |
Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).,Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described.,In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020.,Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors.,We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death.,191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients).,Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03-1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61-12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64-128·55; p=0·0033) on admission.,Median duration of viral shedding was 20·0 days (IQR 17·0-24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors.,The longest observed duration of viral shedding in survivors was 37 days.,The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage.,Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future.,Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development. | COVID-19 first appeared in Wuhan, Hubei Province, China, in December 2019.,Thought to be of zoonotic origin, it has been named SARS-CoV-2 (COVID-19) and has spread rapidly.,As of April 20, 2020, there have been >2.4 million cases recorded worldwide.,The inflammatory process, cytokine storm, and lung injury that are associated with COVID-19 can put patients at an increased risk of thrombosis.,The total incidence of thrombotic events in COVID-19 patients is currently uncertain.,Those with more severe disease and with other risk factors, including increasing age, male sex, obesity, cancer, comorbidities, and intensive care unit admission, are at higher risk of these events.,However, there is little international guidance on managing these risks in COVID-19 patients.,In this paper, we explore the current evidence and theories surrounding thrombosis in these unique patients and reflect on experience from our center. | 1 |
Supplemental Digital Content is available in the text.,Use of ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension.,To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in patients with hypertension and hospitalized due to COVID-19.,This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [interquartile range, 55-68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [interquartile range 57-69]; 53.5% men), who were admitted to 9 hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020.,In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted hazard ratio, 0.42 [95% CI, 0.19-0.92]; P=0.03).,In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted hazard ratio, 0.37 [95% CI, 0.15-0.89]; P=0.03).,Further subgroup propensity score-matched analysis indicated that, compared with use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted hazard ratio, 0.30 [95% CI, 0.12-0.70]; P=0.01) in patients with COVID-19 and coexisting hypertension.,Among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers.,While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk. | Coronavirus disease-2019 (COVID-19), a viral respiratory illness caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), may predispose patients to thrombotic disease, both in the venous and arterial circulations, because of excessive inflammation, platelet activation, endothelial dysfunction, and stasis.,In addition, many patients receiving antithrombotic therapy for thrombotic disease may develop COVID-19, which can have implications for choice, dosing, and laboratory monitoring of antithrombotic therapy.,Moreover, during a time with much focus on COVID-19, it is critical to consider how to optimize the available technology to care for patients without COVID-19 who have thrombotic disease.,Herein, the authors review the current understanding of the pathogenesis, epidemiology, management, and outcomes of patients with COVID-19 who develop venous or arterial thrombosis, of those with pre-existing thrombotic disease who develop COVID-19, or those who need prevention or care for their thrombotic disease during the COVID-19 pandemic.,•COVID-19 may predispose patients to arterial and venous thrombosis.,•Initial series suggest the common occurrence of venous thromboembolic disease in patients with severe COVID-19.,The optimal preventive strategy warrants further investigation.,•Drug-drug interactions between antiplatelet agents and anticoagulants with investigational COVID-19 therapies should be considered.,•The available technology should be used optimally to care for patients without COVID-19 who have thrombotic disease during the pandemic.,COVID-19 may predispose patients to arterial and venous thrombosis.,Initial series suggest the common occurrence of venous thromboembolic disease in patients with severe COVID-19.,The optimal preventive strategy warrants further investigation.,Drug-drug interactions between antiplatelet agents and anticoagulants with investigational COVID-19 therapies should be considered.,The available technology should be used optimally to care for patients without COVID-19 who have thrombotic disease during the pandemic. | 1 |
A higher risk of thrombosis has been described as a prominent feature of coronavirus disease 2019 (COVID-19).,This systematic review synthesizes current data on thrombosis risk, prognostic implications, and anticoagulation effects in COVID-19.,We included 37 studies from 4070 unique citations.,Meta-analysis was performed when feasible.,Coagulopathy and thrombotic events were frequent among patients with COVID-19 and further increased in those with more severe forms of the disease.,We also present guidance on the prevention and management of thrombosis from a multidisciplinary panel of specialists from Mayo Clinic.,The current certainty of evidence is generally very low and continues to evolve. | Emerging evidence shows that severe coronavirus disease 2019 (COVID-19) can be complicated by a significant coagulopathy, that likely manifests in the form of both microthrombosis and VTE.,This recognition has led to the urgent need for practical guidance regarding prevention, diagnosis, and treatment of VTE.,A group of approved panelists developed key clinical questions by using the PICO (Population, Intervention, Comparator, Outcome) format that addressed urgent clinical questions regarding the prevention, diagnosis, and treatment of VTE in patients with COVID-19.,MEDLINE (via PubMed or Ovid), Embase, and Cochrane Controlled Register of Trials were systematically searched for relevant literature, and references were screened for inclusion.,Validated evaluation tools were used to grade the level of evidence to support each recommendation.,When evidence did not exist, guidance was developed based on consensus using the modified Delphi process.,The systematic review and critical analysis of the literature based on 13 Population, Intervention, Comparator, Outcome questions resulted in 22 statements.,Very little evidence exists in the COVID-19 population.,The panel thus used expert consensus and existing evidence-based guidelines to craft the guidance statements.,The evidence on the optimal strategies to prevent, diagnose, and treat VTE in patients with COVID-19 is sparse but rapidly evolving. | 1 |
In pre-clinical models of acute myocardial infarction (MI), mature B cells mobilize inflammatory monocytes into the heart, leading to increased infarct size and deterioration of cardiac function, whilst anti-CD20 antibody-mediated depletion of B cells limits myocardial injury and improves cardiac function.,Rituximab is a monoclonal anti-CD20 antibody targeted against human B cells.,However, its use in cardiovascular disease is untested and is currently contraindicated.,Therefore, we assessed the safety, feasibility, and pharmacodynamic effect of rituximab given to patients with acute ST-elevation MI (STEMI).,Rituximab in patients with acute ST-elevation myocardial infarction (RITA-MI) was a prospective, open-label, dose-escalation, single-arm, phase 1/2a clinical trial, which tested rituximab administered as a single intravenous dose in patients with STEMI within 48 h of symptom onset.,Four escalating doses (200, 500, 700, and 1000 mg) were used.,The primary endpoint was safety, whilst secondary endpoints were changes in circulating immune cell subsets including B cells, and cardiac and inflammatory biomarkers.,A total of 24 patients were dosed.,Rituximab appeared well tolerated.,Seven serious adverse events were reported, none of which were assessed as being related to the rituximab infusion.,Rituximab caused a mean 96.3% (95% confidence interval 93.8-98.8%) depletion of circulating B cells within 30 min of starting the infusion.,Maximal B-cell depletion was seen at Day 6, which was significantly lower than baseline for all doses (P < 0.001).,B-cell repopulation at 6 months was dose-dependent, with modulation of returning B-cell subsets.,Immunoglobulin (IgG, IgM, and IgA) levels were not affected during the 6 months of follow-up.,A single infusion of rituximab appears safe when given in the acute STEMI setting and substantially alters circulating B-cell subsets.,We provide important new insight into the feasibility and pharmacodynamics of rituximab in acute STEMI, which will inform further clinical translation of this potential therapy.,NCT03072199 at https://www.clinicaltrials.gov/ | In response to myocardial infarction (MI), cardiac macrophages regulate inflammation and scar formation.,We hypothesized that macrophages undergo polarization state changes over the MI time course and assessed macrophage polarization transcriptomic signatures over the first week of MI.,C57BL/6 J male mice (3-6 months old) were subjected to permanent coronary artery ligation to induce MI, and macrophages were isolated from the infarct region at days 1, 3, and 7 post-MI.,Day 0, no MI resident cardiac macrophages served as the negative MI control.,Whole transcriptome analysis was performed using RNA-sequencing on n = 4 pooled sets for each time.,Day 1 macrophages displayed a unique pro-inflammatory, extracellular matrix (ECM)-degrading signature.,By flow cytometry, day 0 macrophages were largely F4/80highLy6Clow resident macrophages, whereas day 1 macrophages were largely F4/80lowLy6Chigh infiltrating monocytes.,Day 3 macrophages exhibited increased proliferation and phagocytosis, and expression of genes related to mitochondrial function and oxidative phosphorylation, indicative of metabolic reprogramming.,Day 7 macrophages displayed a pro-reparative signature enriched for genes involved in ECM remodeling and scar formation.,By triple in situ hybridization, day 7 infarct macrophages in vivo expressed collagen I and periostin mRNA.,Our results indicate macrophages show distinct gene expression profiles over the first week of MI, with metabolic reprogramming important for polarization.,In addition to serving as indirect mediators of ECM remodeling, macrophages are a direct source of ECM components.,Our study is the first to report the detailed changes in the macrophage transcriptome over the first week of MI.,The online version of this article (10.1007/s00395-018-0686-x) contains supplementary material, which is available to authorized users. | 1 |
Northern Italy is one of the epicenters of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV 2) pandemic in Europe.,The impact of the pandemic and the consequent lockdown on medical emergencies other than those SARS‐CoV 2 pandemic related is largely unknown.,The aim of this study was to analyze the epidemiologic impact of coronavirus disease 2019 pandemic on hospital admission for severe emergent cardiovascular diseases (SECDs) in a single Northern Italy large tertiary referral center.,We quantified SECDs admissions to the Cardiology Division of Udine University Hospital between March 1, 2020 and March 31, 2020 and compared them with those of the same time frame during 2019.,Compared with March 2019, we observed a significant reduction in all SECDs admissions: −30% for ST‐segment-elevation acute coronary syndromes, −66% for non‐ST‐segment-elevation acute coronary syndromes and −50% for severe bradyarrhythmia.,A significant decrease in all SECDs admissions has been observed during the SARS‐CoV 2. pandemic and was unlikely caused by a reduction in the incidence of cardiovascular diseases.,Fear of contagion may have contributed to the unpredictable drop of SECDs.,Social education about early recognition of symptoms of life‐threatening cardiac conditions requiring appropriate care in a timely fashion may help to reduce this counterproductive phenomenon. | The cardiovascular system is affected broadly by severe acute respiratory syndrome coronavirus 2 infection.,Both direct viral infection and indirect injury resulting from inflammation, endothelial activation, and microvascular thrombosis occur in the context of coronavirus disease 2019.,What determines the extent of cardiovascular injury is the amount of viral inoculum, the magnitude of the host immune response, and the presence of co-morbidities.,Myocardial injury occurs in approximately one-quarter of hospitalized patients and is associated with a greater need for mechanical ventilator support and higher hospital mortality.,The central pathophysiology underlying cardiovascular injury is the interplay between virus binding to the angiotensin-converting enzyme 2 receptor and the impact this action has on the renin-angiotensin system, the body’s innate immune response, and the vascular response to cytokine production.,The purpose of this review was to describe the mechanisms underlying cardiovascular injury, including that of thromboembolic disease and arrhythmia, and to discuss their clinical sequelae.,•The cardiovascular system is affected in diverse ways by severe acute respiratory syndrome coronavirus 2 infection (COVID-19).,•Myocardial injury can be detected in ∼25% of hospitalized patients with COVID-19 and is associated with an increased risk of mortality.,•Described mechanisms of myocardial injury in patients with COVID-19 include oxygen supply-demand imbalance, direct viral myocardial invasion, inflammation, coronary plaque rupture with acute myocardial infarction, microvascular thrombosis, and adrenergic stress.,The cardiovascular system is affected in diverse ways by severe acute respiratory syndrome coronavirus 2 infection (COVID-19).,Myocardial injury can be detected in ∼25% of hospitalized patients with COVID-19 and is associated with an increased risk of mortality.,Described mechanisms of myocardial injury in patients with COVID-19 include oxygen supply-demand imbalance, direct viral myocardial invasion, inflammation, coronary plaque rupture with acute myocardial infarction, microvascular thrombosis, and adrenergic stress. | 1 |
Individuals with established cardiovascular disease or a high burden of cardiovascular risk factors may be particularly vulnerable to develop complications from coronavirus disease 2019 (COVID-19).,We conducted a prospective cohort study at a tertiary care center to identify risk factors for in-hospital mortality and major adverse cardiovascular events (MACE; a composite of myocardial infarction, stroke, new acute decompensated heart failure, venous thromboembolism, ventricular or atrial arrhythmia, pericardial effusion, or aborted cardiac arrest) among consecutively hospitalized adults with COVID-19, using multivariable binary logistic regression analysis.,The study population comprised 586 COVID-19 positive patients.,Median age was 67 (IQR: 55 to 80) years, 47.4% were female, and 36.7% had cardiovascular disease.,Considering risk factors, 60.2% had hypertension, 39.8% diabetes, and 38.6% hyperlipidemia.,Eighty-two individuals (14.0%) died in-hospital, and 135 (23.0%) experienced MACE.,In a model adjusted for demographic characteristics, clinical presentation, and laboratory findings, age (odds ratio [OR], 1.28 per 5 years; 95% confidence interval [CI], 1.13 to 1.45), previous ventricular arrhythmia (OR, 18.97; 95% CI, 3.68 to 97.88), use of P2Y12-inhibitors (OR, 7.91; 95% CI, 1.64 to 38.17), higher C-reactive protein (OR, 1.81: 95% CI, 1.18 to 2.78), lower albumin (OR, 0.64: 95% CI, 0.47 to 0.86), and higher troponin T (OR, 1.84; 95% CI, 1.39 to 2.46) were associated with mortality (p <0.05).,After adjustment for demographics, presentation, and laboratory findings, predictors of MACE were higher respiratory rates, altered mental status, and laboratory abnormalities, including higher troponin T (p <0.05).,In conclusion, poor prognostic markers among hospitalized patients with COVID-19 included older age, pre-existing cardiovascular disease, respiratory failure, altered mental status, and higher troponin T concentrations. | To compare demographic characteristics, clinical presentation, and outcomes of patients with and without concomitant cardiac disease, hospitalized for COVID-19 in Brescia, Lombardy, Italy.,The study population includes 99 consecutive patients with COVID-19 pneumonia admitted to our hospital between 4 March and 25 March 2020.,Fifty-three patients with a history of cardiac disease were compared with 46 without cardiac disease.,Among cardiac patients, 40% had a history of heart failure, 36% had atrial fibrillation, and 30% had coronary artery disease.,Mean age was 67 ± 12 years, and 80 (81%) patients were males.,No differences were found between cardiac and non-cardiac patients except for higher values of serum creatinine, N-terminal probrain natriuretic peptide, and high sensitivity troponin T in cardiac patients.,During hospitalization, 26% patients died, 15% developed thrombo-embolic events, 19% had acute respiratory distress syndrome, and 6% had septic shock.,Mortality was higher in patients with cardiac disease compared with the others (36% vs. 15%, log-rank P = 0.019; relative risk 2.35; 95% confidence interval 1.08-5.09).,The rate of thrombo-embolic events and septic shock during the hospitalization was also higher in cardiac patients (23% vs. 6% and 11% vs. 0%, respectively).,Hospitalized patients with concomitant cardiac disease and COVID-19 have an extremely poor prognosis compared with subjects without a history of cardiac disease, with higher mortality, thrombo-embolic events, and septic shock rates. | 1 |
Early studies suggest that coronavirus disease 2019 (COVID-19) is associated with a high incidence of cardiac arrhythmias.,Severe acute respiratory syndrome coronavirus 2 infection may cause injury to cardiac myocytes and increase arrhythmia risk.,The purpose of this study was to evaluate the risk of cardiac arrest and arrhythmias including incident atrial fibrillation (AF), bradyarrhythmias, and nonsustained ventricular tachycardia (NSVT) in a large urban population hospitalized for COVID-19.,We also evaluated correlations between the presence of these arrhythmias and mortality.,We reviewed the characteristics of all patients with COVID-19 admitted to our center over a 9-week period.,Throughout hospitalization, we evaluated the incidence of cardiac arrests, arrhythmias, and inpatient mortality.,We also used logistic regression to evaluate age, sex, race, body mass index, prevalent cardiovascular disease, diabetes, hypertension, chronic kidney disease, and intensive care unit (ICU) status as potential risk factors for each arrhythmia.,Among 700 patients (mean age 50 ± 18 years; 45% men; 71% African American; 11% received ICU care), there were 9 cardiac arrests, 25 incident AF events, 9 clinically significant bradyarrhythmias, and 10 NSVTs.,All cardiac arrests occurred in patients admitted to the ICU.,In addition, admission to the ICU was associated with incident AF (odds ratio [OR] 4.68; 95% confidence interval [CI] 1.66-13.18) and NSVT (OR 8.92; 95% CI 1.73-46.06) after multivariable adjustment.,Also, age and incident AF (OR 1.05; 95% CI 1.02-1.09) and prevalent heart failure and bradyarrhythmias (OR 9.75; 95% CI 1.95-48.65) were independently associated.,Only cardiac arrests were associated with acute in-hospital mortality.,Cardiac arrests and arrhythmias are likely the consequence of systemic illness and not solely the direct effects of COVID-19 infection. | Emerging evidence shows that severe coronavirus disease 2019 (COVID-19) can be complicated by a significant coagulopathy, that likely manifests in the form of both microthrombosis and VTE.,This recognition has led to the urgent need for practical guidance regarding prevention, diagnosis, and treatment of VTE.,A group of approved panelists developed key clinical questions by using the PICO (Population, Intervention, Comparator, Outcome) format that addressed urgent clinical questions regarding the prevention, diagnosis, and treatment of VTE in patients with COVID-19.,MEDLINE (via PubMed or Ovid), Embase, and Cochrane Controlled Register of Trials were systematically searched for relevant literature, and references were screened for inclusion.,Validated evaluation tools were used to grade the level of evidence to support each recommendation.,When evidence did not exist, guidance was developed based on consensus using the modified Delphi process.,The systematic review and critical analysis of the literature based on 13 Population, Intervention, Comparator, Outcome questions resulted in 22 statements.,Very little evidence exists in the COVID-19 population.,The panel thus used expert consensus and existing evidence-based guidelines to craft the guidance statements.,The evidence on the optimal strategies to prevent, diagnose, and treat VTE in patients with COVID-19 is sparse but rapidly evolving. | 1 |
The new coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has caused more than 210 000 deaths worldwide.,However, little is known about the causes of death and the virus's pathologic features.,To validate and compare clinical findings with data from medical autopsy, virtual autopsy, and virologic tests.,Prospective cohort study.,Autopsies performed at a single academic medical center, as mandated by the German federal state of Hamburg for patients dying with a polymerase chain reaction-confirmed diagnosis of COVID-19.,The first 12 consecutive COVID-19-positive deaths.,Complete autopsy, including postmortem computed tomography and histopathologic and virologic analysis, was performed.,Clinical data and medical course were evaluated.,Results: Median patient age was 73 years (range, 52 to 87 years), 75% of patients were male, and death occurred in the hospital (n = 10) or outpatient sector (n = 2).,Coronary heart disease and asthma or chronic obstructive pulmonary disease were the most common comorbid conditions (50% and 25%, respectively).,Autopsy revealed deep venous thrombosis in 7 of 12 patients (58%) in whom venous thromboembolism was not suspected before death; pulmonary embolism was the direct cause of death in 4 patients.,Postmortem computed tomography revealed reticular infiltration of the lungs with severe bilateral, dense consolidation, whereas histomorphologically diffuse alveolar damage was seen in 8 patients.,In all patients, SARS-CoV-2 RNA was detected in the lung at high concentrations; viremia in 6 of 10 and 5 of 12 patients demonstrated high viral RNA titers in the liver, kidney, or heart.,Limited sample size.,The high incidence of thromboembolic events suggests an important role of COVID-19-induced coagulopathy.,Further studies are needed to investigate the molecular mechanism and overall clinical incidence of COVID-19-related death, as well as possible therapeutic interventions to reduce it.,University Medical Center Hamburg-Eppendorf.,Little is known of the pathologic changes that lead to death in patients with COVID-19.,This study reports the autopsy findings of consecutive patients who died with a diagnosis of COVID-19. | The aim of our study was to determine the incidence, characteristics, and clinical outcomes of patients with the novel coronavirus (COVID-19) infection who had presented with and been treated for acute limb ischemia (ALI) during the 2020 coronavirus pandemic.,We performed a single-center, observational cohort study.,The data from all patients who had tested positive for COVID-19 and had presented with ALI requiring urgent operative treatment were collected in a prospectively maintained database.,For the present series, successful revascularization of the treated arterial segment was defined as the absence of early (<30 days) re-occlusion or major amputation or death within 24 hours.,The primary outcomes were successful revascularization, early (≤30 days) and late (≥30 days) survival, postoperative (≤30 days) complications, and limb salvage.,We evaluated the data from 20 patients with ALI who were positive for COVID-19.,For the period from January to March, the incidence rate of patients presenting with ALI in 2020 was significantly greater than that for the same months in 2019 (23 of 141 [16.3%] vs 3 of 163 [1.8%]; P < .001)].,Of the 20 included patients, 18 were men (90%) and two were women (10%).,Their mean age was 75 ± 9 years (range, 62-95 years).,All 20 patients already had a diagnosis of COVID-19 pneumonia.,Operative treatment was performed in 17 patients (85%).,Revascularization was successful in 12 of the 17 (70.6%).,Although successful revascularization was not significantly associated with the postoperative use of intravenous heparin (64.7% vs 83.3%; P = .622), no patient who had received intravenous heparin required reintervention.,Of the 20 patients, eight (40%) had died in the hospital.,The patients who had died were significantly older (81 ± 10 years vs 71 ± 5 years; P = .008).,The use of continuous postoperative systemic heparin infusion was significantly associated with survival (0% vs 57.1%; P = .042).,In our preliminary experience, the incidence of ALI has significantly increased during the COVID-19 pandemic in the Italian Lombardy region.,Successful revascularization was lower than expected, which we believed was due to a virus-related hypercoagulable state.,The use of prolonged systemic heparin might improve surgical treatment efficacy, limb salvage, and overall survival. | 1 |
Excessive binge alcohol drinking has acute cardiac arrhythmogenic effects, including promotion of atrial fibrillation (AF), which underlies “Holiday Heart Syndrome.”,The mechanism that couples binge alcohol abuse with AF susceptibility remains unclear.,We previously reported stress-activated c-Jun N-terminal kinase (JNK) signaling contributes to AF development.,This is interesting because JNK is implicated in alcohol-caused organ malfunction beyond the heart.,The purpose of this study was to detail how JNK promotes binge alcohol-evoked susceptibility to AF.,The authors found binge alcohol-exposure leads to activated JNK, specifically JNK2.,Furthermore, binge alcohol induces AF (24- vs.,1.8-Hz burst pacing-induced episodes per attempt per animal), higher incidence of diastolic intracellular Ca2+activity (Ca2+waves, sarcoplasmic reticulum [SR] Ca2+leakage), and membrane voltage (Vm) and systolic Ca2+ release spatiotemporal heterogeneity (ΔtVm-Ca).,These changes were completely eliminated by JNK inhibition both in vivo and in vitro. calmodulin kinase II (CaMKII) is a proarrhythmic molecule known to drive SR Ca2+ mishandling.,The authors report for the first time that binge alcohol activates JNK2, which subsequently phosphorylates the CaMKII protein, enhancing CaMKII-driven SR Ca2+ mishandling.,CaMKII inhibition eliminates binge alcohol-evoked arrhythmic activities.,Our studies demonstrate that binge alcohol exposure activates JNK2 in atria, which then drives CaMKII activation, prompting aberrant Ca2+ waves and, thus, enhanced susceptibility to atrial arrhythmia.,Our results reveal a previously unrecognized form of alcohol-driven kinase-on-kinase proarrhythmic crosstalk.,Atrial JNK2 function represents a potential novel therapeutic target to treat and/or prevent AF. | Alcohol is a risk factor for cardiac arrhythmias.,Retrospective analyses suggest supraventricular arrhythmias consecutive to acute alcohol consumption, but prospective data are limited.,We intended to prospectively associate acute alcohol consumption with cardiac arrhythmias.,At the 2015 Munich Octoberfest, we enrolled 3028 voluntary participants who received a smartphone-based ECG and breath alcohol concentration (BAC) measurements.,ECGs were analysed for cardiac arrhythmias (sinus tachycardia, sinus arrhythmia, premature atrial/ventricular complexes, atrial fibrillation/flutter) and respiratory sinus arrhythmia.,By multivariable adjusted logistic regression we associated BACs with cardiac arrhythmias.,Similarly, we analysed 4131 participants of the community-based KORA S4 Study (Co-operative Health Research in the Region of Augsburg) and associated cardiac arrhythmias with chronic alcohol consumption.,In our acute alcohol cohort (mean age 34.4 ± 13.3 years, 29% women), mean BAC was 0.85 ± 0.54 g/kg.,Cardiac arrhythmias occurred in 30.5% (sinus tachycardia 25.9%; other arrhythmia subtypes 5.4%).,Breath alcohol concentration was significantly associated with cardiac arrhythmias overall (odds ratio (OR) per 1-unit change 1.75, 95% confidence interval (CI) 1.50-2.05; P < 0.001) and sinus tachycardia in particular (OR 1.96, 95%CI 1.66-2.31; P < 0.001).,Respiratory sinus arrhythmia measuring autonomic tone was significantly reduced under the influence of alcohol.,In KORA S4, chronic alcohol consumption was associated with sinus tachycardia (OR 1.03, 95%CI 1.01-1.06; P = 0.006).,Acute alcohol consumption is associated with cardiac arrhythmias and sinus tachycardia in particular.,This partly reflects autonomic imbalance as assessed by significantly reduced respiratory sinus arrhythmia.,Such imbalance might lead to sympathetically triggered atrial fibrillation resembling the holiday heart syndrome.,NCT02550340. | 1 |
Supplemental Digital Content is available in the text.,Sodium-glucose cotransporter 2 inhibitors improve outcomes in patients with heart failure with reduced ejection fraction, but additional information is needed about whether glycemic status influences the magnitude of their benefits on heart failure and renal events.,Patients with Class II-IV heart failure and a left ventricular ejection fraction ≤40% were randomized to receive empagliflozin (10 mg daily) or placebo in addition to recommended therapy.,We prespecified a comparison of the effect of empagliflozin in patients with and without diabetes.,Of the 3730 patients enrolled, 1856 (50%) had diabetes, 1268 (34%) had prediabetes (hemoglobin A1c [HbA1c] 5.7-6.4%), and 606 (16%) had normoglycemia (HbA1c <5.7%).,The risks of the primary outcome (cardiovascular death or hospitalization for heart failure), total hospitalizations for heart failure, and adverse renal outcomes were higher in patients with diabetes, but were similar between patients with prediabetes and normoglycemia.,Empagliflozin reduced the risk of the primary outcome in patients with and without diabetes (hazard ratio, 0.72 [95% CI, 0.60-0.87] and 0.78 [95% CI, 0.64-0.97], respectively, P-interaction=0.57).,Patients with and without diabetes also did not differ with respect to the effect of empagliflozin on total hospitalizations for heart failure, on the decline in estimated glomerular filtration rate over time, and on the risk of serious adverse renal outcomes.,Among these end points, the effects of the drug did not differ in patients with prediabetes or normoglycemia.,When analyzed as a continuous variable, baseline HbA1c did not significantly modify the benefits of empagliflozin on the primary outcome (P-interaction=0.40).,Empagliflozin did not lower HbA1c in patients with prediabetes or normoglycemia and was not associated with increased risk of hypoglycemia.,In EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), empagliflozin significantly improved cardiovascular and renal outcomes in patients with heart failure and a reduced ejection fraction, independent of baseline diabetes status and across the continuum of HbA1c.,URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977. | Effects of sodium‐glucose cotransporter 2 inhibitors on reducing hospitalization for heart failure have been reported in randomized controlled trials, but their effects on patients with heart failure with preserved ejection fraction (HFpEF) are unknown.,This study aimed to evaluate the drug efficacy of luseogliflozin, a sodium‐glucose cotransporter 2 inhibitor, in patients with type 2 diabetes mellitus and HFpEF.,We performed a multicenter, open‐label, randomized, controlled trial for comparing luseogliflozin 2.5 mg once daily with voglibose 0.2 mg 3 times daily in patients with type 2 diabetes mellitus suffering from HFpEF (left ventricular ejection fraction >45% and BNP [B‐type natriuretic peptide] concentrations ≥35 pg/mL) in a 1:1 randomization fashion.,The primary outcome was the difference from baseline in BNP levels after 12 weeks of treatment between the 2 drugs.,A total of 173 patients with diabetes mellitus and HFpEF were included.,Of these, 83 patients were assigned to receive luseogliflozin and 82 to receive voglibose.,There was no significant difference in the reduction in BNP concentrations after 12 weeks from baseline between the 2 groups.,The ratio of the mean BNP value at week 12 to the baseline value was 0.79 in the luseogliflozin group and 0.87 in the voglibose group (percent change, −9.0% versus −1.9%; ratio of change with luseogliflozin versus voglibose, 0.93; 95% CI, 0.78-1.10; P=0.26).,In patients with type 2 diabetes mellitus and HFpEF, there is no significant difference in the degree of reduction in BNP concentrations after 12 weeks between luseogliflozin and voglibose.,URL: https://www.umin.ac.jp/ctr/index.htm; Unique identifier: UMIN000018395. | 1 |
Subpleural consolidations have been found in lung ultrasound in patients with COVID-19, possibly deriving from pulmonary embolism (PE).,The diagnostic utility of impact of lung ultrasound in critical-ill patients with COVID-19 for PE diagnostics however is unclear.,We retrospectively evaluated all SARS-CoV2-associated ARDS patients admitted to our ICU between March 8th and May 31th 2020.,They were enrolled in this study, when a lung ultrasound and a computed tomography pulmonary angiography (CTPA) were documented.,In addition, wells score was calculated to estimate the probability of PE.,The CTPA was used as the gold standard for the detection of PE.,Twenty out of 25 patients met the inclusion criteria.,In 12/20 patients (60%) (sub-) segmental PE were detected by CT-angiography.,Lung ultrasound found subpleural consolidations in 90% of patients.,PE-typical large supleural consolidations with a size ≥ 1 cm were detectable in 65% of patients and were significant more frequent in patients with PE compared to those without (p = 0.035).,Large consolidations predicted PE with a sensitivity of 77% and a specificity of 71%.,The Wells score was significantly higher in patients with PE compared to those without (2.7 ± 0.8 and 1.7 ± 0.5, respectively, p = 0.042) and predicted PE with an AUC of 0.81.,When combining the two modalities, comparing patients with considered/probable PE using LUS plus a Wells score ≥ 2 to patients with possible/unlikely PE in LUS plus a Wells score < 2, PE could be predicted with a sensitivity of 100% and a specificity of 80%.,Large consolidations detected in lung ultrasound were found frequently in COVID-19 ARDS patients with pulmonary embolism.,In combination with a Wells score > 2, this might indicate a high-risk for PE in COVID-19.,The online version of this article (10.1007/s11239-020-02323-0) contains supplementary material, which is available to authorized users. | To evaluate the prevalence of acute pulmonary embolism (APE) in non-hospitalized COVID-19 patients referred to CT pulmonary angiography (CTPA) by the emergency department.,From March 14 to April 6, 2020, 72 non-hospitalized patients referred by the emergency department to CTPA for COVID-19 pneumonia were retrospectively identified.,Relevant clinical and laboratory data and CT scan findings were collected for each patient.,CTPA scans were reviewed by two radiologists to determinate the presence or absence of APE.,Clinical classification, lung involvement of COVID-19 pneumonia, and CT total severity score were compared between APE group and non-APE group.,APE was identified in 13 (18%) CTPA scans.,The mean age and D-dimer of patients from the APE group were higher in comparison with those from the non-APE group (74.4 vs.,59.6 years, p = 0.008, and 7.29 vs.,3.29 μg/ml, p = 0.011).,There was no significant difference between APE and non-APE groups concerning clinical type, COVID-19 pneumonia lung lesions (ground-glass opacity: 85% vs. 97%; consolidation: 69% vs. 68%; crazy paving: 38% vs. 37%; linear reticulation: 69% vs.,78%), CT severity score (6.3 vs.,7.1, p = 0.365), quality of CTPA (1.8 vs.,2.0, p = 0.518), and pleural effusion (38% vs. 19%, p = 0.146).,Non-hospitalized patients with COVID-19 pneumonia referred to CT scan by the emergency departments are at risk of APE.,The presence of APE was not limited to severe or critical clinical type of COVID-19 pneumonia.,• Acute pulmonary embolism was found in 18% of non-hospitalized COVID-19 patients referred by the emergency department to CTPA.,Two (15%) patients had main, four (30%) lobar, and seven (55%) segmental acute pulmonary embolism.,• Five of 13 (38%) patients with acute pulmonary embolism had a moderate clinical type.,• Severity and radiological features of COVID-19 pneumonia showed no significant difference between patients with or without acute pulmonary embolism. | 1 |
At the end of last year, a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulted in an acute respiratory illness epidemic in Wuhan, China [1, 2].,The World Health Organization (WHO) termed this illness coronavirus disease 2019 (COVID-19).,The coronavirus family have been shown to enter cells through binding angiotensin-converting enzyme 2 (ACE-2), found mainly on alveolar epithelium and endothelium.,Activation of endothelial cells is thought to be the primary driver for the increasingly recognised complication of thrombosis.,Pulmonary thrombosis appears to be common in COVID-19 pneumonia and takes two forms, proximal pulmonary emboli and/or distal thrombosis.,The possible mechanisms and clinical implications are discussed.https://bit.ly/372Xdhw | Acute respiratory failure and a systemic coagulopathy are critical aspects of the morbidity and mortality characterizing infection with severe acute respiratory distress syndrome-associated coronavirus-2, the etiologic agent of Coronavirus disease 2019 (COVID-19).,We examined skin and lung tissues from 5 patients with severe COVID-19 characterized by respiratory failure (n= 5) and purpuric skin rash (n = 3).,COVID-19 pneumonitis was predominantly a pauci-inflammatory septal capillary injury with significant septal capillary mural and luminal fibrin deposition and permeation of the interalveolar septa by neutrophils.,No viral cytopathic changes were observed and the diffuse alveolar damage (DAD) with hyaline membranes, inflammation, and type II pneumocyte hyperplasia, hallmarks of classic acute respiratory distress syndrome, were not prominent.,These pulmonary findings were accompanied by significant deposits of terminal complement components C5b-9 (membrane attack complex), C4d, and mannose binding lectin (MBL)-associated serine protease (MASP)2, in the microvasculature, consistent with sustained, systemic activation of the complement pathways.,The purpuric skin lesions similarly showed a pauci-inflammatory thrombogenic vasculopathy, with deposition of C5b-9 and C4d in both grossly involved and normally-appearing skin.,In addition, there was co-localization of COVID-19 spike glycoproteins with C4d and C5b-9 in the interalveolar septa and the cutaneous microvasculature of 2 cases examined.,In conclusion, at least a subset of sustained, severe COVID-19 may define a type of catastrophic microvascular injury syndrome mediated by activation of complement pathways and an associated procoagulant state.,It provides a foundation for further exploration of the pathophysiologic importance of complement in COVID-19, and could suggest targets for specific intervention. | 1 |
Unlabelled Image,•Venous thromboembolism (VTE) is a frequent complication in COVID-19 patients.,•Single-center study of COVID-19 patients admitted to general ward.,•17.0% of patients with VTE•Lack of thromboprophylaxis and leukocytosis were independent risk factors of VTE.,•VTE is independently associated with worse in-hospital outcomes.,Venous thromboembolism (VTE) is a frequent complication in COVID-19 patients.,Single-center study of COVID-19 patients admitted to general ward.,17.0% of patients with VTE,Lack of thromboprophylaxis and leukocytosis were independent risk factors of VTE.,VTE is independently associated with worse in-hospital outcomes. | We recently reported a high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 admitted to the intensive care units (ICUs) of three Dutch hospitals.,In answering questions raised regarding our study, we updated our database and repeated all analyses.,We re-evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction and/or systemic arterial embolism in all COVID-19 patients admitted to the ICUs of 2 Dutch university hospitals and 1 Dutch teaching hospital from ICU admission to death, ICU discharge or April 22nd 2020, whichever came first.,We studied the same 184 ICU patients as reported on previously, of whom a total of 41 died (22%) and 78 were discharged alive (43%).,The median follow-up duration increased from 7 to 14 days.,All patients received pharmacological thromboprophylaxis.,The cumulative incidence of the composite outcome, adjusted for competing risk of death, was 49% (95% confidence interval [CI] 41-57%).,The majority of thrombotic events were PE (65/75; 87%).,In the competing risk model, chronic anticoagulation therapy at admission was associated with a lower risk of the composite outcome (Hazard Ratio [HR] 0.29, 95%CI 0.091-0.92).,Patients diagnosed with thrombotic complications were at higher risk of all-cause death (HR 5.4; 95%CI 2.4-12).,Use of therapeutic anticoagulation was not associated with all-cause death (HR 0.79, 95%CI 0.35-1.8).,In this updated analysis, we confirm the very high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 pneumonia. | 1 |
Evaluate the risk of pre-existing comorbidities on COVID-19 mortality, and provide clinical suggestions accordingly.,A nested case-control design using confirmed case reports released from the news or the national/provincial/municipal health commissions of China between 18 December 2019 and 8 March 2020.,Patients with confirmed SARS-CoV-2 infection, excluding asymptomatic patients, in mainland China outside of Hubei Province.,Patient demographics, survival time and status, and history of comorbidities.,A total of 94 publicly reported deaths in locations outside of Hubei Province, mainland China, were included as cases.,Each case was matched with up to three controls, based on gender and age ±1 year old (94 cases and 181 controls).,The inverse probability-weighted Cox proportional hazard model was performed, controlling for age, gender and the early period of the outbreak.,Of the 94 cases, the median age was 72.5 years old (IQR=16), and 59.6% were men, while in the control group the median age was 67 years old (IQR=22), and 64.6% were men.,Adjusting for age, gender and the early period of the outbreak, poor health conditions were associated with a higher risk of COVID-19 mortality (HR of comorbidity score, 1.31 [95% CI 1.11 to 1.54]; p=0.001).,The estimated mortality risk in patients with pre-existing coronary heart disease (CHD) was three times that of those without CHD (p<0.001).,The estimated 30-day survival probability for a profile patient with pre-existing CHD (65-year-old woman with no other comorbidities) was 0.53 (95% CI 0.34 to 0.82), while it was 0.85 (95% CI 0.79 to 0.91) for those without CHD.,Older age was also associated with increased mortality risk: every 1-year increase in age was associated with a 4% increased risk of mortality (p<0.001).,Extra care and early medical interventions are needed for patients with pre-existing comorbidities, especially CHD. | The aim of this study was to identify factors associated with the death of patients with COVID-19 pneumonia caused by the novel coronavirus SARS-CoV-2.,All clinical and laboratory parameters were collected prospectively from a cohort of patients with COVID-19 pneumonia who were hospitalised to Wuhan Pulmonary Hospital (Wuhan City, Hubei Province, China) between 25 December 2019 and 7 February 2020.,Univariate and multivariate logistic regression was performed to investigate the relationship between each variable and the risk of death of COVID-19 pneumonia patients.,In total, 179 patients with COVID-19 pneumonia (97 male and 82 female) were included in the present prospective study, of whom 21 died.,Univariate and multivariate logistic regression analysis revealed that age ≥65 years (OR 3.765, 95% CI 1.146-17.394; p=0.023), pre-existing concurrent cardiovascular or cerebrovascular diseases (OR 2.464, 95% CI 0.755-8.044; p=0.007), CD3+CD8+ T-cells ≤75 cells·μL−1 (OR 3.982, 95% CI 1.132-14.006; p<0.001) and cardiac troponin I ≥0.05 ng·mL−1 (OR 4.077, 95% CI 1.166-14.253; p<0.001) were associated with an increase in risk of mortality from COVID-19 pneumonia.,In a sex-, age- and comorbid illness-matched case-control study, CD3+CD8+ T-cells ≤75 cells·μL−1 and cardiac troponin I ≥0.05 ng·mL−1 remained as predictors for high mortality from COVID-19 pneumonia.,We identified four risk factors: age ≥65 years, pre-existing concurrent cardiovascular or cerebrovascular diseases, CD3+CD8+ T-cells ≤75 cells·μL−1 and cardiac troponin I ≥0.05 ng·mL−1.,The latter two factors, especially, were predictors for mortality of COVID-19 pneumonia patients.,These data showed that age ≥65 years, pre-existing concurrent cardiovascular or cerebrovascular diseases, CD3+CD8+ T-cells ≤75 cells·μL−1 and cardiac troponin I ≥0.05 ng·mL−1 were four risk factors predicting high mortality of COVID-19 pneumonia patientshttps://bit.ly/2Rh6Nqv | 1 |
Diffuse leukoencephalopathy and juxtacortical and/or callosal microhemorrhages were brain imaging features in critically ill patients with coronavirus disease 2019.,Coronavirus disease 2019 (COVID-19) has been reported in association with a variety of brain imaging findings such as ischemic infarct, hemorrhage, and acute hemorrhagic necrotizing encephalopathy.,Herein, the authors report brain imaging features in 11 critically ill patients with COVID-19 with persistently diminished mental status who underwent MRI between April 5 and April 25, 2020.,These imaging features include (a) confluent T2 hyperintensity and mild restricted diffusion in bilateral supratentorial deep and subcortical white matter (in 10 of 11 patients) and (b) multiple punctate microhemorrhages in juxtacortical and callosal white matter (in seven of 11 patients).,The authors also discuss potential pathogeneses.,© RSNA, 2020,Online supplemental material is available for this article. | The coronavirus 2019 (COVID-19) pandemic has had a dramatic impact on health care systems and a variable disease course.,Emerging evidence demonstrates that severe acute respiratory syndrome coronavirus 2 is associated with central nervous system disease.,We describe central nervous system manifestations in critical patients with COVID-19 at our tertiary center.,We conducted a single-center retrospective analysis of all actively critical patients with COVID-19 admitted to our tertiary care academic center in New Orleans, Louisiana, on April 22, 2020, with new onset of neurologic disease.,Patients were grouped into 1 of 3 categories according to imaging and clinical features; encephalopathy, acute necrotizing encephalopathy, and vasculopathy.,A total of 27 of 76 (35.5%) critical patients with COVID-19 met inclusion criteria.,Twenty patients (74%) were designated with COVID-19-associated encephalopathy, 2 (7%) with COVID-19-associated acute necrotizing encephalopathy, and 5 (19%) with COVID-19-associated vasculopathy.,Sixty-three percent of neurologic findings were demonstrated on computed tomography, 30% on magnetic resonance imaging, and 44% on electroencephalography.,Findings most often included ischemic strokes, diffuse hypoattenuation, subcortical parenchymal hemorrhages, and focal hypodensities within deep structures.,Magnetic resonance imaging findings included diffuse involvement of deep white matter, the corpus callosum, and the basal ganglia.,For patients with large-territory ischemic stroke, all but one displayed irregular proximal focal stenosis of the supraclinoid internal carotid artery.,Analysis of active critical COVID-19 admissions at our revealed a high percentage of patients with new neurologic disease.,Although variable, presentations followed 1 of 3 broad categories.,A better understanding of the neurologic sequalae and radiographic findings will help clinicians mitigate the impact of this disease. | 1 |
Coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become pandemic, with substantial mortality.,To evaluate the pathologic changes of organ systems and the clinicopathologic basis for severe and fatal outcomes.,Prospective autopsy study.,Single pathology department.,11 deceased patients with COVID-19 (10 of whom were selected at random for autopsy).,Systematic macroscopic, histopathologic, and viral analysis (SARS-CoV-2 on real-time polymerase chain reaction assay), with correlation of pathologic and clinical features, including comorbidities, comedication, and laboratory values.,Patients' age ranged from 66 to 91 years (mean, 80.5 years; 8 men, 3 women).,Ten of the 11 patients received prophylactic anticoagulant therapy; venous thromboembolism was not clinically suspected antemortem in any of the patients.,Both lungs showed various stages of diffuse alveolar damage (DAD), including edema, hyaline membranes, and proliferation of pneumocytes and fibroblasts.,Thrombosis of small and mid-sized pulmonary arteries was found in various degrees in all 11 patients and was associated with infarction in 8 patients and bronchopneumonia in 6 patients.,Kupffer cell proliferation was seen in all patients, and chronic hepatic congestion in 8 patients.,Other changes in the liver included hepatic steatosis, portal fibrosis, lymphocytic infiltrates and ductular proliferation, lobular cholestasis, and acute liver cell necrosis, together with central vein thrombosis.,Additional frequent findings included renal proximal tubular injury, focal pancreatitis, adrenocortical hyperplasia, and lymphocyte depletion of spleen and lymph nodes.,Viral RNA was detectable in pharyngeal, bronchial, and colonic mucosa but not bile.,The sample was small.,COVID-19 predominantly involves the lungs, causing DAD and leading to acute respiratory insufficiency.,Death may be caused by the thrombosis observed in segmental and subsegmental pulmonary arterial vessels despite the use of prophylactic anticoagulation.,Studies are needed to further understand the thrombotic complications of COVID-19, together with the roles for strict thrombosis prophylaxis, laboratory, and imaging studies and early anticoagulant therapy for suspected pulmonary arterial thrombosis or thromboembolism.,None.,The clinicopathological basis for morbidity and mortality with SARS-CoV-2 infection is not well understood.,This study reports the clinical and autopsy findings of patients who died of COVID-19. | Little evidence of increased thrombotic risk is available in COVID-19 patients.,Our purpose was to assess thrombotic risk in severe forms of SARS-CoV-2 infection.,All patients referred to 4 intensive care units (ICUs) from two centers of a French tertiary hospital for acute respiratory distress syndrome (ARDS) due to COVID-19 between March 3rd and 31st 2020 were included.,Medical history, symptoms, biological data and imaging were prospectively collected.,Propensity score matching was performed to analyze the occurrence of thromboembolic events between non-COVID-19 ARDS and COVID-19 ARDS patients.,150 COVID-19 patients were included (122 men, median age 63 [53; 71] years, SAPSII 49 [37; 64] points).,Sixty-four clinically relevant thrombotic complications were diagnosed in 150 patients, mainly pulmonary embolisms (16.7%). 28/29 patients (96.6%) receiving continuous renal replacement therapy experienced circuit clotting.,Three thrombotic occlusions (in 2 patients) of centrifugal pump occurred in 12 patients (8%) supported by ECMO.,Most patients (> 95%) had elevated D-dimer and fibrinogen.,No patient developed disseminated intravascular coagulation.,Von Willebrand (vWF) activity, vWF antigen and FVIII were considerably increased, and 50/57 tested patients (87.7%) had positive lupus anticoagulant.,Comparison with non-COVID-19 ARDS patients (n = 145) confirmed that COVID-19 ARDS patients (n = 77) developed significantly more thrombotic complications, mainly pulmonary embolisms (11.7 vs.,2.1%, p < 0.008).,Coagulation parameters significantly differed between the two groups.,Despite anticoagulation, a high number of patients with ARDS secondary to COVID-19 developed life-threatening thrombotic complications.,Higher anticoagulation targets than in usual critically ill patients should therefore probably be suggested.,The online version of this article (10.1007/s00134-020-06062-x) contains supplementary material, which is available to authorized users. | 1 |
Coronavirus disease 2019 (COVID‐19) can lead to systemic coagulation activation and thrombotic complications.,To investigate the incidence of objectively confirmed venous thromboembolism (VTE) in hospitalized patients with COVID‐19.,Single‐center cohort study of 198 hospitalized patients with COVID‐19.,Seventy‐five patients (38%) were admitted to the intensive care unit (ICU).,At time of data collection, 16 (8%) were still hospitalized and 19% had died.,During a median follow‐up of 7 days (IQR, 3‐13), 39 patients (20%) were diagnosed with VTE of whom 25 (13%) had symptomatic VTE, despite routine thrombosis prophylaxis.,The cumulative incidences of VTE at 7, 14 and 21 days were 16% (95% CI, 10‐22), 33% (95% CI, 23‐43) and 42% (95% CI 30‐54) respectively.,For symptomatic VTE, these were 10% (95% CI, 5.8‐16), 21% (95% CI, 14‐30) and 25% (95% CI 16‐36).,VTE appeared to be associated with death (adjusted HR, 2.4; 95% CI, 1.02‐5.5).,The cumulative incidence of VTE was higher in the ICU (26% (95% CI, 17‐37), 47% (95% CI, 34‐58), and 59% (95% CI, 42‐72) at 7, 14 and 21 days) than on the wards (any VTE and symptomatic VTE 5.8% (95% CI, 1.4‐15), 9.2% (95% CI, 2.6‐21), and 9.2% (2.6‐21) at 7, 14, and 21 days).,The observed risk for VTE in COVID‐19 is high, particularly in ICU patients, which should lead to a high level of clinical suspicion and low threshold for diagnostic imaging for DVT or PE.,Future research should focus on optimal diagnostic and prophylactic strategies to prevent VTE and potentially improve survival. | Beyond its role in hemostasis, von Willebrand factor (VWF) is an emerging mediator of vascular inflammation.,Recent studies highlight the involvement of VWF and its regulator, ADAMTS13, in mechanisms that underlie vascular inflammation and immunothrombosis, like leukocyte rolling, adhesion, and extravasation; vascular permeability; ischemia/reperfusion injury; complements activation; and NETosis.,The VWF/ADAMTS13 axis is implicated in the pathogenesis of atherosclerosis, promoting plaque formation and inflammation through macrophage and neutrophil recruitment in inflamed lesions.,Moreover, VWF and ADAMTS13 have been recently proposed as prognostic biomarkers in cardiovascular, metabolic, and inflammatory diseases, such as diabetes, stroke, myocardial infarction, and sepsis.,All these features make VWF an attractive therapeutic target in thromboinflammation.,Several lines of research have recently investigated “tailor-made” inhibitors of VWF.,Results from animal models and clinical studies support the potent anti-inflammatory and antithrombotic effect of VWF antagonism, providing reassuring data on its safety profile.,This review describes the role of VWF in vascular inflammation “from bench to bedside” and provides an updated overview of the drugs that can directly interfere with the VWF/ADAMTS13 axis. | 1 |
Three months ago, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) broke out in Wuhan, China, and spread rapidly around the world.,Severe novel coronavirus pneumonia (NCP) patients have abnormal blood coagulation function, but their venous thromboembolism (VTE) prevalence is still rarely mentioned.,To determine the incidence of VTE in patients with severe NCP.,In this study, 81 severe NCP patients in the intensive care unit (ICU) of Union Hospital (Wuhan, China) were enrolled.,The results of conventional coagulation parameters and lower limb vein ultrasonography of these patients were retrospectively collected and analyzed.,The incidence of VTE in these patients was 25% (20/81), of which 8 patients with VTE events died.,The VTE group was different from the non‐VTE group in age, lymphocyte counts, activated partial thromboplastin time (APTT), D‐dimer, etc.,If 1.5 µg/mL was used as the D‐dimer cut‐off value to predicting VTE, the sensitivity was 85.0%, the specificity was 88.5%, and the negative predictive value (NPV) was 94.7%.,The incidence of VTE in patients with severe NCP is 25% (20/81), which may be related to poor prognosis.,The significant increase of D‐dimer in severe NCP patients is a good index for identifying high‐risk groups of VTE. | To delineate the clinical characteristics of patients with coronavirus disease 2019 (covid-19) who died.,Retrospective case series.,Tongji Hospital in Wuhan, China.,Among a cohort of 799 patients, 113 who died and 161 who recovered with a diagnosis of covid-19 were analysed.,Data were collected until 28 February 2020.,Clinical characteristics and laboratory findings were obtained from electronic medical records with data collection forms.,The median age of deceased patients (68 years) was significantly older than recovered patients (51 years).,Male sex was more predominant in deceased patients (83; 73%) than in recovered patients (88; 55%).,Chronic hypertension and other cardiovascular comorbidities were more frequent among deceased patients (54 (48%) and 16 (14%)) than recovered patients (39 (24%) and 7 (4%)).,Dyspnoea, chest tightness, and disorder of consciousness were more common in deceased patients (70 (62%), 55 (49%), and 25 (22%)) than in recovered patients (50 (31%), 48 (30%), and 1 (1%)).,The median time from disease onset to death in deceased patients was 16 (interquartile range 12.0-20.0) days.,Leukocytosis was present in 56 (50%) patients who died and 6 (4%) who recovered, and lymphopenia was present in 103 (91%) and 76 (47%) respectively.,Concentrations of alanine aminotransferase, aspartate aminotransferase, creatinine, creatine kinase, lactate dehydrogenase, cardiac troponin I, N-terminal pro-brain natriuretic peptide, and D-dimer were markedly higher in deceased patients than in recovered patients.,Common complications observed more frequently in deceased patients included acute respiratory distress syndrome (113; 100%), type I respiratory failure (18/35; 51%), sepsis (113; 100%), acute cardiac injury (72/94; 77%), heart failure (41/83; 49%), alkalosis (14/35; 40%), hyperkalaemia (42; 37%), acute kidney injury (28; 25%), and hypoxic encephalopathy (23; 20%).,Patients with cardiovascular comorbidity were more likely to develop cardiac complications.,Regardless of history of cardiovascular disease, acute cardiac injury and heart failure were more common in deceased patients.,Severe acute respiratory syndrome coronavirus 2 infection can cause both pulmonary and systemic inflammation, leading to multi-organ dysfunction in patients at high risk.,Acute respiratory distress syndrome and respiratory failure, sepsis, acute cardiac injury, and heart failure were the most common critical complications during exacerbation of covid-19. | 1 |
There is concern about the potential of an increased risk related to medications that act on the renin-angiotensin-aldosterone system in patients exposed to coronavirus disease 2019 (Covid-19), because the viral receptor is angiotensin-converting enzyme 2 (ACE2).,We assessed the relation between previous treatment with ACE inhibitors, angiotensin-receptor blockers, beta-blockers, calcium-channel blockers, or thiazide diuretics and the likelihood of a positive or negative result on Covid-19 testing as well as the likelihood of severe illness (defined as intensive care, mechanical ventilation, or death) among patients who tested positive.,Using Bayesian methods, we compared outcomes in patients who had been treated with these medications and in untreated patients, overall and in those with hypertension, after propensity-score matching for receipt of each medication class.,A difference of at least 10 percentage points was prespecified as a substantial difference.,Among 12,594 patients who were tested for Covid-19, a total of 5894 (46.8%) were positive; 1002 of these patients (17.0%) had severe illness.,A history of hypertension was present in 4357 patients (34.6%), among whom 2573 (59.1%) had a positive test; 634 of these patients (24.6%) had severe illness.,There was no association between any single medication class and an increased likelihood of a positive test.,None of the medications examined was associated with a substantial increase in the risk of severe illness among patients who tested positive.,We found no substantial increase in the likelihood of a positive test for Covid-19 or in the risk of severe Covid-19 among patients who tested positive in association with five common classes of antihypertensive medications. | Mortality from coronavirus disease 2019 (COVID-19) is strongly associated with cardiovascular disease, diabetes, and hypertension.,These disorders share underlying pathophysiology related to the renin-angiotensin system (RAS) that may be clinically insightful.,In particular, activity of the angiotensin-converting enzyme 2 (ACE2) is dysregulated in cardiovascular disease, and this enzyme is used by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to initiate the infection.,Cardiovascular disease and pharmacologic RAS inhibition both increase ACE2 levels, which may increase the virulence of SARS-CoV-2 within the lung and heart.,Conversely, mechanistic evidence from related coronaviruses suggests that SARS-CoV-2 infection may downregulate ACE2, leading to toxic overaccumulation of angiotensin II that induces acute respiratory distress syndrome and fulminant myocarditis.,RAS inhibition could mitigate this effect.,With conflicting mechanistic evidence, we propose key clinical research priorities necessary to clarify the role of RAS inhibition in COVID-19 mortality that could be rapidly addressed by the international research community.,The association between coronavirus disease 2019 (COVID-19) mortality and cardiovascular disease is likely mediated by dysregulation of the renin-angiotensin system (RAS).,Pharmacoepidemiologic studies are needed to clarify whether RAS inhibition mediates this association and is helpful or harmful. | 1 |
Supplemental Digital Content is available in the text.,Clinical trials have shown cardiovascular benefits and potential risks from sodium glucose cotransporter 2 inhibitors (SGLT2i).,Trials may have limited ability to address individual end points or safety concerns.,We performed a population-based cohort study among patients with type 2 diabetes mellitus with established cardiovascular disease newly initiated on antihyperglycemic agents within the US Department of Defense Military Health System between April 1, 2013, and December 31, 2016.,Incidence rates, hazard ratios (HRs), and 95% confidence intervals (CIs) for time to first composite end point of all-cause mortality and hospitalization for heart failure event, major adverse cardiovascular events (defined as all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke), and individual end points were evaluated using conditional Cox models comparing new SGLT2i users with other antihyperglycemic agents.,The exploratory safety end point was below-knee lower extremity amputation.,Intent-to-treat and on-treatment analyses were performed.,After propensity matching, 25 258 patients were followed for a median of 1.6 years.,Compared with non-SGLT2i, initiation of SGLT2i was associated with a lower rate of all-cause mortality and hospitalization for heart failure (1.73 versus 3.01 events per 100 person-years; HR, 0.57; 95% CI, 0.50-0.65) and major adverse cardiovascular events (2.31 versus 3.45 events per 100 person-years; HR, 0.67; 95% CI, 0.60-0.75).,SGLT2i initiation was also associated with an ≈2-fold higher risk of below-knee lower extremity amputation (0.17 versus 0.09 events per 100 person-years; HR, 1.99; 95% CI, 1.12-3.51).,Because of the disproportionate canagliflozin exposure in the database, the majority of amputations were observed on canagliflozin.,Results were consistent in the on-treatment analysis.,In this high-risk cohort, initiation of SGLT2i was associated with lower risk of all-cause mortality, hospitalization for heart failure, and major adverse cardiovascular events and higher risk of below-knee lower extremity amputation.,Findings underscore the potential benefit and risks to be aware of when initiating SGLT2i.,It remains unclear whether the below-knee lower extremity amputation risk extends across the class of medication, because the study was not powered to make comparisons among individual treatments. | Supplemental Digital Content is available in the text.,Reduction in cardiovascular death and hospitalization for heart failure (HHF) was recently reported with the sodium-glucose cotransporter-2 inhibitor (SGLT-2i) empagliflozin in patients with type 2 diabetes mellitus who have atherosclerotic cardiovascular disease.,We compared HHF and death in patients newly initiated on any SGLT-2i versus other glucose-lowering drugs in 6 countries to determine if these benefits are seen in real-world practice and across SGLT-2i class.,Data were collected via medical claims, primary care/hospital records, and national registries from the United States, Norway, Denmark, Sweden, Germany, and the United Kingdom.,Propensity score for SGLT-2i initiation was used to match treatment groups.,Hazard ratios for HHF, death, and their combination were estimated by country and pooled to determine weighted effect size.,Death data were not available for Germany.,After propensity matching, there were 309 056 patients newly initiated on either SGLT-2i or other glucose-lowering drugs (154 528 patients in each treatment group).,Canagliflozin, dapagliflozin, and empagliflozin accounted for 53%, 42%, and 5% of the total exposure time in the SGLT-2i class, respectively.,Baseline characteristics were balanced between the 2 groups.,There were 961 HHF cases during 190 164 person-years follow-up (incidence rate, 0.51/100 person-years).,Of 215 622 patients in the United States, Norway, Denmark, Sweden, and the United Kingdom, death occurred in 1334 (incidence rate, 0.87/100 person-years), and HHF or death in 1983 (incidence rate, 1.38/100 person-years).,Use of SGLT-2i, versus other glucose-lowering drugs, was associated with lower rates of HHF (hazard ratio, 0.61; 95% confidence interval, 0.51-0.73; P<0.001); death (hazard ratio, 0.49; 95% confidence interval, 0.41-0.57; P<0.001); and HHF or death (hazard ratio, 0.54; 95% confidence interval, 0.48-0.60; P<0.001) with no significant heterogeneity by country.,In this large multinational study, treatment with SGLT-2i versus other glucose-lowering drugs was associated with a lower risk of HHF and death, suggesting that the benefits seen with empagliflozin in a randomized trial may be a class effect applicable to a broad population of patients with type 2 diabetes mellitus in real-world practice.,URL: http://www.clinicaltrials.gov.,Unique identifier: NCT02993614. | 1 |
Digital therapeutics is a new approach to facilitate the non-pharmacological treatment of hypertension using software programmes such as smartphone applications and/or device algorithms.,Based on promising findings from a small pilot trial, the HERB Digital Hypertension 1 (HERB-DH1) pivotal trial investigated the efficacy of digital therapeutics in patients with hypertension not receiving antihypertensive medication.,This prospective, open-label, randomized controlled study was performed at 12 sites in Japan.,Patients with hypertension [office systolic blood pressure (SBP) 140 to <180 mmHg and 24 h SBP ≥130 mmHg] were randomly assigned 1:1 to the digital therapeutics group (HERB system + standard lifestyle modification) or control group (standard lifestyle modification alone).,The primary efficacy endpoint was the mean change in 24 h ambulatory SBP from baseline to 12 weeks; key secondary efficacy endpoints were mean changes in office and home blood pressure (BP) from baseline to 12 weeks.,All analyses were conducted in the full analysis set population.,Between December 2019 and June 2020, 390 patients were randomly assigned to the digital therapeutics group (n = 199) or control (n = 191) group.,Between-group differences in 24-h ambulatory, home, and office SBPs at 12 weeks were −2.4 (95% confidence interval −4.5 to −0.3), −4.3 (−6.7 to −1.9), and −3.6 (−6.2 to −1.0) mmHg, respectively.,No major programme-related safety events occurred up to 24 weeks.,The HERB-DH1 pivotal study showed the superiority of digital therapeutics compared with standard lifestyle modification alone to reduce 24-h ambulatory, home, and office BPs in the absence of antihypertensive medications. | Out-of-office blood pressure measurement is an essential part of diagnosing and managing hypertension.,In the era of advanced digital health information technology, the approach to achieving this is shifting from traditional methods (ambulatory and home blood pressure monitoring) to wearable devices and technology.,Wearable blood pressure monitors allow frequent blood pressure measurements (ideally continuous beat-by-beat monitoring of blood pressure) with minimal stress on the patient.,It is expected that wearable devices will dramatically change the quality of detection and management of hypertension by increasing the number of measurements in different situations, allowing accurate detection of phenotypes that have a negative impact on cardiovascular prognosis, such as masked hypertension and abnormal blood pressure variability.,Frequent blood pressure measurements and the addition of new features such as monitoring of environmental conditions allows interpretation of blood pressure data in the context of daily stressors and different situations.,This new digital approach to hypertension contributes to anticipation medicine, which refers to strategies designed to identify increasing risk and predict the onset of cardiovascular events based on a series of data collected over time, allowing proactive interventions to reduce risk.,To achieve this, further research and validation is required to develop wearable blood pressure monitoring devices that provide the same accuracy as current approaches and can effectively contribute to personalized medicine. | 1 |
Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, there have been concerns about the association between exposure to renin-angiotensin-aldosterone system (RAAS) inhibitors and the risk and severity of COVID-19.,We performed a case-control study that utilized up-to-date data on the South Korean population provided by the Korean National Health Insurance System.,Of the 62,909 patients with hypertension or heart failure tested for COVID-19, there were 1,644 (2.6%) confirmed cases.,After case-control matching, multivariable-adjusted conditional logistic regression analysis was performed.,Comparison between patients exposed to RAAS inhibitors and those not exposed to RAAS inhibitors revealed that the adjusted odds ratio (OR) and 95% confidence interval (CI) for COVID-19 infection and death were 0.981 (95% CI, 0.849 to 1.135) and 0.875 (95% CI, 0.548 to 1.396), respectively.,Subgroup analysis for the major confounders, age and region of diagnosis, resulted in OR of 0.912 (95% CI, 0.751 to 1.108) and 0.942 (95% CI, 0.791 to 1.121), respectively.,The present study demonstrated no evidence of association between RAAS inhibitor exposure and risk and severity of COVID-19. | To describe the characteristics of patients hospitalized with COVID-19 (including their long-term at-home medication use), and compare them with regard to the course of the disease.,To assess the association between renin-angiotensin system inhibitors (RASIs) and disease progression and critical outcomes.,All consecutive hospitalized patients with laboratory-confirmed COVID-19 in a university hospital in Amiens (France) were included in this study.,The primary composite endpoint was admission to an intensive care unit (ICU) or death before ICU admission.,Univariable and multivariable logistic regression models were used to identify factors associated with the composite endpoint.,Between 28 February 2020 and 30 March 2020, a total of 499 local patients tested positive for SARS-CoV-2.,Of these, 231 were not hospitalized {males 33%; median [interquartile range (IQR)] age: 44 (32-54)}, and 268 were hospitalized [males 58%; median (IQR) age: 73 (61-84)].,A total of 116 patients met the primary endpoint: 47 died before ICU admission, and 69 were admitted to the ICU.,Patients meeting the primary endpoint were more likely than patients not meeting the primary endpoint to have coronary heart disease and to have been taking RASIs; however, the two subsets of patients did not differ with regard to median age.,After adjustment for other associated variables, the risk of meeting the composite endpoint was 1.73 times higher (odds ratio 1.73, 95% confidence interval 1.02-2.93) in patients treated at baseline with a RASI than in patients not treated with this drug class.,This association was confirmed when the analysis was restricted to patients treated with antihypertensive agents.,We highlighted a potential safety signal for RASIs, the long-term use of which was independently associated with a higher risk of severe COVID-19 and a poor outcome.,Due to the widespread use of this important drug class, formal proof based on clinical trials is needed to better understand the association between RASIs and complications of COVID-19. | 1 |
Angiotensin converting enzyme-2 (ACE2) receptors mediate the entry into the cell of three strains of coronavirus: SARS-CoV, NL63 and SARS-CoV-2.,ACE2 receptors are ubiquitous and widely expressed in the heart, vessels, gut, lung (particularly in type 2 pneumocytes and macrophages), kidney, testis and brain.,ACE2 is mostly bound to cell membranes and only scarcely present in the circulation in a soluble form.,An important salutary function of membrane-bound and soluble ACE2 is the degradation of angiotensin II to angiotensin1-7.,Consequently, ACE2 receptors limit several detrimental effects resulting from binding of angiotensin II to AT1 receptors, which include vasoconstriction, enhanced inflammation and thrombosis.,The increased generation of angiotensin1-7 also triggers counter-regulatory protective effects through binding to G-protein coupled Mas receptors.,Unfortunately, the entry of SARS-CoV2 into the cells through membrane fusion markedly down-regulates ACE2 receptors, with loss of the catalytic effect of these receptors at the external site of the membrane.,Increased pulmonary inflammation and coagulation have been reported as unwanted effects of enhanced and unopposed angiotensin II effects via the ACE→Angiotensin II→AT1 receptor axis.,Clinical reports of patients infected with SARS-CoV-2 show that several features associated with infection and severity of the disease (i.e., older age, hypertension, diabetes, cardiovascular disease) share a variable degree of ACE2 deficiency.,We suggest that ACE2 down-regulation induced by viral invasion may be especially detrimental in people with baseline ACE2 deficiency associated with the above conditions.,The additional ACE2 deficiency after viral invasion might amplify the dysregulation between the ‘adverse’ ACE→Angiotensin II→AT1 receptor axis and the ‘protective’ ACE2→Angiotensin1-7→Mas receptor axis.,In the lungs, such dysregulation would favor the progression of inflammatory and thrombotic processes triggered by local angiotensin II hyperactivity unopposed by angiotensin1-7.,In this setting, recombinant ACE2, angiotensin1-7 and angiotensin II type 1 receptor blockers could be promising therapeutic approaches in patients with SARS-CoV-2 infection. | This case series study evaluates the association of underlying cardiovascular disease and myocardial injury on fatal outcomes in patients with coronavirus disease 2019 (COVID-19).,What is the impact of underlying cardiovascular disease (CVD) and myocardial injury on fatal outcomes in patients with coronavirus disease 2019 (COVID-19)?,In this case series study of 187 patients with COVID-19, 27.8% of patients had myocardial injury, which resulted in cardiac dysfunction and arrhythmias.,Myocardial injury has a significant association with fatal outcome of COVID-19, while the prognosis of patients with underlying CVD but without myocardial injury were relatively favorable.,It is reasonable to triage patients with COVID-19 according to the presence of underlying CVD and evidence of myocardial injury for prioritized treatment and even more aggressive strategies.,Increasing numbers of confirmed cases and mortality rates of coronavirus disease 2019 (COVID-19) are occurring in several countries and continents.,Information regarding the impact of cardiovascular complication on fatal outcome is scarce.,To evaluate the association of underlying cardiovascular disease (CVD) and myocardial injury with fatal outcomes in patients with COVID-19.,This retrospective single-center case series analyzed patients with COVID-19 at the Seventh Hospital of Wuhan City, China, from January 23, 2020, to February 23, 2020.,Analysis began February 25, 2020.,Demographic data, laboratory findings, comorbidities, and treatments were collected and analyzed in patients with and without elevation of troponin T (TnT) levels.,Among 187 patients with confirmed COVID-19, 144 patients (77%) were discharged and 43 patients (23%) died.,The mean (SD) age was 58.50 (14.66) years.,Overall, 66 (35.3%) had underlying CVD including hypertension, coronary heart disease, and cardiomyopathy, and 52 (27.8%) exhibited myocardial injury as indicated by elevated TnT levels.,The mortality during hospitalization was 7.62% (8 of 105) for patients without underlying CVD and normal TnT levels, 13.33% (4 of 30) for those with underlying CVD and normal TnT levels, 37.50% (6 of 16) for those without underlying CVD but elevated TnT levels, and 69.44% (25 of 36) for those with underlying CVD and elevated TnTs.,Patients with underlying CVD were more likely to exhibit elevation of TnT levels compared with the patients without CVD (36 [54.5%] vs 16 [13.2%]).,Plasma TnT levels demonstrated a high and significantly positive linear correlation with plasma high-sensitivity C-reactive protein levels (β = 0.530, P < .001) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (β = 0.613, P < .001).,Plasma TnT and NT-proBNP levels during hospitalization (median [interquartile range (IQR)], 0.307 [0.094-0.600]; 1902.00 [728.35-8100.00]) and impending death (median [IQR], 0.141 [0.058-0.860]; 5375 [1179.50-25695.25]) increased significantly compared with admission values (median [IQR], 0.0355 [0.015-0.102]; 796.90 [401.93-1742.25]) in patients who died (P = .001; P < .001), while no significant dynamic changes of TnT (median [IQR], 0.010 [0.007-0.019]; 0.013 [0.007-0.022]; 0.011 [0.007-0.016]) and NT-proBNP (median [IQR], 352.20 [174.70-636.70]; 433.80 [155.80-1272.60]; 145.40 [63.4-526.50]) was observed in survivors (P = .96; P = .16).,During hospitalization, patients with elevated TnT levels had more frequent malignant arrhythmias, and the use of glucocorticoid therapy (37 [71.2%] vs 69 [51.1%]) and mechanical ventilation (31 [59.6%] vs 14 [10.4%]) were higher compared with patients with normal TnT levels.,The mortality rates of patients with and without use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers was 36.8% (7 of 19) and 21.4% (36 of 168) (P = .13).,Myocardial injury is significantly associated with fatal outcome of COVID-19, while the prognosis of patients with underlying CVD but without myocardial injury is relatively favorable.,Myocardial injury is associated with cardiac dysfunction and arrhythmias.,Inflammation may be a potential mechanism for myocardial injury.,Aggressive treatment may be considered for patients at high risk of myocardial injury. | 1 |
COVID-19 has rapidly impacted on mortality worldwide.1 There is unprecedented urgency to understand who is most at risk of severe outcomes, requiring new approaches for timely analysis of large datasets.,Working on behalf of NHS England we created OpenSAFELY: a secure health analytics platform covering 40% of all patients in England, holding patient data within the existing data centre of a major primary care electronic health records vendor.,Primary care records of 17,278,392 adults were pseudonymously linked to 10,926 COVID-19 related deaths.,COVID-19 related death was associated with: being male (hazard ratio 1.59, 95%CI 1.53-1.65); older age and deprivation (both with a strong gradient); diabetes; severe asthma; and various other medical conditions.,Compared to people with white ethnicity, black and South Asian people were at higher risk even after adjustment for other factors (HR 1.48, 1.29-1.69 and 1.45, 1.32-1.58 respectively).,We have quantified a range of clinical risk factors for COVID-19 related death in the largest cohort study conducted by any country to date.,OpenSAFELY is rapidly adding further patients’ records; we will update and extend results regularly. | To assess the association between risk of venous thromboembolism and use of different types of hormone replacement therapy.,Two nested case-control studies.,UK general practices contributing to the QResearch or Clinical Practice Research Datalink (CPRD) databases, and linked to hospital, mortality, and social deprivation data.,80 396 women aged 40-79 with a primary diagnosis of venous thromboembolism between 1998 and 2017, matched by age, general practice, and index date to 391 494 female controls.,Venous thromboembolism recorded on general practice, mortality, or hospital records.,Odds ratios were adjusted for demographics, smoking status, alcohol consumption, comorbidities, recent medical events, and other prescribed drugs.,Overall, 5795 (7.2%) women who had venous thromboembolism and 21 670 (5.5%) controls had been exposed to hormone replacement therapy within 90 days before the index date.,Of these two groups, 4915 (85%)and 16 938 (78%) women used oral therapy, respectively, which was associated with a significantly increased risk of venous thromboembolism compared with no exposure (adjusted odds ratio 1.58, 95% confidence interval 1.52 to 1.64), for both oestrogen only preparations (1.40, 1.32 to 1.48) and combined preparations (1.73, 1.65 to 1.81).,Estradiolhad a lower risk than conjugated equine oestrogen for oestrogen only preparations (0.85, 0.76 to 0.95) and combined preparations (0.83, 0.76 to 0.91).,Compared with no exposure, conjugated equine oestrogen with medroxyprogesterone acetate had the highest risk (2.10, 1.92 to 2.31), and estradiol with dydrogesterone had the lowest risk (1.18, 0.98 to 1.42).,Transdermal preparations were not associated with risk of venous thromboembolism, which was consistent for different regimens (overall adjusted odds ratio 0.93, 95% confidence interval 0.87 to 1.01).,In the present study, transdermal treatment was the safest type of hormone replacement therapy when risk of venous thromboembolism was assessed.,Transdermal treatment appears to be underused, with the overwhelming preference still for oral preparations. | 1 |
Effective triage of patients with emergent large vessel occlusion (ELVO) to endovascular therapy capable centers may decrease time to treatment and improve outcome for these patients.,Here we performed a derivation study to evaluate the accuracy of a portable, non-invasive, and easy to use severe stroke detector.,The volumetric impedance phase shift spectroscopy (VIPS) device was used to assign a bioimpedance asymmetry score to 248 subjects across three cohorts, including 41 subjects presenting as acute stroke codes at a major comprehensive stroke center (CSC), 79 healthy volunteers, and 128 patients presenting to CSCs with a wide variety of brain pathology including additional stroke codes.,Diagnostic parameters were calculated for the ability of the device to discern (1) severe stroke from minor stroke and (2) severe stroke from all other subjects.,Patients with intracranial hardware were excluded from the analysis.,The VIPS device was able to differentiate severe stroke from minor strokes with a sensitivity of 93% (95% CI 83 to 98), specificity of 92% (95% CI 75 to 99), and an area under the curve (AUC) of 0.93 (95% CI 0.85 to 0.97).,The device was able to differentiate severe stroke from all other subjects with a sensitivity of 93% (95% CI 83 to 98), specificity of 87% (95% CI 81 to 92), and an AUC of 0.95 (95% CI 0.89 to 0.96).,The VIPS device is a portable, non-invasive, and easy to use tool that may aid in the detection of severe stroke, including ELVO, with a sensitivity of 93% and specificity of 92% in this derivation study.,This device has the potential to improve the triage of patients suffering severe stroke. | The major therapy for ischemic stroke is thrombolytic treatment, but severe consequences occur when this method is used to treat hemorrhagic stroke.,Currently, computed tomography and magnetic resonance imaging are used to differentiate between two types of stroke, but these two methods are ineffective for pre-hospital care.,We developed a new brain diagnostic device for rabbits based on electromagnetic induction to non-invasively differentiate two types of stroke.,The device includes two coils and a phase difference measurement system that detects the magnetic inductive phase shift (MIPS) value to reflect the tissue’s condition.,The hemorrhage model was established through the injection of autologous blood into the internal capsule of a rabbit’s brain.,Ischemia was induced in the brain of a rabbit by bilateral carotid artery occlusion.,Two types of animal models were measured with our device.,The MIPS value gradually decreased with increasing injected blood and increased with ischemia time.,The MIPS changes induced by the two types of strokes were exact opposites, and the absolute values of MIPS variation in the hemorrhagic and the ischemic groups were significantly larger than those of the normal control group (P < 0.05).,The tested technique can differentiate ischemic stroke from hemorrhagic stroke on rabbit brain in a non-invasive, continuous, and bulk monitoring manner by using a simple and inexpensive apparatus. | 1 |
Cardiomyopathies are an important cause of heart failure and sudden cardiac death.,Little is known about the role of rare genetic variants in inflammatory cardiomyopathy.,Chronic Chagas disease cardiomyopathy (CCC) is an inflammatory cardiomyopathy prevalent in Latin America, developing in 30% of the 6 million patients chronically infected by the protozoan Trypanosoma cruzi, while 60% remain free of heart disease (asymptomatic (ASY)).,The cytokine interferon-γ and mitochondrial dysfunction are known to play a major pathogenetic role.,Chagas disease provides a unique model to probe for genetic variants involved in inflammatory cardiomyopathy.,We used whole exome sequencing to study nuclear families containing multiple cases of Chagas disease.,We searched for rare pathogenic variants shared by all family members with CCC but absent in infected ASY siblings and in unrelated ASY.,We identified heterozygous, pathogenic variants linked to CCC in all tested families on 22 distinct genes, from which 20 were mitochondrial or inflammation-related - most of the latter involved in proinflammatory cytokine production.,Significantly, incubation with IFN-γ on a human cardiomyocyte line treated with an inhibitor of dihydroorotate dehydrogenase brequinar (enzyme showing a loss-of-function variant in one family) markedly reduced mitochondrial membrane potential (ΔψM), indicating mitochondrial dysfunction.,Mitochondrial dysfunction and inflammation may be genetically determined in CCC, driven by rare genetic variants.,We hypothesize that CCC-linked genetic variants increase mitochondrial susceptibility to IFN-γ-induced damage in the myocardium, leading to the cardiomyopathy phenotype in Chagas disease.,This mechanism may also be operative in other inflammatory cardiomyopathies.,The online version contains supplementary material available at 10.1007/s10875-021-01000-y. | DNA methylation analysis on global gene expression in myocardial samples from patients with end-stage chronic Chagas cardiomyopathy leads to the identification of novel potential disease pathways and therapeutic targets linked to electrical conduction or immune response modulation.,Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and affects 10 million people worldwide.,Approximately 12000 deaths attributable to Chagas disease occur annually due to chronic Chagas disease cardiomyopathy (CCC), an inflammatory cardiomyopathy presenting with heart failure and arrythmia; 30% of infected subjects develop CCC years after infection.,Genetic mechanisms play a role in differential progression to CCC, but little is known about the role of epigenetic modifications in pathological gene expression patterns in CCC patients’ myocardium.,DNA methylation is the most common modification in the mammalian genome.,We investigated the impact of genome-wide cardiac DNA methylation on global gene expression in myocardial samples from end-stage CCC patients, compared to control samples from organ donors.,In total, 4720 genes were differentially methylated between CCC patients and controls, of which 399 were also differentially expressed.,Several of them were related to heart function or to the immune response and had methylation sites in their promoter region.,Reporter gene and in silico transcription factor binding analyses indicated promoter methylation modified expression of key genes.,Among those, we found potassium channel genes KCNA4 and KCNIP4, involved in electrical conduction and arrythmia, SMOC2, involved in matrix remodeling, as well as enkephalin and RUNX3, potentially involved in the increased T-helper 1 cytokine-mediated inflammatory damage in heart.,Results support that DNA methylation plays a role in the regulation of expression of pathogenically relevant genes in CCC myocardium, and identify novel potential disease pathways and therapeutic targets in CCC. | 1 |
Ischemic heart disease (IHD) has several risk factors, among which diabetes mellitus represents one of the most important.,In diabetic patients, the pathophysiology of myocardial ischemia remains unclear yet: some have atherosclerotic plaque which obstructs coronary blood flow, others show myocardial ischemia due to coronary microvascular dysfunction in the absence of plaques in epicardial vessels.,In the cross-talk between myocardial metabolism and coronary blood flow (CBF), ion channels have a main role, and, in diabetic patients, they are involved in the pathophysiology of IHD.,The exposition to the different cardiovascular risk factors and the ischemic condition determine an imbalance of the redox state, defined as oxidative stress, which shows itself with oxidant accumulation and antioxidant deficiency.,In particular, several products of myocardial metabolism, belonging to oxidative stress, may influence ion channel function, altering their capacity to modulate CBF, in response to myocardial metabolism, and predisposing to myocardial ischemia.,For this reason, considering the role of oxidative and ion channels in the pathophysiology of myocardial ischemia, it is allowed to consider new therapeutic perspectives in the treatment of IHD. | Diabetes mellitus is one the strongest risk factors for cardiovascular disease and, in particular, for ischemic heart disease (IHD).,The pathophysiology of myocardial ischemia in diabetic patients is complex and not fully understood: some diabetic patients have mainly coronary stenosis obstructing blood flow to the myocardium; others present with coronary microvascular disease with an absence of plaques in the epicardial vessels.,Ion channels acting in the cross-talk between the myocardial energy state and coronary blood flow may play a role in the pathophysiology of IHD in diabetic patients.,In particular, some genetic variants for ATP-dependent potassium channels seem to be involved in the determinism of IHD. | 1 |
To explore mechanisms by which SGLT2 inhibitors protect diabetic hearts from heart failure, we examined the effect of empagliflozin (Empa) on the ultrastructure of cardiomyocytes in the noninfarcted region of the diabetic heart after myocardial infarction (MI).,OLETF, a rat model of type 2 diabetes, and its nondiabetic control, LETO, received a sham operation or left coronary artery ligation 12 h before tissue sampling.,Tissues were sampled from the posterior ventricle (i.e., the remote noninfarcted region in rats with MI).,The number of mitochondria was larger and small mitochondria were more prevalent in OLETF than in LETO.,Fis1 expression level was higher in OLETF than in LETO, while phospho‐Ser637‐Drp1, total Drp1, Mfn1/2, and OPA1 levels were comparable.,MI further reduced the size of mitochondria with increased Drp1‐Ser616 phosphorylation in OLETF.,The number of autophagic vacuoles was unchanged after MI in LETO but was decreased in OLETF.,Lipid droplets in cardiomyocytes and tissue triglycerides were increased in OLETF.,Empa administration (10 mg/kg per day) reduced blood glucose and triglycerides and paradoxically increased lipid droplets in cardiomyocytes in OLETF.,Empa suppressed Fis1 upregulation, increased Bnip3 expression, and prevented reduction in both mitochondrial size and autophagic vacuole number after MI in OLETF.,Together with the results of our parallel study showing upregulation of SOD2 and catalase by Empa, the results indicate that Empa normalizes the size and number of mitochondria in diabetic hearts and that diabetes‐induced excessive reduction in mitochondrial size after MI was prevented by Empa via suppression of ROS and restoration of autophagy. | Type 2 diabetes (T2D) is associated with generalized vascular dysfunction characterized by increases in large artery stiffness, endothelial dysfunction, and vascular smooth muscle dysfunction.,Sodium glucose cotransporter 2 inhibitors (SGLT2i) represent the most recently approved class of oral medications for the treatment of T2D, and have been shown to reduce cardiovascular and overall mortality.,Although it is currently unclear how SGLT2i decrease cardiovascular risk, an improvement in vascular function is one potential mechanism.,The aim of the current study was to examine if dapagliflozin, a widely prescribed STLT2i, improves generalized vascular dysfunction in type 2 diabetic mice.,In light of several studies demonstrating a bi-directional relation between orally ingested medications and the gut microbiota, a secondary aim was to determine the effects of dapagliflozin on the gut microbiota.,Male diabetic mice (Db, n = 24) and control littermates (Con; n = 23) were randomized to receive either a standard diet or a standard diet containing dapagliflozin (60 mg dapagliflozin/kg diet; 0.006%) for 8 weeks.,Arterial stiffness was assessed by aortic pulse wave velocity; endothelial function and vascular smooth muscle dysfunction were assessed by dilatory responses to acetylcholine and sodium nitroprusside, respectively.,Compared to untreated diabetic mice, diabetic mice treated with dapagliflozin displayed significantly lower arterial stiffness (Db = 469 cm/s vs.,Db + dapa = 435 cm/s, p < 0.05), and improvements in endothelial dysfunction (area under the curve [AUC] Db = 57.2 vs.,Db + dapa = 117.0, p < 0.05) and vascular smooth muscle dysfunction (AUC, Db = 201.7 vs.,Db + dapa = 285.5, p < 0.05).,These vascular improvements were accompanied by reductions in hyperglycemia and circulating markers of inflammation.,The microbiota of Db and Con mice were distinctly different, and dapagliflozin treatment was associated with minor alterations in gut microbiota composition, particularly in Db mice, although these effects did not conclusively mediate the improvements in vascular function.,Dapagliflozin treatment improves arterial stiffness, endothelial dysfunction and vascular smooth muscle dysfunction, and subtly alters microbiota composition in type 2 diabetic mice.,Collectively, the improvements in generalized vascular function may represent an important mechanism underlying the cardiovascular benefits of SGLT2i treatment. | 1 |
Coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become pandemic, with substantial mortality.,To evaluate the pathologic changes of organ systems and the clinicopathologic basis for severe and fatal outcomes.,Prospective autopsy study.,Single pathology department.,11 deceased patients with COVID-19 (10 of whom were selected at random for autopsy).,Systematic macroscopic, histopathologic, and viral analysis (SARS-CoV-2 on real-time polymerase chain reaction assay), with correlation of pathologic and clinical features, including comorbidities, comedication, and laboratory values.,Patients' age ranged from 66 to 91 years (mean, 80.5 years; 8 men, 3 women).,Ten of the 11 patients received prophylactic anticoagulant therapy; venous thromboembolism was not clinically suspected antemortem in any of the patients.,Both lungs showed various stages of diffuse alveolar damage (DAD), including edema, hyaline membranes, and proliferation of pneumocytes and fibroblasts.,Thrombosis of small and mid-sized pulmonary arteries was found in various degrees in all 11 patients and was associated with infarction in 8 patients and bronchopneumonia in 6 patients.,Kupffer cell proliferation was seen in all patients, and chronic hepatic congestion in 8 patients.,Other changes in the liver included hepatic steatosis, portal fibrosis, lymphocytic infiltrates and ductular proliferation, lobular cholestasis, and acute liver cell necrosis, together with central vein thrombosis.,Additional frequent findings included renal proximal tubular injury, focal pancreatitis, adrenocortical hyperplasia, and lymphocyte depletion of spleen and lymph nodes.,Viral RNA was detectable in pharyngeal, bronchial, and colonic mucosa but not bile.,The sample was small.,COVID-19 predominantly involves the lungs, causing DAD and leading to acute respiratory insufficiency.,Death may be caused by the thrombosis observed in segmental and subsegmental pulmonary arterial vessels despite the use of prophylactic anticoagulation.,Studies are needed to further understand the thrombotic complications of COVID-19, together with the roles for strict thrombosis prophylaxis, laboratory, and imaging studies and early anticoagulant therapy for suspected pulmonary arterial thrombosis or thromboembolism.,None.,The clinicopathological basis for morbidity and mortality with SARS-CoV-2 infection is not well understood.,This study reports the clinical and autopsy findings of patients who died of COVID-19. | The Bergamo province, which is extensively affected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic, is a natural observatory of virus manifestations in the general population.,In the past month we recorded an outbreak of Kawasaki disease; we aimed to evaluate incidence and features of patients with Kawasaki-like disease diagnosed during the SARS-CoV-2 epidemic.,All patients diagnosed with a Kawasaki-like disease at our centre in the past 5 years were divided according to symptomatic presentation before (group 1) or after (group 2) the beginning of the SARS-CoV-2 epidemic.,Kawasaki- like presentations were managed as Kawasaki disease according to the American Heart Association indications.,Kawasaki disease shock syndrome (KDSS) was defined by presence of circulatory dysfunction, and macrophage activation syndrome (MAS) by the Paediatric Rheumatology International Trials Organisation criteria.,Current or previous infection was sought by reverse-transcriptase quantitative PCR in nasopharyngeal and oropharyngeal swabs, and by serological qualitative test detecting SARS-CoV-2 IgM and IgG, respectively.,Group 1 comprised 19 patients (seven boys, 12 girls; aged 3·0 years [SD 2·5]) diagnosed between Jan 1, 2015, and Feb 17, 2020.,Group 2 included ten patients (seven boys, three girls; aged 7·5 years [SD 3·5]) diagnosed between Feb 18 and April 20, 2020; eight of ten were positive for IgG or IgM, or both.,The two groups differed in disease incidence (group 1 vs group 2, 0·3 vs ten per month), mean age (3·0 vs 7·5 years), cardiac involvement (two of 19 vs six of ten), KDSS (zero of 19 vs five of ten), MAS (zero of 19 vs five of ten), and need for adjunctive steroid treatment (three of 19 vs eight of ten; all p<0·01).,In the past month we found a 30-fold increased incidence of Kawasaki-like disease.,Children diagnosed after the SARS-CoV-2 epidemic began showed evidence of immune response to the virus, were older, had a higher rate of cardiac involvement, and features of MAS.,The SARS-CoV-2 epidemic was associated with high incidence of a severe form of Kawasaki disease.,A similar outbreak of Kawasaki-like disease is expected in countries involved in the SARS-CoV-2 epidemic.,None. | 1 |
Patients with coronavirus disease 2019 (COVID-19) have elevated D-dimer levels.,Early reports describe high venous thromboembolism (VTE) and disseminated intravascular coagulation (DIC) rates, but data are limited.,This multicenter retrospective study describes the rate and severity of hemostatic and thrombotic complications of 400 hospital-admitted COVID-19 patients (144 critically ill) primarily receiving standard-dose prophylactic anticoagulation.,Coagulation and inflammatory parameters were compared between patients with and without coagulation-associated complications.,Multivariable logistic models examined the utility of these markers in predicting coagulation-associated complications, critical illness, and death.,The radiographically confirmed VTE rate was 4.8% (95% confidence interval [CI], 2.9-7.3), and the overall thrombotic complication rate was 9.5% (95% CI, 6.8-12.8).,The overall and major bleeding rates were 4.8% (95% CI, 2.9-7.3) and 2.3% (95% CI, 1.0-4.2), respectively.,In the critically ill, radiographically confirmed VTE and major bleeding rates were 7.6% (95% CI, 3.9-13.3) and 5.6% (95% CI, 2.4-10.7), respectively.,Elevated D-dimer at initial presentation was predictive of coagulation-associated complications during hospitalization (D-dimer >2500 ng/mL, adjusted odds ratio [OR] for thrombosis, 6.79 [95% CI, 2.39-19.30]; adjusted OR for bleeding, 3.56 [95% CI, 1.01-12.66]), critical illness, and death.,Additional markers at initial presentation predictive of thrombosis during hospitalization included platelet count >450 × 109/L (adjusted OR, 3.56 [95% CI, 1.27-9.97]), C-reactive protein (CRP) >100 mg/L (adjusted OR, 2.71 [95% CI, 1.26-5.86]), and erythrocyte sedimentation rate (ESR) >40 mm/h (adjusted OR, 2.64 [95% CI, 1.07-6.51]).,ESR, CRP, fibrinogen, ferritin, and procalcitonin were higher in patients with thrombotic complications than in those without.,DIC, clinically relevant thrombocytopenia, and reduced fibrinogen were rare and were associated with significant bleeding manifestations.,Given the observed bleeding rates, randomized trials are needed to determine any potential benefit of intensified anticoagulant prophylaxis in COVID-19 patients.,•In addition to thrombotic complications, bleeding is a significant cause of morbidity in patients with COVID-19.,•D-dimer elevation at admission was predictive of bleeding, thrombosis, critical illness, and death in patients with COVID-19.,In addition to thrombotic complications, bleeding is a significant cause of morbidity in patients with COVID-19.,D-dimer elevation at admission was predictive of bleeding, thrombosis, critical illness, and death in patients with COVID-19. | A remarkably high incidence of venous thromboembolism (VTE) has been reported among critically ill patients with COVID‐19 assisted in the intensive care unit (ICU).,However, VTE burden among non‐ICU patients hospitalized for COVID‐19 that receive guideline‐recommended thromboprophylaxis is unknown.,To determine the incidence of VTE among non‐ICU patients hospitalized for COVID‐19 that receive pharmacological thromboprophylaxis.,We performed a systematic screening for the diagnosis of deep vein thrombosis (DVT) by lower limb vein compression ultrasonography (CUS) in consecutive non‐ICU patients hospitalized for COVID‐19, independent of the presence of signs or symptoms of DVT.,All patients were receiving pharmacological thromboprophylaxis with either enoxaparin or fondaparinux.,The population that we screened consisted of 84 consecutive patients, with a mean age of 67.6 ± 13.5 years and a mean Padua Prediction Score of 5.1 ± 1.6.,Seventy‐two patients (85.7%) had respiratory insufficiency, required oxygen supplementation, and had reduced mobility or were bedridden.,In this cohort, we found 10 cases of DVT, with an incidence of 11.9% (95% confidence interval [CI] 4.98‐18.82).,Of these, 2 were proximal DVT (incidence rate 2.4%, 95% CI −0.87‐5.67) and 8 were distal DVT (incidence rate 9.5%, 95% CI 3.23‐5.77).,Significant differences between subjects with and without DVT were D‐dimer > 3000 µg/L (P < .05), current or previous cancer (P < .05), and need of high flow nasal oxygen therapy and/or non‐invasive ventilation (P < .01).,DVT may occur among non‐ICU patients hospitalized for COVID‐19, despite guideline‐recommended thromboprophylaxis. | 1 |
Coronavirus disease 2019 (COVID-19) is associated with abnormal inflammatory and coagulation markers, potentially mediating thrombotic events.,Our objective was to investigate the incidence, time course, laboratory features, and in-hospital outcomes of COVID-19 patients with suspected venous thromboembolism (VTE).,A retrospective observational cohort study was conducted of patients hospitalized with COVID-19 who had undergone ultrasound imaging for suspected VTE from March 13 to May 18, 2020.,The medical records of the included patients were reviewed for D-dimer, fibrinogen, prothrombin time, partial thromboplastin time, platelet count, C-reactive protein (CRP), and high-sensitivity troponin T at admission and at up to seven time points before and after ultrasound examination.,The clinical outcomes included superficial venous thrombosis, deep vein thrombosis, pulmonary embolism, intubation, and death.,Mixed effects logistic, linear, and Cox proportional hazards methods were used to evaluate the relationships between the laboratory markers and VTE and other in-hospital outcomes.,Of 138 patients who had undergone imaging studies, 44 (31.9%) had evidence of VTE.,On univariable analysis, an elevated admission CRP (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.01-1.09; P = .02; per 10-U increase in CRP), platelet count (OR, 1.48; 95% CI, 1.04-2.12; P = .03; per 1000-U increase in platelet count), and male sex (OR, 2.64; 95% CI, 1.19-5.84; P = .02), were associated with VTE.,However only male sex remained significant on multivariable analysis (OR, 2.37; 95% CI, 1.01-5.56; P = .048).,The independent predictors of death included older age (hazard ratio [HR], 1.04; 95% CI, 1.00-1.07; P = .04), active malignancy (HR, 4.39; 95% CI, 1.39-13.91; P = .01), elevated admission D-dimer (HR, 1.016; 95% CI, 1.003-1.029; P = .02), and evidence of disseminated intravascular coagulation (HR, 4.81; 95% CI, 1.76-13.10; P = .002).,Male sex, elevated CRP, and elevated platelet count at admission were associated with VTE on univariable analysis.,However, only male sex remained significant on multivariable analysis.,Older age, active malignancy, disseminated intravascular coagulation, and elevated D-dimer at admission were independently associated with death for patients hospitalized with COVID-19. | The objective of this study was to investigate the clinical usefulness of d-dimer in excluding a diagnosis of deep vein thrombosis (DVT) in patients with coronavirus disease (COVID-19) infection, potentially limiting the need for venous duplex ultrasound examination.,We retrospectively reviewed consecutive patients admitted to our institution with confirmed COVID-19 status by polymerase chain reaction between March 1, 2020, and May 13, 2020, and selected those who underwent both d-dimer and venous duplex ultrasound examination.,This cohort was divided into two groups, those with and without DVT based on duplex ultrasound examination.,These groups were then compared to determine the value of d-dimer in establishing this diagnosis.,A total of 1170 patients were admitted with COVID-19, of which 158 were selected for this study.,Of the 158, there were 52 patients with DVT and 106 without DVT.,There were no differences in sex, age, race, or ethnicity between groups.,Diabetes and routine hemodialysis were less commonly seen in the group with DVT.,More than 90% of patients in both groups received prophylactic anticoagulation, but the use of low-molecular-weight heparin or subcutaneous heparin prophylaxis was not predictive of DVT.,All patients had elevated acute-phase d-dimer levels using conventional criteria, and 154 of the 158 (97.5%) had elevated levels with age-adjusted criteria (mean d-dimer 16,163 ± 5395 ng/mL).,Those with DVT had higher acute-phase d-dimer levels than those without DVT (median, 13,602 [interquartile range, 6616-36,543 ng/mL] vs 2880 [interquartile range, 1030-9126 ng/mL], P < .001).,An optimal d-dimer cutoff of 6494 ng/mL was determined to differentiate those with and without DVT (sensitivity 80.8%, specificity 68.9%, negative predictive value 88.0%).,Wells DVT criteria was not found to be a significant predictor of DVT.,Elevated d-dimer as defined by our optimal metric was a statistically significant predictor of DVT in both univariate and multivariable analyses when adjusting for other factors (odds ratio, 6.12; 95% confidence interval, 2.79-13.39; P < .001).,d-dimer levels are uniformly elevated in patients with COVID-19.,Although standard predictive criteria failed to predict DVT, our analysis showed a d-dimer of less than 6494 ng/mL may exclude DVT, potentially limiting the need for venous duplex ultrasound examination. | 1 |
Delayed admission of myocardial infarction (MI) patients is an important prognostic factor.,In the present nationwide registry (TURKMI-2), we evaluated the treatment delays and outcomes of patients with acute MI during the Covid-19 pandemic and compaired with a recent pre-pandemic registry (TURKMI-1).,The pandemic and pre-pandemic studies were conducted prospectively as 15-day snapshot registries in the same 48 centers.,The inclusion criteria for both registries were aged ≥18 years and a final diagnosis of acute MI (AMI) with positive troponin levels.,The only difference between the 2 registries was that the pre-pandemic (TURKMI-1) registry (n=1872) included only patients presenting within the first 48 hours after symptom-onset.,TURKMI-2 enrolled all consecutive patients (n=1113) presenting with AMI during the pandemic period.,A comparison of the patients with acute MI presenting within the 48-hour of symptom-onset in the pre-pandemic and pandemic registries revealed an overall 47.1% decrease in acute MI admissions during the pandemic.,Median time from symptom-onset to hospital-arrival increased from 150 min to 185 min in patients with ST elevation MI (STEMI) and 295 min to 419 min in patients presenting with non-STEMI (NSTEMI) (p-values <0.001).,Door-to-balloon time was similar in the two periods (37 vs. 40 min, p=0.448).,In the pandemic period, percutaneous coronary intervention (PCI) decreased, especially in the NSTEMI group (60.3% vs.,47.4% in NSTEMI, p<0.001; 94.8% vs.,91.1% in STEMI, p=0.013) but the decrease was not significant in STEMI patients admitted within 12 hours of symptom-onset (94.9% vs.,92.1%; p=0.075).,In-hospital major adverse cardiac events (MACE) were significantly increased during the pandemic period [4.8% vs.,8.9%; p<0.001; age- and sex-adjusted Odds ratio (95% CI) 1.96 (1.20-3.22) for NSTEMI, p=0.007; and 2.08 (1.38-3.13) for STEMI, p<0.001].,The present comparison of 2 nationwide registries showed a significant delay in treatment of patients presenting with acute MI during the COVID-19 pandemic.,Although PCI was performed in a timely fashion, an increase in treatment delay might be responsible for the increased risk of MACE.,Public education and establishing COVID-free hospitals are necessary to overcome patients’ fear of using healthcare services and mitigate the potential complications of AMI during the pandemic. | To assess the impact of the lockdown due to coronavirus disease 2019 (COVID-19) on key quality indicators for the treatment of ST-segment elevation myocardial infarction (STEMI) patients.,Data were obtained from 41 hospitals participating in the prospective Feedback Intervention and Treatment Times in ST-Elevation Myocardial Infarction (FITT-STEMI) study, including 15,800 patients treated for acute STEMI from January 2017 to the end of March 2020.,There was a 12.6% decrease in the total number of STEMI patients treated at the peak of the pandemic in March 2020 as compared to the mean number treated in the March months of the preceding years.,This was accompanied by a significant difference among the modes of admission to hospitals (p = 0.017) with a particular decline in intra-hospital infarctions and transfer patients from other hospitals, while the proportion of patients transported by emergency medical service (EMS) remained stable.,In EMS-transported patients, predefined quality indicators, such as percentages of pre-hospital ECGs (both 97%, 95% CI = − 2.2-2.7, p = 0.846), direct transports from the scene to the catheterization laboratory bypassing the emergency department (68% vs.,66%, 95% CI = − 4.9-7.9, p = 0.641), and contact-to-balloon-times of less than or equal to 90 min (58.3% vs.,57.8%, 95%CI = − 6.2-7.2, p = 0.879) were not significantly altered during the COVID-19 crisis, as was in-hospital mortality (9.2% vs.,8.5%, 95% CI = − 3.2-4.5, p = 0.739).,Clinically important indicators for STEMI management were unaffected at the peak of COVID-19, suggesting that the pre-existing logistic structure in the regional STEMI networks preserved high-quality standards even when challenged by a threatening pandemic.,NCT00794001,The online version of this article (10.1007/s00392-020-01703-z) contains supplementary material, which is available to authorized users. | 1 |
Background: Cardiac damage is frequently referred to in patients with SARS-CoV-2, is usually diagnosed by enzyme elevations, and is generally thought to be due to underlying coronary artery disease.,There are references to cardiomyopathies accompanying coronavirus, but there has been no histologic confirmation.,Case report: A previously healthy 17 year male old presented in full cardiac arrest to the emergency department after a 2 day history of headache, dizziness, nausea and vomiting.,Autopsy demonstrated an enlarged flabby heart with eosinophilic myocarditis.,There was no interstitial pneumonia or diffuse alveolar damage.,Postmortem nasopharyngeal swabs detected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) known to cause coronavirus disease 2019 (COVID-19).,No other cause for the eosinophilic myocarditis was elucidated.,Conclusion: Like other viruses, SARS-CoV-2 may be associated with fulminant myocarditis. | This case series study evaluates the association of underlying cardiovascular disease and myocardial injury on fatal outcomes in patients with coronavirus disease 2019 (COVID-19).,What is the impact of underlying cardiovascular disease (CVD) and myocardial injury on fatal outcomes in patients with coronavirus disease 2019 (COVID-19)?,In this case series study of 187 patients with COVID-19, 27.8% of patients had myocardial injury, which resulted in cardiac dysfunction and arrhythmias.,Myocardial injury has a significant association with fatal outcome of COVID-19, while the prognosis of patients with underlying CVD but without myocardial injury were relatively favorable.,It is reasonable to triage patients with COVID-19 according to the presence of underlying CVD and evidence of myocardial injury for prioritized treatment and even more aggressive strategies.,Increasing numbers of confirmed cases and mortality rates of coronavirus disease 2019 (COVID-19) are occurring in several countries and continents.,Information regarding the impact of cardiovascular complication on fatal outcome is scarce.,To evaluate the association of underlying cardiovascular disease (CVD) and myocardial injury with fatal outcomes in patients with COVID-19.,This retrospective single-center case series analyzed patients with COVID-19 at the Seventh Hospital of Wuhan City, China, from January 23, 2020, to February 23, 2020.,Analysis began February 25, 2020.,Demographic data, laboratory findings, comorbidities, and treatments were collected and analyzed in patients with and without elevation of troponin T (TnT) levels.,Among 187 patients with confirmed COVID-19, 144 patients (77%) were discharged and 43 patients (23%) died.,The mean (SD) age was 58.50 (14.66) years.,Overall, 66 (35.3%) had underlying CVD including hypertension, coronary heart disease, and cardiomyopathy, and 52 (27.8%) exhibited myocardial injury as indicated by elevated TnT levels.,The mortality during hospitalization was 7.62% (8 of 105) for patients without underlying CVD and normal TnT levels, 13.33% (4 of 30) for those with underlying CVD and normal TnT levels, 37.50% (6 of 16) for those without underlying CVD but elevated TnT levels, and 69.44% (25 of 36) for those with underlying CVD and elevated TnTs.,Patients with underlying CVD were more likely to exhibit elevation of TnT levels compared with the patients without CVD (36 [54.5%] vs 16 [13.2%]).,Plasma TnT levels demonstrated a high and significantly positive linear correlation with plasma high-sensitivity C-reactive protein levels (β = 0.530, P < .001) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (β = 0.613, P < .001).,Plasma TnT and NT-proBNP levels during hospitalization (median [interquartile range (IQR)], 0.307 [0.094-0.600]; 1902.00 [728.35-8100.00]) and impending death (median [IQR], 0.141 [0.058-0.860]; 5375 [1179.50-25695.25]) increased significantly compared with admission values (median [IQR], 0.0355 [0.015-0.102]; 796.90 [401.93-1742.25]) in patients who died (P = .001; P < .001), while no significant dynamic changes of TnT (median [IQR], 0.010 [0.007-0.019]; 0.013 [0.007-0.022]; 0.011 [0.007-0.016]) and NT-proBNP (median [IQR], 352.20 [174.70-636.70]; 433.80 [155.80-1272.60]; 145.40 [63.4-526.50]) was observed in survivors (P = .96; P = .16).,During hospitalization, patients with elevated TnT levels had more frequent malignant arrhythmias, and the use of glucocorticoid therapy (37 [71.2%] vs 69 [51.1%]) and mechanical ventilation (31 [59.6%] vs 14 [10.4%]) were higher compared with patients with normal TnT levels.,The mortality rates of patients with and without use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers was 36.8% (7 of 19) and 21.4% (36 of 168) (P = .13).,Myocardial injury is significantly associated with fatal outcome of COVID-19, while the prognosis of patients with underlying CVD but without myocardial injury is relatively favorable.,Myocardial injury is associated with cardiac dysfunction and arrhythmias.,Inflammation may be a potential mechanism for myocardial injury.,Aggressive treatment may be considered for patients at high risk of myocardial injury. | 1 |
Supplemental Digital Content is available in the text.,Pulmonary thrombosis is observed in severe acute respiratory syndrome coronavirus 2 pneumonia.,Aim was to investigate whether subpopulations of platelets were programmed to procoagulant and inflammatory activities in coronavirus disease 2019 (COVID-19) patients with pneumonia, without comorbidities predisposing to thromboembolism.,Overall, 37 patients and 28 healthy subjects were studied.,Platelet-leukocyte aggregates, platelet-derived microvesicles, the expression of P-selectin, and active fibrinogen receptor on platelets were quantified by flow cytometry.,The profile of 45 cytokines, chemokines, and growth factors released by platelets was defined by immunoassay.,The contribution of platelets to coagulation factor activity was selectively measured.,Numerous platelet-monocyte (mean±SE, 67.9±4.9%, n=17 versus 19.4±3.0%, n=22; P<0.0001) and platelet-granulocyte conjugates (34.2±4.04% versus 8.6±0.7%; P<0.0001) were detected in patients.,Resting patient platelets had similar levels of P-selectin (10.9±2.6%, n=12) to collagen-activated control platelets (8.7±1.5%), which was not further increased by collagen activation on patient platelets (12.4±2.5%, P=nonsignificant).,The agonist-stimulated expression of the active fibrinogen receptor was reduced by 60% in patients (P<0.0001 versus controls).,Cytokines (IL [interleukin]-1α, IL-1β, IL-1RA, IL-4, IL-10, IL-13, IL, 17, IL-27, IFN [interferon]-α, and IFN-γ), chemokines (MCP-1/CCL2 [monocyte chemoattractant protein 1]), and growth factors (VEGF [vascular endothelial growth factor]-A/D) were released in significantly larger amounts upon stimulation of COVID-19 platelets.,Platelets contributed to increased fibrinogen, VWF (von Willebrand factor), and factor XII in COVID-19 patients.,Patients (28.5±0.7 s, n=32), unlike controls (31.6±0.5 s, n=28; P<0.001), showed accelerated factor XII-dependent coagulation.,Platelets in COVID-19 pneumonia are primed to spread proinflammatory and procoagulant activities in systemic circulation. | Critically ill patients diagnosed with COVID-19 may develop a pro-thrombotic state that places them at a dramatically increased lethal risk.,Although platelet activation is critical for thrombosis and is responsible for the thrombotic events and cardiovascular complications, the role of platelets in the pathogenesis of COVID-19 remains unclear.,Using platelets from healthy volunteers, non-COVID-19 and COVID-19 patients, as well as wild-type and hACE2 transgenic mice, we evaluated the changes in platelet and coagulation parameters in COVID-19 patients.,We investigated ACE2 expression and direct effect of SARS-CoV-2 virus on platelets by RT-PCR, flow cytometry, Western blot, immunofluorescence, and platelet functional studies in vitro, FeCl3-induced thrombus formation in vivo, and thrombus formation under flow conditions ex vivo.,We demonstrated that COVID-19 patients present with increased mean platelet volume (MPV) and platelet hyperactivity, which correlated with a decrease in overall platelet count.,Detectable SARS-CoV-2 RNA in the blood stream was associated with platelet hyperactivity in critically ill patients.,Platelets expressed ACE2, a host cell receptor for SARS-CoV-2, and TMPRSS2, a serine protease for Spike protein priming.,SARS-CoV-2 and its Spike protein directly enhanced platelet activation such as platelet aggregation, PAC-1 binding, CD62P expression, α granule secretion, dense granule release, platelet spreading, and clot retraction in vitro, and thereby Spike protein enhanced thrombosis formation in wild-type mice transfused with hACE2 transgenic platelets, but this was not observed in animals transfused with wild-type platelets in vivo.,Further, we provided evidence suggesting that the MAPK pathway, downstream of ACE2, mediates the potentiating role of SARS-CoV-2 on platelet activation, and that platelet ACE2 expression decreases following SARS-COV-2 stimulation.,SARS-CoV-2 and its Spike protein directly stimulated platelets to facilitate the release of coagulation factors, the secretion of inflammatory factors, and the formation of leukocyte-platelet aggregates.,Recombinant human ACE2 protein and anti-Spike monoclonal antibody could inhibit SARS-CoV-2 Spike protein-induced platelet activation.,Our findings uncovered a novel function of SARS-CoV-2 on platelet activation via binding of Spike to ACE2.,SARS-CoV-2-induced platelet activation may participate in thrombus formation and inflammatory responses in COVID-19 patients. | 1 |
Clinical and laboratory data on patients with coronavirus disease 2019 (COVID‐19) in Beijing, China, remain extremely limited.,In this study, we summarized the clinical characteristics of patients with COVID‐19 from a designated hospital in Beijing.,In total, 55 patients with laboratory‐confirmed SARS‐CoV‐2 infection in Beijing 302 Hospital were enrolled in this study.,Demographic data, symptoms, comorbidities, laboratory values, treatments, and clinical outcomes were all collected and retrospectively analyzed.,A total of 15 (27.3%) patients had severe symptoms, the mean age was 44.0 years (interquartile range [IQR], 34.0‐56.0), and the median incubation period was 7.5 days (IQR, 5.0‐11.8).,A total of 26 (47.3%) patients had exposure history in Wuhan of less than 2 weeks, whereas 20 (36.4%) patients were associated with familial clusters.,Also, eighteen (32.7%) patients had underlying comorbidities including hypertension.,The most common symptom of illness was fever (45; 81.8%); 51 (92.7%) patients had abnormal findings on chest computed tomography.,Laboratory findings showed that neutrophil count, percentage of lymphocyte, percentage of eosinophil, eosinophil count, erythrocyte sedimentation rate, albumin, and serum ferritin are potential risk factors for patients with a poor prognosis.,A total of 26 patients (47.3%) were still hospitalized, whereas 29 (52.7%) patients had been discharged.,Compared with patients in Wuhan, China, the symptoms of patients in Beijing are relatively mild.,Older age, more comorbidities, and more abnormal prominent laboratory markers were associated with a severe condition.,On the basis of antiviral drugs, it is observed that antibiotics treatment, appropriate dosage of corticosteroid, and gamma globulin therapy significantly improve patients' outcomes.,Early identification and timely medical treatment are important to reduce the severity of patients with COVID‐19. | The outbreak of the novel coronavirus in China (SARS‐CoV‐2) that began in December 2019 presents a significant and urgent threat to global health.,This study was conducted to provide the international community with a deeper understanding of this new infectious disease.,Epidemiological, clinical features, laboratory findings, radiological characteristics, treatment, and clinical outcomes of 135 patients in northeast Chongqing were collected and analyzed in this study.,A total of 135 hospitalized patients with COVID‐19 were enrolled.,The median age was 47 years (interquartile range, 36‐55), and there was no significant gender difference (53.3% men).,The majority of patients had contact with people from the Wuhan area.,Forty‐three (31.9%) patients had underlying disease, primarily hypertension (13 [9.6%]), diabetes (12 [8.9%]), cardiovascular disease (7 [5.2%]), and malignancy (4 [3.0%]).,Common symptoms included fever (120 [88.9%]), cough (102 [76.5%]), and fatigue (44 [32.5%]).,Chest computed tomography scans showed bilateral patchy shadows or ground glass opacity in the lungs of all the patients.,All patients received antiviral therapy (135 [100%]) (Kaletra and interferon were both used), antibacterial therapy (59 [43.7%]), and corticosteroids (36 [26.7%]).,In addition, many patients received traditional Chinese medicine (TCM) (124 [91.8%]).,It is suggested that patients should receive Kaletra early and should be treated by a combination of Western and Chinese medicines.,Compared to the mild cases, the severe ones had lower lymphocyte counts and higher plasma levels of Pt, APTT, d‐dimer, lactate dehydrogenase, PCT, ALB, C‐reactive protein, and aspartate aminotransferase.,This study demonstrates the clinic features and therapies of 135 COVID‐19 patients.,Kaletra and TCM played an important role in the treatment of the viral pneumonia.,Further studies are required to explore the role of Kaletra and TCM in the treatment of COVID‐19.,83.7% of the patients had contact history in Wuhan or had been to Wuhan or had contact with people from Wuhan.Common symptoms included fever, cough, and fatigue.,Other symptoms include myalgia, fatigue, dyspnea, anorexia, etc.Common complications of the patients include acute respiratory distress syndrome, acute cardiac injury, acute kidney injury, secondary infection and shock.,ICU patients were more likely to have these complications than non‐ICU patients.Compared with non‐ICU patients, ICU patients had lower lymphocyte count, and higher plasma levels of the Pt, APTT, D‐dimer, LDH, PCT, ALB, CRP, AST.All patients received antiviral therapy (kaletra or interferon), antibacterial therapy and corticosteroid and many received traditional chinese medicine.,It was suggested that patients should use kaletra early.,83.7% of the patients had contact history in Wuhan or had been to Wuhan or had contact with people from Wuhan.,Common symptoms included fever, cough, and fatigue.,Other symptoms include myalgia, fatigue, dyspnea, anorexia, etc.,Common complications of the patients include acute respiratory distress syndrome, acute cardiac injury, acute kidney injury, secondary infection and shock.,ICU patients were more likely to have these complications than non‐ICU patients.,Compared with non‐ICU patients, ICU patients had lower lymphocyte count, and higher plasma levels of the Pt, APTT, D‐dimer, LDH, PCT, ALB, CRP, AST.,All patients received antiviral therapy (kaletra or interferon), antibacterial therapy and corticosteroid and many received traditional chinese medicine.,It was suggested that patients should use kaletra early. | 1 |
To present a single-centre experience on CT pulmonary angiography (CTPA) for the assessment of hospitalised COVID-19 patients with moderate-to-high risk of pulmonary thromboembolism (PTE).,We analysed consecutive COVID-19 patients (RT-PCR confirmed) undergoing CTPA in March 2020 for PTE clinical suspicion.,Clinical data were retrieved.,Two experienced radiologists reviewed CTPAs to assess pulmonary parenchyma and vascular findings.,Among 34 patients who underwent CTPA, 26 had PTE (76%, 20 males, median age 61 years, interquartile range 54-70), 20/26 (77%) with comorbidities (mainly hypertension, 44%), and 8 (31%) subsequently dying.,Eight PTE patients were under thromboprophylaxis with low-molecular-weight heparin, four PTE patients had lower-limbs deep vein thrombosis at ultrasound examination (performed in 33/34 patients).,Bilateral PTE characterised 19/26 cases, with main branches involved in 10/26 cases.,Twelve patients had a parenchymal involvement >75%, the predominant pneumonia pattern being consolidation in 10/26 patients, ground glass opacities in 9/26, crazy paving in 5/26, and both ground glass opacities and consolidation in 2/26.,COVID-19 patients are prone to PTE.,PTE, potentially attributable to an underlying thrombophilic status, may be more frequent than expected in COVID-19 patients.,Extension of prophylaxis and adaptation of diagnostic criteria should be considered. | Unlabelled Image,•An association between COVID-19 and venous thromboembolism (VTE) is now recognized.,•The prevalence of VTE is high in COVID-19 patients hospitalized in standard care units.,•The prevalence of VTE is high even though thromboprophylaxis and in patients estimated at low risk.,•A high index of suspicion for VTE is crucial in patients with SARS-CoV-2 infection.,An association between COVID-19 and venous thromboembolism (VTE) is now recognized.,The prevalence of VTE is high in COVID-19 patients hospitalized in standard care units.,The prevalence of VTE is high even though thromboprophylaxis and in patients estimated at low risk.,A high index of suspicion for VTE is crucial in patients with SARS-CoV-2 infection. | 1 |
To describe the place and causes of acute cardiovascular death during the COVID-19 pandemic.,Retrospective cohort of adult (age ≥18 years) acute cardiovascular deaths (n=5 87 225) in England and Wales, from 1 January 2014 to 30 June 2020.,The exposure was the COVID-19 pandemic (from onset of the first COVID-19 death in England, 2 March 2020).,The main outcome was acute cardiovascular events directly contributing to death.,After 2 March 2020, there were 28 969 acute cardiovascular deaths of which 5.1% related to COVID-19, and an excess acute cardiovascular mortality of 2085 (+8%).,Deaths in the community accounted for nearly half of all deaths during this period.,Death at home had the greatest excess acute cardiovascular deaths (2279, +35%), followed by deaths at care homes and hospices (1095, +32%) and in hospital (50, +0%).,The most frequent cause of acute cardiovascular death during this period was stroke (10 318, 35.6%), followed by acute coronary syndrome (ACS) (7 098, 24.5%), heart failure (6 770, 23.4%), pulmonary embolism (2 689, 9.3%) and cardiac arrest (1 328, 4.6%).,The greatest cause of excess cardiovascular death in care homes and hospices was stroke (715, +39%), compared with ACS (768, +41%) at home and cardiogenic shock (55, +15%) in hospital.,The COVID-19 pandemic has resulted in an inflation in acute cardiovascular deaths, nearly half of which occurred in the community and most did not relate to COVID-19 infection suggesting there were delays to seeking help or likely the result of undiagnosed COVID-19. | Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).,Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described.,In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020.,Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors.,We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death.,191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients).,Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03-1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61-12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64-128·55; p=0·0033) on admission.,Median duration of viral shedding was 20·0 days (IQR 17·0-24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors.,The longest observed duration of viral shedding in survivors was 37 days.,The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage.,Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future.,Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development. | 1 |
Inflammation is an independent causal risk factor for atherosclerotic cardiovascular diseases (ASCVDs).,However, whether hsCRP (high‐sensitivity C‐reactive protein) is prognostic across various levels of atherogenic lipid measures such as low‐density lipoprotein cholesterol, non-high‐density lipoprotein cholesterol, apolipoprotein B and total cholesterol/high‐density lipoprotein cholesterol in primary prevention is unknown.,We studied 9748 ARIC (Atherosclerosis Risk in Communities) study participants who were free of ASCVD at baseline (visit 4, 1996-1998) and had measurements of lipids, apolipoprotein B, and hsCRP.,We used multivariable adjusted Cox models to estimate the risk of incident ASCVD events associated with hsCRP levels (less than/greater than or equal to median) in individuals where triple lipid measures combined (low‐density lipoprotein cholesterol + non-high‐density lipoprotein cholesterol + apolipoprotein B) or quadruple measures combined [triple + total cholesterol/high‐density lipoprotein cholesterol] were less than versus greater than or equal to median cut points.,Mean age of participants was 62.6±5.6 years; 59% women, 22% black.,There were 1574 ASCVD events over median (interquartile range) follow‐up of 18.4 (12.8-19.5) years, and discordance between hsCRP and lipid measures was prevalent in 50% of the population. hsCRP greater than or equal to median (2.4 mg/L), compared with less than median, was associated with an increased risk of ASCVD in individuals with less than median levels of the triple (adjusted hazard ratio, 1.33; 95% CI, 1.09-1.60) and quadruple (adjusted hazard ratio,1.47; 95% CI, 1.18-1.85) lipid measures.,Such increased risk was consistent among individuals with low (<7.5%) or high (≥7.5%) estimated risk by the pooled cohort equation.,There were no interactions by sex, diabetes mellitus, or statin use.,Our findings suggest that inflammation is independently associated with ASCVD regardless of atherogenic lipid levels and pooled cohort equation risk score in individuals without known ASCVD. | We propose a control-theoretic aggregate model of the progression of atherosclerosis plaque, a chronic inflammatory disease of the arterial wall, to study the basic features of this disease.,In the model, we exploit the role of inflammation in the disease progression, and use statins-drugs commonly recommended in atherosclerosis-to control this progression.,We use a logistic function to allow for constrained growth of plaque.,In the model, both the patient’s age and overall health impact the plaque growth and its sensitivity to statins.,The model parameters are estimated using original data, or calibrated using published research as well as our own clinical and laboratory studies.,We contend that our model helps to gauge the statins’ impact on a patient’s plaque thickness, hence the disease’s progression and cardiovascular risk, without requiring artery scans. | 1 |
Coronavirus disease 2019 (COVID-19), currently a worldwide pandemic, is a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).,The suspected contribution of thrombotic events to morbidity and mortality in COVID-19 patients has prompted a search for novel potential options for preventing COVID-19-associated thrombotic disease.,In this article by the Global COVID-19 Thrombosis Collaborative Group, we describe novel dosing approaches for commonly used antithrombotic agents (especially heparin-based regimens) and the potential use of less widely used antithrombotic drugs in the absence of confirmed thrombosis.,Although these therapies may have direct antithrombotic effects, other mechanisms of action, including anti-inflammatory or antiviral effects, have been postulated.,Based on survey results from this group of authors, we suggest research priorities for specific agents and subgroups of patients with COVID-19.,Further, we review other agents, including immunomodulators, that may have antithrombotic properties.,It is our hope that the present document will encourage and stimulate future prospective studies and randomized trials to study the safety, efficacy, and optimal use of these agents for prevention or management of thrombosis in COVID-19. | Three months ago, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) broke out in Wuhan, China, and spread rapidly around the world.,Severe novel coronavirus pneumonia (NCP) patients have abnormal blood coagulation function, but their venous thromboembolism (VTE) prevalence is still rarely mentioned.,To determine the incidence of VTE in patients with severe NCP.,In this study, 81 severe NCP patients in the intensive care unit (ICU) of Union Hospital (Wuhan, China) were enrolled.,The results of conventional coagulation parameters and lower limb vein ultrasonography of these patients were retrospectively collected and analyzed.,The incidence of VTE in these patients was 25% (20/81), of which 8 patients with VTE events died.,The VTE group was different from the non‐VTE group in age, lymphocyte counts, activated partial thromboplastin time (APTT), D‐dimer, etc.,If 1.5 µg/mL was used as the D‐dimer cut‐off value to predicting VTE, the sensitivity was 85.0%, the specificity was 88.5%, and the negative predictive value (NPV) was 94.7%.,The incidence of VTE in patients with severe NCP is 25% (20/81), which may be related to poor prognosis.,The significant increase of D‐dimer in severe NCP patients is a good index for identifying high‐risk groups of VTE. | 1 |
Coronavirus disease 2019 (COVID-19) represents a public health crisis of pandemic proportions.,Caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the symptoms most commonly reported include cough, fever and shortness of breath, but extra-pulmonary symptoms may also be present, such as neurological and gastroenterological manifestations.,Endothelial cell dysfunction and impaired microcirculatory function contribute markedly to life-threatening complications of COVID-19, such as venous thromboembolic disease and multiple organ involvementhttps://bit.ly/3cZMjKV | Although the pathophysiology underlying severe COVID19 remains poorly understood, accumulating data suggest that a lung‐centric coagulopathy may play an important role.,Elevated D‐dimer levels which correlated inversely with overall survival were recently reported in Chinese cohort studies.,Critically however, ethnicity has major effects on thrombotic risk, with a 3-4‐fold lower risk in Chinese compared to Caucasians and a significantly higher risk in African‐Americans.,In this study, we investigated COVID19 coagulopathy in Caucasian patients.,Our findings confirm that severe COVID19 infection is associated with a significant coagulopathy that correlates with disease severity.,Importantly however, Caucasian COVID19 patients on low molecular weight heparin thromboprophylaxis rarely develop overt disseminated intravascular coagulation (DIC).,In rare COVID19 cases where DIC does develop, it tends to be restricted to late‐stage disease.,Collectively, these data suggest that the diffuse bilateral pulmonary inflammation observed in COVID19 is associated with a novel pulmonary‐specific vasculopathy termed pulmonary intravascular coagulopathy (PIC) as distinct to DIC.,Given that thrombotic risk is significantly impacted by race, coupled with the accumulating evidence that coagulopathy is important in COVID19 pathogenesis, our findings raise the intriguing possibility that pulmonary vasculopathy may contribute to the unexplained differences that are beginning to emerge highlighting racial susceptibility to COVID19 mortality. | 1 |
Doxorubicin (DOX) is a chemotherapy drug for malignant tumors.,The clinical application of DOX is limited due to its dosage relative cardiotoxicity.,Oxidative damage and cardiac inflammation appear to be involved in DOX-related cardiotoxicity.,Shenmai injection (SMI), which mainly consists of Panax ginsengC.A.Mey.and Ophiopogon japonicus (Thunb.),Ker Gawl, is widely used for the treatment of atherosclerotic coronary heart disease and viral myocarditis in China.,In this study, we investigated the protective effect of Shenmai injection on doxorubicin-induced acute cardiac injury via the regulation of inflammatory mediators.,Male ICR mice were randomly divided into seven groups: control, DOX (10 mg/kg), SMI (5 g/kg), DOX with pretreatment with SMI (0.5 g/kg, 1.5 g/kg or 5 g/kg) and DOX with post-treatment with SMI (5 g/kg).,Forty-eight hours after the last DOX administration, all mice were anesthetized for ultrasound echocardiography.,Then, serum was collected for biochemical and inflammatory cytokine detection, and heart tissue was collected for histological and Western blot detection.,A cumulative dose of DOX (10 mg/kg) induced acute cardiotoxicity in mice manifested by altered echocardiographic outcome, and increased tumor necrosis factor, interleukin 6 (IL-6), monocyte chemotactic protein 1, interferon-γ, and serum AST and LDH levels, as well as cardiac cytoplasmic vacuolation and myofibrillar disarrangement.,DOX also caused the increase in the expression of IKK-α and iNOS and produced a large amount of NO, resulting in the accumulation of nitrotyrosine in the heart tissue.,Pretreatment with SMI elicited a dose-dependent cardioprotective effect in DOX-dosed mice as evidenced by the normalization of serum inflammatory mediators, as well as improve dcardiac function and myofibril disarrangement.,SMI could recover inflammatory cytokine levels and suppress the expression of IKK-α and iNOS in vivo, which was increased by DOX.,Overall, there was evidence that SMI could ameliorate DOX-induced cardiotoxicity by inhibiting inflammation and recovering heart dysfunction. | Anthracycline chemotherapy maintains a prominent role in treating many forms of cancer.,Cardiotoxic side effects limit their dosing and improved cancer outcomes expose the cancer survivor to increased cardiovascular morbidity and mortality.,The basic mechanisms of cardiotoxicity may involve direct pathways for reactive oxygen species generation and topoisomerase 2 as well as other indirect pathways.,Cardioprotective treatments are few and those that have been examined include renin angiotensin system blockade, beta blockers, or the iron chelator dexrazoxane.,New treatments exploiting the ErbB or other novel pro-survival pathways, such as conditioning, are on the cardioprotection horizon.,Even in the forthcoming era of targeted cancer therapies, the substantial proportion of today’s anthracycline-treated cancer patients may become tomorrow’s cardiac patient. | 1 |
This case series study evaluates the association of underlying cardiovascular disease and myocardial injury on fatal outcomes in patients with coronavirus disease 2019 (COVID-19).,What is the impact of underlying cardiovascular disease (CVD) and myocardial injury on fatal outcomes in patients with coronavirus disease 2019 (COVID-19)?,In this case series study of 187 patients with COVID-19, 27.8% of patients had myocardial injury, which resulted in cardiac dysfunction and arrhythmias.,Myocardial injury has a significant association with fatal outcome of COVID-19, while the prognosis of patients with underlying CVD but without myocardial injury were relatively favorable.,It is reasonable to triage patients with COVID-19 according to the presence of underlying CVD and evidence of myocardial injury for prioritized treatment and even more aggressive strategies.,Increasing numbers of confirmed cases and mortality rates of coronavirus disease 2019 (COVID-19) are occurring in several countries and continents.,Information regarding the impact of cardiovascular complication on fatal outcome is scarce.,To evaluate the association of underlying cardiovascular disease (CVD) and myocardial injury with fatal outcomes in patients with COVID-19.,This retrospective single-center case series analyzed patients with COVID-19 at the Seventh Hospital of Wuhan City, China, from January 23, 2020, to February 23, 2020.,Analysis began February 25, 2020.,Demographic data, laboratory findings, comorbidities, and treatments were collected and analyzed in patients with and without elevation of troponin T (TnT) levels.,Among 187 patients with confirmed COVID-19, 144 patients (77%) were discharged and 43 patients (23%) died.,The mean (SD) age was 58.50 (14.66) years.,Overall, 66 (35.3%) had underlying CVD including hypertension, coronary heart disease, and cardiomyopathy, and 52 (27.8%) exhibited myocardial injury as indicated by elevated TnT levels.,The mortality during hospitalization was 7.62% (8 of 105) for patients without underlying CVD and normal TnT levels, 13.33% (4 of 30) for those with underlying CVD and normal TnT levels, 37.50% (6 of 16) for those without underlying CVD but elevated TnT levels, and 69.44% (25 of 36) for those with underlying CVD and elevated TnTs.,Patients with underlying CVD were more likely to exhibit elevation of TnT levels compared with the patients without CVD (36 [54.5%] vs 16 [13.2%]).,Plasma TnT levels demonstrated a high and significantly positive linear correlation with plasma high-sensitivity C-reactive protein levels (β = 0.530, P < .001) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (β = 0.613, P < .001).,Plasma TnT and NT-proBNP levels during hospitalization (median [interquartile range (IQR)], 0.307 [0.094-0.600]; 1902.00 [728.35-8100.00]) and impending death (median [IQR], 0.141 [0.058-0.860]; 5375 [1179.50-25695.25]) increased significantly compared with admission values (median [IQR], 0.0355 [0.015-0.102]; 796.90 [401.93-1742.25]) in patients who died (P = .001; P < .001), while no significant dynamic changes of TnT (median [IQR], 0.010 [0.007-0.019]; 0.013 [0.007-0.022]; 0.011 [0.007-0.016]) and NT-proBNP (median [IQR], 352.20 [174.70-636.70]; 433.80 [155.80-1272.60]; 145.40 [63.4-526.50]) was observed in survivors (P = .96; P = .16).,During hospitalization, patients with elevated TnT levels had more frequent malignant arrhythmias, and the use of glucocorticoid therapy (37 [71.2%] vs 69 [51.1%]) and mechanical ventilation (31 [59.6%] vs 14 [10.4%]) were higher compared with patients with normal TnT levels.,The mortality rates of patients with and without use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers was 36.8% (7 of 19) and 21.4% (36 of 168) (P = .13).,Myocardial injury is significantly associated with fatal outcome of COVID-19, while the prognosis of patients with underlying CVD but without myocardial injury is relatively favorable.,Myocardial injury is associated with cardiac dysfunction and arrhythmias.,Inflammation may be a potential mechanism for myocardial injury.,Aggressive treatment may be considered for patients at high risk of myocardial injury. | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells through ACE2 receptors, leading to coronavirus disease (COVID-19)-related pneumonia, while also causing acute myocardial injury and chronic damage to the cardiovascular system.,Therefore, particular attention should be given to cardiovascular protection during treatment for COVID-19. | 1 |
Critically ill COVID-19 patients have a clear pattern of inflammation and hypercoagulable state.,The main aim of the study was to evaluate the outcome of severe COVID-19 patients basing on prothrombotic risk factors (i.e.,D-dimer).,We also evaluated the impact of different doses of low molecular weight heparin (LMWH) on the incidence of bleedings.,The data of forty-two patients admitted to the Intensive Care Unit (ICU) were retrospectively analyzed.,On ICU admission, patients with D-dimer < 3000 ng/mL (Group 1) received enoxaparin 4000 UI (6000 UI, if body mass index >35) subcutaneously b.i.d. and patients with D-dimer ≥ 3000 ng/mL (Group 2) received enoxaparin 100 UI/kg every 12 h.,Aspirin was administered to all patients once a day.,Both groups presented a high incidence of perivascular thrombosis (40.9% in Group 1 and 30% in Group 2).,Patients of Group 2 suffered a higher incidence of venous thromboembolism (VTE) than Group 1 (65% vs 13.6%, p = 0.001).,One patient (4.5%) of Group 1 and three patients (15%) of Group 2 suffered from minor bleeding; no patient had major bleeding.,Group 2 had a longer ICU and hospital stay than Group 1 (11.5 ± 5.6 vs 9.0 ± 4.8 and 30 ± 4.9 vs 21 ± 2.3, p < 0.05, respectively) as well as increased ICU mortality (25% vs 9.1%).,More severe critically ill COVID-19 patients have a high incidence of VTE and worse outcome, despite the use of heparin at the therapeutic dose.,However, the use of heparin did not increase the incidence of bleeding complications.,•Risk stratification based on D-dimer values is fundamental in critically ill patients with COVID-19 pneumonia.,•High-risk patients have a higher incidence of thromboembolic events and worse outcome compared with low risk ones.,•The use of heparin in therapeutic doses did not lead to an increase of bleeding risk.,Risk stratification based on D-dimer values is fundamental in critically ill patients with COVID-19 pneumonia.,High-risk patients have a higher incidence of thromboembolic events and worse outcome compared with low risk ones.,The use of heparin in therapeutic doses did not lead to an increase of bleeding risk. | An increased risk of venous thromboembolism (VTE) in patients with COVID-19 pneumonia admitted to intensive care unit (ICU) has been reported.,Whether COVID-19 increases the risk of VTE in non-ICU wards remains unknown.,We aimed to evaluate the burden of asymptomatic deep vein thrombosis (DVT) in COVID-19 patients with elevated D-dimer levels.,In this prospective study consecutive patients hospitalized in non-intensive care units with diagnosis of COVID-19 pneumonia and D-dimer > 1000 ng/ml were screened for asymptomatic DVT with complete compression doppler ultrasound (CCUS).,The study was approved by the Institutional Ethics Committee.,The study comprised 156 patients (65.4% male).,All but three patients received standard doses of thromboprophylaxis.,Median days of hospitalization until CCUS was 9 (IQR 5-17).,CCUS was positive for DVT in 23 patients (14.7%), of whom only one was proximal DVT.,Seven patients (4.5%) had bilateral distal DVT.,Patients with DVT had higher median D-dimer levels: 4527 (IQR 1925-9144) ng/ml vs 2050 (IQR 1428-3235) ng/ml; p < 0.001.,D-dimer levels > 1570 ng/ml were associated with asymptomatic DVT (OR 9.1; CI 95% 1.1-70.1).,D-dimer showed an acceptable discriminative capacity (area under the ROC curve 0.72, 95% CI 0.61-0.84).,In patients admitted with COVID-19 pneumonia and elevated D-dimer levels, the incidence of asymptomatic DVT is similar to that described in other series.,Higher cut-off levels for D-dimer might be necessary for the diagnosis of DVT in COVID-19 patients.,•An increased risk of VTE in patients with COVID-19 pneumonia admitted to intensive care unit has been reported.,•The most consistent hemostatic abnormalities with COVID-19 include mild thrombocytopenia and increased D-dimer levels.,•In COVID-19 patients with high D-dimer levels, the incidence of asymptomatic DVT is similar to that described in other series.,•Higher cut-off levels for D-dimer might be necessary for the diagnosis of DVT in COVID-19 patients.,An increased risk of VTE in patients with COVID-19 pneumonia admitted to intensive care unit has been reported.,The most consistent hemostatic abnormalities with COVID-19 include mild thrombocytopenia and increased D-dimer levels.,In COVID-19 patients with high D-dimer levels, the incidence of asymptomatic DVT is similar to that described in other series.,Higher cut-off levels for D-dimer might be necessary for the diagnosis of DVT in COVID-19 patients. | 1 |
Coronavirus disease 2019 (COVID-19)-related critical illness and acute illness are associated with a risk of venous thromboembolism (VTE).,These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in decisions about the use of anticoagulation for thromboprophylaxis for patients with COVID-19-related critical illness and acute illness who do not have confirmed or suspected VTE.,ASH formed a multidisciplinary guideline panel and applied strict management strategies to minimize potential bias from conflicts of interest.,The panel included 3 patient representatives.,The McMaster University GRADE Centre supported the guideline-development process, including performing systematic evidence reviews (up to 19 August 2020).,The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients.,The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment.,The panel agreed on 2 recommendations.,The panel issued conditional recommendations in favor of prophylactic-intensity anticoagulation over intermediate-intensity or therapeutic-intensity anticoagulation for patients with COVID-19-related critical illness or acute illness who do not have confirmed or suspected VTE.,These recommendations were based on very low certainty in the evidence, underscoring the need for high-quality, randomized controlled trials comparing different intensities of anticoagulation.,They will be updated using a living recommendation approach as new evidence becomes available. | Little evidence of increased thrombotic risk is available in COVID-19 patients.,Our purpose was to assess thrombotic risk in severe forms of SARS-CoV-2 infection.,All patients referred to 4 intensive care units (ICUs) from two centers of a French tertiary hospital for acute respiratory distress syndrome (ARDS) due to COVID-19 between March 3rd and 31st 2020 were included.,Medical history, symptoms, biological data and imaging were prospectively collected.,Propensity score matching was performed to analyze the occurrence of thromboembolic events between non-COVID-19 ARDS and COVID-19 ARDS patients.,150 COVID-19 patients were included (122 men, median age 63 [53; 71] years, SAPSII 49 [37; 64] points).,Sixty-four clinically relevant thrombotic complications were diagnosed in 150 patients, mainly pulmonary embolisms (16.7%). 28/29 patients (96.6%) receiving continuous renal replacement therapy experienced circuit clotting.,Three thrombotic occlusions (in 2 patients) of centrifugal pump occurred in 12 patients (8%) supported by ECMO.,Most patients (> 95%) had elevated D-dimer and fibrinogen.,No patient developed disseminated intravascular coagulation.,Von Willebrand (vWF) activity, vWF antigen and FVIII were considerably increased, and 50/57 tested patients (87.7%) had positive lupus anticoagulant.,Comparison with non-COVID-19 ARDS patients (n = 145) confirmed that COVID-19 ARDS patients (n = 77) developed significantly more thrombotic complications, mainly pulmonary embolisms (11.7 vs.,2.1%, p < 0.008).,Coagulation parameters significantly differed between the two groups.,Despite anticoagulation, a high number of patients with ARDS secondary to COVID-19 developed life-threatening thrombotic complications.,Higher anticoagulation targets than in usual critically ill patients should therefore probably be suggested.,The online version of this article (10.1007/s00134-020-06062-x) contains supplementary material, which is available to authorized users. | 1 |
The COVID-19 pandemic is an unprecedented healthcare emergency causing mortality and illness across the world.,Although primarily affecting the lungs, the SARS-CoV-2 virus also affects the cardiovascular system.,In addition to cardiac effects, e.g. myocarditis, arrhythmias, and myocardial damage, the vasculature is affected in COVID-19, both directly by the SARS-CoV-2 virus, and indirectly as a result of a systemic inflammatory cytokine storm.,This includes the role of the vascular endothelium in the recruitment of inflammatory leucocytes where they contribute to tissue damage and cytokine release, which are key drivers of acute respiratory distress syndrome (ARDS), in disseminated intravascular coagulation, and cardiovascular complications in COVID-19.,There is also evidence linking endothelial cells (ECs) to SARS-CoV-2 infection including: (i) the expression and function of its receptor angiotensin-converting enzyme 2 (ACE2) in the vasculature; (ii) the prevalence of a Kawasaki disease-like syndrome (vasculitis) in COVID-19; and (iii) evidence of EC infection with SARS-CoV-2 in patients with fatal COVID-19.,Here, the Working Group on Atherosclerosis and Vascular Biology together with the Council of Basic Cardiovascular Science of the European Society of Cardiology provide a Position Statement on the importance of the endothelium in the underlying pathophysiology behind the clinical presentation in COVID-19 and identify key questions for future research to address.,We propose that endothelial biomarkers and tests of function (e.g. flow-mediated dilatation) should be evaluated for their usefulness in the risk stratification of COVID-19 patients.,A better understanding of the effects of SARS-CoV-2 on endothelial biology in both the micro- and macrovasculature is required, and endothelial function testing should be considered in the follow-up of convalescent COVID-19 patients for early detection of long-term cardiovascular complications. | While the thrombotic complications of COVID-19 have been well described, there are limited data on clinically significant bleeding complications including hemorrhagic stroke.,The clinical characteristics, underlying stroke mechanism, and outcomes in this particular subset of patients are especially salient as therapeutic anticoagulation becomes increasingly common in the treatment and prevention of thrombotic complications of COVID-19.,We conducted a retrospective cohort study of patients with hemorrhagic stroke (both non-traumatic intracerebral hemorrhage and spontaneous non-aneurysmal subarachnoid hemorrhage) who were hospitalized between March 1, 2020, and May 15, 2020, within a major healthcare system in New York, during the coronavirus pandemic.,Patients with hemorrhagic stroke on admission and who developed hemorrhage during hospitalization were both included.,We compared the clinical characteristics of patients with hemorrhagic stroke and COVID-19 to those without COVID-19 admitted to our hospital system between March 1, 2020, and May 15, 2020 (contemporary controls), and March 1, 2019, and May 15, 2019 (historical controls).,Demographic variables and clinical characteristics between the individual groups were compared using Fischer’s exact test for categorical variables and nonparametric test for continuous variables.,We adjusted for multiple comparisons using the Bonferroni method.,During the study period in 2020, out of 4071 patients who were hospitalized with COVID-19, we identified 19 (0.5%) with hemorrhagic stroke.,Of all COVID-19 with hemorrhagic stroke, only three had isolated non-aneurysmal SAH with no associated intraparenchymal hemorrhage.,Among hemorrhagic stroke in patients with COVID-19, coagulopathy was the most common etiology (73.7%); empiric anticoagulation was started in 89.5% of these patients versus 4.2% in contemporary controls (p ≤ .001) and 10.0% in historical controls (p ≤ .001).,Compared to contemporary and historical controls, patients with COVID-19 had higher initial NIHSS scores, INR, PTT, and fibrinogen levels.,Patients with COVID-19 also had higher rates of in-hospital mortality (84.6% vs.,4.6%, p ≤ 0.001).,Sensitivity analyses excluding patients with strictly subarachnoid hemorrhage yielded similar results.,We observed an overall low rate of imaging-confirmed hemorrhagic stroke among patients hospitalized with COVID-19.,Most hemorrhages in patients with COVID-19 infection occurred in the setting of therapeutic anticoagulation and were associated with increased mortality.,Further studies are needed to evaluate the safety and efficacy of therapeutic anticoagulation in patients with COVID-19. | 1 |
Myocardial injury in hospitalized patients is associated with poor prognosis.,This study aimed to evaluate risk factors for myocardial injury in hospitalized patients with coronavirus disease 2019 (COVID-19) and its prognostic value.,We retrieved all consecutive patients who were hospitalized in internal medicine departments in a tertiary medical center from February 9th, 2020 to August 28th with a diagnosis of COVID-19.,A total of 559 adult patients were hospitalized in the Sheba Medical Center with a diagnosis of COVID-19, 320 (57.24%) of whom were tested for troponin levels within 24-hours of admission, and 91 (28.44%) had elevated levels.,Predictors for elevated troponin levels were age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.01-1.06), female sex (OR, 3.03; 95% CI 1.54-6.25), low systolic blood pressure (OR, 5.91; 95% CI 2.42-14.44) and increased creatinine level (OR, 2.88; 95% CI 1.44-5.73).,The risk for death (hazard ratio [HR] 4.32, 95% CI 2.08-8.99) and a composite outcome of invasive ventilation support and death (HR 1.96, 95% CI 1.15-3.37) was significantly higher among patients who had elevated troponin levels.,In conclusion, in hospitalized patients with COVID-19, elevated troponin levels are associated with poor prognosis.,Hence, troponin levels may be used as an additional tool for risk stratification and a decision guide in patients hospitalized with COVID-19. | Myocardial injury is frequent among patients hospitalized with coronavirus disease-2019 (COVID-19) and is associated with a poor prognosis.,However, the mechanisms of myocardial injury remain unclear and prior studies have not reported cardiovascular imaging data.,This study sought to characterize the echocardiographic abnormalities associated with myocardial injury and their prognostic impact in patients with COVID-19.,We conducted an international, multicenter cohort study including 7 hospitals in New York City and Milan of hospitalized patients with laboratory-confirmed COVID-19 who had undergone transthoracic echocardiographic (TTE) and electrocardiographic evaluation during their index hospitalization.,Myocardial injury was defined as any elevation in cardiac troponin at the time of clinical presentation or during the hospitalization.,A total of 305 patients were included.,Mean age was 63 years and 205 patients (67.2%) were male.,Overall, myocardial injury was observed in 190 patients (62.3%).,Compared with patients without myocardial injury, those with myocardial injury had more electrocardiographic abnormalities, higher inflammatory biomarkers and an increased prevalence of major echocardiographic abnormalities that included left ventricular wall motion abnormalities, global left ventricular dysfunction, left ventricular diastolic dysfunction grade II or III, right ventricular dysfunction and pericardial effusions.,Rates of in-hospital mortality were 5.2%, 18.6%, and 31.7% in patients without myocardial injury, with myocardial injury without TTE abnormalities, and with myocardial injury and TTE abnormalities.,Following multivariable adjustment, myocardial injury with TTE abnormalities was associated with higher risk of death but not myocardial injury without TTE abnormalities.,Among patients with COVID-19 who underwent TTE, cardiac structural abnormalities were present in nearly two-thirds of patients with myocardial injury.,Myocardial injury was associated with increased in-hospital mortality particularly if echocardiographic abnormalities were present. | 1 |
Coronavirus disease 2019 (COVID-19), caused by a strain of coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic that has affected the lives of billions of individuals.,Extensive studies have revealed that SARS-CoV-2 shares many biological features with SARS-CoV, the zoonotic virus that caused the 2002 outbreak of severe acute respiratory syndrome, including the system of cell entry, which is triggered by binding of the viral spike protein to angiotensin-converting enzyme 2.,Clinical studies have also reported an association between COVID-19 and cardiovascular disease.,Pre-existing cardiovascular disease seems to be linked with worse outcomes and increased risk of death in patients with COVID-19, whereas COVID-19 itself can also induce myocardial injury, arrhythmia, acute coronary syndrome and venous thromboembolism.,Potential drug-disease interactions affecting patients with COVID-19 and comorbid cardiovascular diseases are also becoming a serious concern.,In this Review, we summarize the current understanding of COVID-19 from basic mechanisms to clinical perspectives, focusing on the interaction between COVID-19 and the cardiovascular system.,By combining our knowledge of the biological features of the virus with clinical findings, we can improve our understanding of the potential mechanisms underlying COVID-19, paving the way towards the development of preventative and therapeutic solutions.,The presence of cardiovascular comorbidities is linked with worse outcomes in patients with coronavirus disease 2019 (COVID-19), and COVID-19 can induce cardiovascular damage.,In this Review, Wu and colleagues summarize the latest mechanistic and clinical studies that contribute to our current understanding of COVID-19-related cardiovascular disease.,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), shares many biological features with SARS-CoV, the virus that causes severe acute respiratory syndrome, owing to 80% genomic sequence identity.The interaction between the viral spike (S) protein and angiotensin-converting enzyme 2, which triggers entry of the virus into host cells, is likely to be involved in the cardiovascular manifestations of COVID-19.,The presence of underlying cardiovascular comorbidities in patients with COVID-19 is associated with high mortality.COVID-19 can cause cardiovascular disorders, including myocardial injury, arrhythmias, acute coronary syndrome and venous thromboembolism.Several medications used for the treatment of COVID-19 have uncertain safety and efficacy profiles.,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), shares many biological features with SARS-CoV, the virus that causes severe acute respiratory syndrome, owing to 80% genomic sequence identity.,The interaction between the viral spike (S) protein and angiotensin-converting enzyme 2, which triggers entry of the virus into host cells, is likely to be involved in the cardiovascular manifestations of COVID-19.,The presence of underlying cardiovascular comorbidities in patients with COVID-19 is associated with high mortality.,COVID-19 can cause cardiovascular disorders, including myocardial injury, arrhythmias, acute coronary syndrome and venous thromboembolism.,Several medications used for the treatment of COVID-19 have uncertain safety and efficacy profiles. | The novel coronavirus disease (COVID-19) outbreak, caused by SARS-CoV-2, represents the greatest medical challenge in decades.,We provide a comprehensive review of the clinical course of COVID-19, its comorbidities, and mechanistic considerations for future therapies.,While COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome (ARDS), it also affects multiple organs, particularly the cardiovascular system.,Risk of severe infection and mortality increase with advancing age and male sex.,Mortality is increased by comorbidities: cardiovascular disease, hypertension, diabetes, chronic pulmonary disease, and cancer.,The most common complications include arrhythmia (atrial fibrillation, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury [elevated highly sensitive troponin I (hs-cTnI) and creatine kinase (CK) levels], fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation (DIC).,Mechanistically, SARS-CoV-2, following proteolytic cleavage of its S protein by a serine protease, binds to the transmembrane angiotensin-converting enzyme 2 (ACE2) -a homologue of ACE-to enter type 2 pneumocytes, macrophages, perivascular pericytes, and cardiomyocytes.,This may lead to myocardial dysfunction and damage, endothelial dysfunction, microvascular dysfunction, plaque instability, and myocardial infarction (MI).,While ACE2 is essential for viral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis.,Hence, patients should not discontinue their use.,Moreover, renin-angiotensin-aldosterone system (RAAS) inhibitors might be beneficial in COVID-19.,Initial immune and inflammatory responses induce a severe cytokine storm [interleukin (IL)-6, IL-7, IL-22, IL-17, etc.] during the rapid progression phase of COVID-19.,Early evaluation and continued monitoring of cardiac damage (cTnI and NT-proBNP) and coagulation (D-dimer) after hospitalization may identify patients with cardiac injury and predict COVID-19 complications.,Preventive measures (social distancing and social isolation) also increase cardiovascular risk.,Cardiovascular considerations of therapies currently used, including remdesivir, chloroquine, hydroxychloroquine, tocilizumab, ribavirin, interferons, and lopinavir/ritonavir, as well as experimental therapies, such as human recombinant ACE2 (rhACE2), are discussed. | 1 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Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).,Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described.,In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020.,Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors.,We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death.,191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients).,Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03-1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61-12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64-128·55; p=0·0033) on admission.,Median duration of viral shedding was 20·0 days (IQR 17·0-24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors.,The longest observed duration of viral shedding in survivors was 37 days.,The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage.,Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future.,Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development. | •COVID-19 is a viral disease caused by SARS-CoV-2.,•Twenty-three autopsy cases demonstrate that COVID-19 is a systemic disease with major pulmonary and cardiac manifestations.,•COVID-19 produces an acute interstitial pneumonia, usually with a prominent diffuse alveolar damage (DAD) component, often coupled with a thrombotic microangiopathy.,•The heart frequently shows acute cardiomyocyte injury and, in some cases, pericarditis and/or myocarditis.,•Patients with fatal COVID-19 frequently are obese and have pre-existing cardiac disease, hypertension and/or diabetes mellitus.,COVID-19 is a viral disease caused by SARS-CoV-2.,Twenty-three autopsy cases demonstrate that COVID-19 is a systemic disease with major pulmonary and cardiac manifestations.,COVID-19 produces an acute interstitial pneumonia, usually with a prominent diffuse alveolar damage (DAD) component, often coupled with a thrombotic microangiopathy.,The heart frequently shows acute cardiomyocyte injury and, in some cases, pericarditis and/or myocarditis.,Patients with fatal COVID-19 frequently are obese and have pre-existing cardiac disease, hypertension and/or diabetes mellitus.,This paper collates the pathological findings from initial published autopsy reports on 23 patients with coronavirus disease 2019 (COVID-19) from 5 centers in the United States of America, including 3 cases from Houston, Texas.,Findings confirm that COVID-19 is a systemic disease with major involvement of the lungs and heart.,Acute COVID-19 pneumonia has features of a distinctive acute interstitial pneumonia with a diffuse alveolar damage component, coupled with microvascular involvement with intra- and extravascular fibrin deposition and intravascular trapping of neutrophils, and, frequently, with formation of microthombi in arterioles.,Major pulmonary thromboemboli with pulmonary infarcts and/or hemorrhage occurred in 5 of the 23 patients.,Two of the Houston cases had interstitial pneumonia with diffuse alveolar damage pattern.,One of the Houston cases had multiple bilateral segmental pulmonary thromboemboli with infarcts and hemorrhages coupled with, in nonhemorrhagic areas, a distinctive interstitial lymphocytic pneumonitis with intra-alveolar fibrin deposits and no hyaline membranes, possibly representing a transition form to acute fibrinous and organizing pneumonia.,Multifocal acute injury of cardiac myocytes was frequently observed.,Lymphocytic myocarditis was reported in 1 case.,In addition to major pulmonary pathology, the 3 Houston cases had evidence of lymphocytic pericarditis, multifocal acute injury of cardiomyocytes without inflammatory cellular infiltrates, depletion of splenic white pulp, focal hepatocellular degeneration and rare glomerular capillary thrombosis.,Each had evidence of chronic cardiac disease: hypertensive left ventricular hypertrophy (420 g heart), dilated cardiomyopathy (1070 g heart), and hypertrophic cardiomyopathy (670 g heart).,All 3 subjects were obese (BMIs of 33.8, 51.65, and 35.2 Kg/m2).,Overall, the autopsy findings support the concept that the pathogenesis of severe COVID-19 disease involves direct viral-induced injury of multiple organs, including heart and lungs, coupled with the consequences of a procoagulant state with coagulopathy. | 1 |
Arrhythmias in children are often paroxysmal, complicating the ability to capture the abnormal rhythm on routine ECG during an outpatient visit.,The Alivecor Kardia Mobile (KM) device is a wireless mobile health (mHealth) device that generates a single lead ECG tracing with a FDA-approved algorithm for detection of atrial fibrillation in adults.,The goal of this study is to assess the accuracy of interval measurements on KM tracings by directly comparing to standard 12-lead ECGs in pediatric patients.,This single center, prospective study enrolled pediatric outpatients, age <18 years presenting for cardiology clinic visits, into 3 groups based on age: 0-5 years, 6-10 years, and 11-18 years.,Patients were excluded if 12-lead ECG was not ordered during the visit.,Each enrolled subject underwent standard 12-lead ECG followed by 30-second KM tracing.,ECG parameters were batch read by 2 blinded pediatric electrophysiologists.,Thirty patients were recruited with 10 patients/group.,Structural heart disease and/or conduction abnormality was present in 20 patients (67%).,Majority of tracings (27/30, 90%) were of diagnostic quality on first attempt.,Overall, the ΔPR was 15.2±10.8ms (r = 0.86), ΔQRS was 9.6±8ms (r = 0.86), and ΔQTc was 15.6±12.7ms (r = 0.83).,There were 9 patients with ΔQTc measurements >20ms with 4/9 (44%) having a conduction disorder and 2/9 (22%) having marked sinus arrhythmia.,Bland-Altman method of agreement demonstrated strong agreement for QRSd and QTc.,The AF algorithm reported 4/30 (13%) false positive "possible AF" diagnoses (rhythm over-read on KM demonstrated n = 3 marked sinus arrhythmia, n = 1 sinus rhythm with aberrated PACs) resulting in a specificity of 87%.,The Alivecor Kardia device produces accurate single lead ECG tracings in both healthy children and children with cardiac disease or rhythm abnormalities across the pediatric spectrum.,This mHealth application provides an accurate, non-invasive, real-time approach for ambulatory ECG monitoring in children and adolescents. | We aimed to evaluate a novel method of atrial fibrillation (AF) screening using an iPhone camera to detect and analyze photoplethysmographic signals from the face without physical contact by extracting subtle beat‐to‐beat variations of skin color that reflect the cardiac pulsatile signal.,Patients admitted to the cardiology ward of the hospital for clinical reasons were recruited.,Simultaneous facial and fingertip photoplethysmographic measurements were obtained from 217 hospital inpatients (mean age, 70.3±13.9 years; 71.4% men) facing the front camera and with an index finger covering the back camera of 2 independent iPhones before a 12‐lead ECG was recorded.,Backdrop and background light intensity was monitored during signal acquisition.,Three successive 20‐second (total, 60 seconds) recordings were acquired per patient and analyzed for heart rate regularity by Cardiio Rhythm (Cardiio Inc, Cambridge, MA) smartphone application.,Pulse irregularity in ≥1 photoplethysmographic readings or 3 uninterpretable photoplethysmographic readings were considered a positive AF screening result.,AF was present on 12‐lead ECG in 34.6% (n=75/217) patients.,The Cardiio Rhythm facial photoplethysmographic application demonstrated high sensitivity (95%; 95% confidence interval, 87%-98%) and specificity (96%; 95% confidence interval, 91%-98%) in discriminating AF from sinus rhythm compared with 12‐lead ECG.,The positive and negative predictive values were 92% (95% confidence interval, 84%-96%) and 97% (95% confidence interval, 93%-99%), respectively.,Detection of a facial photoplethysmographic signal to determine pulse irregularity attributable to AF is feasible.,The Cardiio Rhythm smartphone application showed high sensitivity and specificity, with low negative likelihood ratio for AF from facial photoplethysmographic signals.,The convenience of a contact‐free approach is attractive for community screening and has the potential to be useful for distant AF screening. | 1 |
Myocardial inflammation in COVID-19 has been documented.,Its pathogenesis is not fully elucidated, but the two main theories foresee a direct role of ACE2 receptor and a hyperimmune response, which may also lead to isolated presentation of COVID-19-mediated myocarditis.,The frequency and prognostic impact of COVID-19-mediated myocarditis is unknown.,This review aims to summarise current evidence on this topic.,We performed a systematic review of MEDLINE and Cochrane Library (1/12/19-30/09/20).,We also searched clinicaltrials.gov for unpublished studies testing therapies with potential implication for COVID-19-mediated cardiovascular complication.,Eligible studies had laboratory confirmed COVID-19 and a clinical and/or histological diagnosis of myocarditis by ESC or WHO/ISFC criteria.,Reports of 38 cases were included (26 male patients, 24 aged < 50 years).,The first histologically proven case was a virus-negative lymphocytic myocarditis; however, biopsy evidence of myocarditis secondary to SARS-CoV-2 cardiotropism has been recently demonstrated.,Histological data was found in 12 cases (8 EMB and 4 autopsies) and CMR was the main imaging modality to confirm a diagnosis of myocarditis (25 patients).,There was a substantial variability in biventricular systolic function during the acute episode and in therapeutic regimen used.,Five patients died in hospital.,Cause-effect relationship between SARS-CoV-2 infection and myocarditis is difficult to demonstrate.,However, current evidence demonstrates myocardial inflammation with or without direct cardiomyocyte damage, suggesting different pathophysiology mechanisms responsible of COVID-mediated myocarditis.,Established clinical approaches should be pursued until future evidence support different actions.,Large multicentre registries are advisable to elucidate further.,The online version contains supplementary material available at 10.1007/s10741-021-10087-9. | The coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 that has significant implications for the cardiovascular care of patients.,First, those with COVID-19 and pre-existing cardiovascular disease have an increased risk of severe disease and death.,Second, infection has been associated with multiple direct and indirect cardiovascular complications including acute myocardial injury, myocarditis, arrhythmias, and venous thromboembolism.,Third, therapies under investigation for COVID-19 may have cardiovascular side effects.,Fourth, the response to COVID-19 can compromise the rapid triage of non-COVID-19 patients with cardiovascular conditions.,Finally, the provision of cardiovascular care may place health care workers in a position of vulnerability as they become hosts or vectors of virus transmission.,We hereby review the peer-reviewed and pre-print reports pertaining to cardiovascular considerations related to COVID-19 and highlight gaps in knowledge that require further study pertinent to patients, health care workers, and health systems.,•Patients with pre-existing CVD appear to have worse outcomes with COVID-19.,•CV complications include biomarker elevations, myocarditis, heart failure, and venous thromboembolism, which may be exacerbated by delays in care.,•Therapies under investigation for COVID-19 may have significant drug-drug interactions with CV medications.,•Health care workers and health systems should take measures to ensure safety while providing high-quality care for COVID-19 patients.,Patients with pre-existing CVD appear to have worse outcomes with COVID-19.,CV complications include biomarker elevations, myocarditis, heart failure, and venous thromboembolism, which may be exacerbated by delays in care.,Therapies under investigation for COVID-19 may have significant drug-drug interactions with CV medications.,Health care workers and health systems should take measures to ensure safety while providing high-quality care for COVID-19 patients. | 1 |
Supplemental Digital Content is available in the text.,Information on the cardiac manifestations of coronavirus disease 2019 (COVID-19) is scarce.,We performed a systematic and comprehensive echocardiographic evaluation of consecutive patients hospitalized with COVID-19 infection.,One hundred consecutive patients diagnosed with COVID-19 infection underwent complete echocardiographic evaluation within 24 hours of admission and were compared with reference values.,Echocardiographic studies included left ventricular (LV) systolic and diastolic function and valve hemodynamics and right ventricular (RV) assessment, as well as lung ultrasound.,A second examination was performed in case of clinical deterioration.,Thirty-two patients (32%) had a normal echocardiogram at baseline.,The most common cardiac pathology was RV dilatation and dysfunction (observed in 39% of patients), followed by LV diastolic dysfunction (16%) and LV systolic dysfunction (10%).,Patients with elevated troponin (20%) or worse clinical condition did not demonstrate any significant difference in LV systolic function compared with patients with normal troponin or better clinical condition, but they had worse RV function.,Clinical deterioration occurred in 20% of patients.,In these patients, the most common echocardiographic abnormality at follow-up was RV function deterioration (12 patients), followed by LV systolic and diastolic deterioration (in 5 patients).,Femoral deep vein thrombosis was diagnosed in 5 of 12 patients with RV failure.,In COVID-19 infection, LV systolic function is preserved in the majority of patients, but LV diastolic function and RV function are impaired.,Elevated troponin and poorer clinical grade are associated with worse RV function.,In patients presenting with clinical deterioration at follow-up, acute RV dysfunction, with or without deep vein thrombosis, is more common, but acute LV systolic dysfunction was noted in ≈20%. | This case series study evaluates the association of underlying cardiovascular disease and myocardial injury on fatal outcomes in patients with coronavirus disease 2019 (COVID-19).,What is the impact of underlying cardiovascular disease (CVD) and myocardial injury on fatal outcomes in patients with coronavirus disease 2019 (COVID-19)?,In this case series study of 187 patients with COVID-19, 27.8% of patients had myocardial injury, which resulted in cardiac dysfunction and arrhythmias.,Myocardial injury has a significant association with fatal outcome of COVID-19, while the prognosis of patients with underlying CVD but without myocardial injury were relatively favorable.,It is reasonable to triage patients with COVID-19 according to the presence of underlying CVD and evidence of myocardial injury for prioritized treatment and even more aggressive strategies.,Increasing numbers of confirmed cases and mortality rates of coronavirus disease 2019 (COVID-19) are occurring in several countries and continents.,Information regarding the impact of cardiovascular complication on fatal outcome is scarce.,To evaluate the association of underlying cardiovascular disease (CVD) and myocardial injury with fatal outcomes in patients with COVID-19.,This retrospective single-center case series analyzed patients with COVID-19 at the Seventh Hospital of Wuhan City, China, from January 23, 2020, to February 23, 2020.,Analysis began February 25, 2020.,Demographic data, laboratory findings, comorbidities, and treatments were collected and analyzed in patients with and without elevation of troponin T (TnT) levels.,Among 187 patients with confirmed COVID-19, 144 patients (77%) were discharged and 43 patients (23%) died.,The mean (SD) age was 58.50 (14.66) years.,Overall, 66 (35.3%) had underlying CVD including hypertension, coronary heart disease, and cardiomyopathy, and 52 (27.8%) exhibited myocardial injury as indicated by elevated TnT levels.,The mortality during hospitalization was 7.62% (8 of 105) for patients without underlying CVD and normal TnT levels, 13.33% (4 of 30) for those with underlying CVD and normal TnT levels, 37.50% (6 of 16) for those without underlying CVD but elevated TnT levels, and 69.44% (25 of 36) for those with underlying CVD and elevated TnTs.,Patients with underlying CVD were more likely to exhibit elevation of TnT levels compared with the patients without CVD (36 [54.5%] vs 16 [13.2%]).,Plasma TnT levels demonstrated a high and significantly positive linear correlation with plasma high-sensitivity C-reactive protein levels (β = 0.530, P < .001) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (β = 0.613, P < .001).,Plasma TnT and NT-proBNP levels during hospitalization (median [interquartile range (IQR)], 0.307 [0.094-0.600]; 1902.00 [728.35-8100.00]) and impending death (median [IQR], 0.141 [0.058-0.860]; 5375 [1179.50-25695.25]) increased significantly compared with admission values (median [IQR], 0.0355 [0.015-0.102]; 796.90 [401.93-1742.25]) in patients who died (P = .001; P < .001), while no significant dynamic changes of TnT (median [IQR], 0.010 [0.007-0.019]; 0.013 [0.007-0.022]; 0.011 [0.007-0.016]) and NT-proBNP (median [IQR], 352.20 [174.70-636.70]; 433.80 [155.80-1272.60]; 145.40 [63.4-526.50]) was observed in survivors (P = .96; P = .16).,During hospitalization, patients with elevated TnT levels had more frequent malignant arrhythmias, and the use of glucocorticoid therapy (37 [71.2%] vs 69 [51.1%]) and mechanical ventilation (31 [59.6%] vs 14 [10.4%]) were higher compared with patients with normal TnT levels.,The mortality rates of patients with and without use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers was 36.8% (7 of 19) and 21.4% (36 of 168) (P = .13).,Myocardial injury is significantly associated with fatal outcome of COVID-19, while the prognosis of patients with underlying CVD but without myocardial injury is relatively favorable.,Myocardial injury is associated with cardiac dysfunction and arrhythmias.,Inflammation may be a potential mechanism for myocardial injury.,Aggressive treatment may be considered for patients at high risk of myocardial injury. | 1 |
The lymphatic vasculature has an essential role in maintaining normal fluid balance in tissues and modulating the inflammatory response to injury or pathogens.,Disruption of normal development or function of lymphatic vessels can have severe consequences.,In the heart, reduced lymphatic function can lead to myocardial oedema and persistent inflammation.,Macrophages, which are phagocytic cells of the innate immune system, contribute to cardiac development and to fibrotic repair and regeneration of cardiac tissue after myocardial infarction.,In this Review, we discuss the cardiac lymphatic vasculature with a focus on developments over the past 5 years arising from the study of mammalian and zebrafish model organisms.,In addition, we examine the interplay between the cardiac lymphatics and macrophages during fibrotic repair and regeneration after myocardial infarction.,Finally, we discuss the therapeutic potential of targeting the cardiac lymphatic network to regulate immune cell content and alleviate inflammation in patients with ischaemic heart disease.,This Review summarizes the latest knowledge on cardiac lymphatic development, structure and function, discusses the role of the cardiac lymphatics after myocardial injury during fibrotic repair and regeneration, and highlights the therapeutic potential of targeting the cardiac lymphatics in myocardial infarction.,The cardiac lymphatic vasculature appears during embryonic development and continues to mature structurally and functionally until late postnatal stages.Both venous and non-venous sources contribute to the lymphatic endothelium of the heart, and the identity of the lymphatic endothelial cells of venous origin is defined very early in development during specification of the embryonic mesoderm.In adult mice, the cardiac lymphatics respond to cardiac injury by sprouting within the damaged area in an attempt to clear the immune cells and excess tissue fluid (oedema).,Drug-induced augmentation of the lymphatic response to injury improves heart repair and function in adult mice, suggesting that the lymphatics could be a possible drug target for myocardial infarction and for other diseases.The neonatal mouse heart has regenerative capacity that requires the presence of pro-reparative macrophages, which suggests an alternative function for the cardiac lymphatics during neonatal heart regeneration.Adult zebrafish can regenerate their heart after cryoinjury, and the lymphatics respond to the site of injury to clear infiltrating immune cells, a process that is essential for complete regeneration.,The cardiac lymphatic vasculature appears during embryonic development and continues to mature structurally and functionally until late postnatal stages.,Both venous and non-venous sources contribute to the lymphatic endothelium of the heart, and the identity of the lymphatic endothelial cells of venous origin is defined very early in development during specification of the embryonic mesoderm.,In adult mice, the cardiac lymphatics respond to cardiac injury by sprouting within the damaged area in an attempt to clear the immune cells and excess tissue fluid (oedema).,Drug-induced augmentation of the lymphatic response to injury improves heart repair and function in adult mice, suggesting that the lymphatics could be a possible drug target for myocardial infarction and for other diseases.,The neonatal mouse heart has regenerative capacity that requires the presence of pro-reparative macrophages, which suggests an alternative function for the cardiac lymphatics during neonatal heart regeneration.,Adult zebrafish can regenerate their heart after cryoinjury, and the lymphatics respond to the site of injury to clear infiltrating immune cells, a process that is essential for complete regeneration. | Recent studies suggested a beneficial role of lymphatics in restoring heart function after cardiac injury1-6.,Here we report that in mice lymphatics promote cardiac growth, repair and cardio-protection.,We show that a lymphoangiocrine signal produced by lymphatic endothelial cells (LECs) controls cardiomyocyte (CM) proliferation and survival during heart development, improves neonatal cardiac regeneration and is cardioprotective after myocardial infarction (MI).,Embryos devoid of LECs develop smaller hearts as a consequence of reduced CM proliferation and increased CM apoptosis.,Culturing primary mouse CMs in LEC-conditioned media increases CM proliferation and survival, indicating that LECs produce lymphoangiocrine signals controlling CM homeostasis.,Characterization of the LEC secretome identified Reelin as a key player responsible for such function.,Moreover, we report that LEC-specific Reln-null embryos also develop smaller hearts, that Reelin is required for efficient heart repair and function following neonatal MI, and that cardiac delivery of REELIN using collagen patches improves adult heart function after MI through a cardioprotective effect.,These results identify a lymphoangiocrine role of LECs during cardiac development and injury response, and Reelin as an important mediator of this function. | 1 |
COVID-19 affects millions of patients worldwide, with clinical presentation ranging from isolated thrombosis to acute respiratory distress syndrome (ARDS) requiring ventilator support.,Neutrophil extracellular traps (NETs) originate from decondensed chromatin released to immobilize pathogens, and they can trigger immunothrombosis.,We studied the connection between NETs and COVID-19 severity and progression.,We conducted a prospective cohort study of COVID-19 patients (n = 33) and age- and sex-matched controls (n = 17).,We measured plasma myeloperoxidase (MPO)-DNA complexes (NETs), platelet factor 4, RANTES, and selected cytokines.,Three COVID-19 lung autopsies were examined for NETs and platelet involvement.,We assessed NET formation ex vivo in COVID-19 neutrophils and in healthy neutrophils incubated with COVID-19 plasma.,We also tested the ability of neonatal NET-inhibitory factor (nNIF) to block NET formation induced by COVID-19 plasma.,Plasma MPO-DNA complexes increased in COVID-19, with intubation (P < .0001) and death (P < .0005) as outcome.,Illness severity correlated directly with plasma MPO-DNA complexes (P = .0360), whereas Pao2/fraction of inspired oxygen correlated inversely (P = .0340).,Soluble and cellular factors triggering NETs were significantly increased in COVID-19, and pulmonary autopsies confirmed NET-containing microthrombi with neutrophil-platelet infiltration.,Finally, COVID-19 neutrophils ex vivo displayed excessive NETs at baseline, and COVID-19 plasma triggered NET formation, which was blocked by nNIF.,Thus, NETs triggering immunothrombosis may, in part, explain the prothrombotic clinical presentations in COVID-19, and NETs may represent targets for therapeutic intervention.,•NETs contribute to microthrombi through platelet-neutrophil interactions in COVID-19 ARDS.•nNIF blocks NETs induced by COVID-19 plasma and represents a potential therapeutic intervention in COVID-19.,NETs contribute to microthrombi through platelet-neutrophil interactions in COVID-19 ARDS.,nNIF blocks NETs induced by COVID-19 plasma and represents a potential therapeutic intervention in COVID-19. | This case series reports a systematic assessment of deep vein thrombosis among patients in an intensive care unit in France with severe coronavirus disease 2019 (COVID-19). | 1 |
The association of severe coronavirus disease 2019 (COVID-19) with an increased risk of venous thromboembolism (VTE) has resulted in specific guidelines for its prevention and management.,The VTE risk appears highest in those with critical care admission.,The need for postdischarge thromboprophylaxis remains controversial, which is reflected in conflicting expert guideline recommendations.,Our local protocol provides thromboprophylaxis to COVID-19 patients during admission only.,We report postdischarge VTE data from an ongoing quality improvement program incorporating root-cause analysis of hospital-associated VTE (HA-VTE).,Following 1877 hospital discharges associated with COVID-19, 9 episodes of HA-VTE were diagnosed within 42 days, giving a postdischarge rate of 4.8 per 1000 discharges.,Over 2019, following 18 159 discharges associated with a medical admission; there were 56 episodes of HA-VTE within 42 days (3.1 per 1000 discharges).,The odds ratio for postdischarge HA-VTE associated with COVID-19 compared with 2019 was 1.6 (95% confidence interval, 0.77-3.1).,COVID-19 hospitalization does not appear to increase the risk of postdischarge HA-VTE compared with hospitalization with other acute medical illness.,Given that the risk-benefit ratio of postdischarge thromboprophylaxis remains uncertain, randomized controlled trials to evaluate the role of continuing thromboprophylaxis in COVID-19 patients following hospital discharge are required.,•The rate of symptomatic postdischarge VTE following hospitalization with COVID-19 is low.,The rate of symptomatic postdischarge VTE following hospitalization with COVID-19 is low. | COVID-19 may predispose to both venous and arterial thromboembolism due to excessive inflammation, hypoxia, immobilisation and diffuse intravascular coagulation.,Reports on the incidence of thrombotic complications are however not available.,We evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction or systemic arterial embolism in all COVID-19 patients admitted to the ICU of 2 Dutch university hospitals and 1 Dutch teaching hospital.,We studied 184 ICU patients with proven COVID-19 pneumonia of whom 23 died (13%), 22 were discharged alive (12%) and 139 (76%) were still on the ICU on April 5th 2020.,All patients received at least standard doses thromboprophylaxis.,The cumulative incidence of the composite outcome was 31% (95%CI 20-41), of which CTPA and/or ultrasonography confirmed VTE in 27% (95%CI 17-37%) and arterial thrombotic events in 3.7% (95%CI 0-8.2%).,PE was the most frequent thrombotic complication (n = 25, 81%).,Age (adjusted hazard ratio (aHR) 1.05/per year, 95%CI 1.004-1.01) and coagulopathy, defined as spontaneous prolongation of the prothrombin time > 3 s or activated partial thromboplastin time > 5 s (aHR 4.1, 95%CI 1.9-9.1), were independent predictors of thrombotic complications.,The 31% incidence of thrombotic complications in ICU patients with COVID-19 infections is remarkably high.,Our findings reinforce the recommendation to strictly apply pharmacological thrombosis prophylaxis in all COVID-19 patients admitted to the ICU, and are strongly suggestive of increasing the prophylaxis towards high-prophylactic doses, even in the absence of randomized evidence. | 1 |
Patients with stroke-like symptoms may be underutilising emergency medical services and avoiding hospitalisation during the COVID-19 pandemic.,We investigated a decline in admissions for stroke and transient ischaemic attack (TIA) and emergency department (ED) stroke alert activations.,We retrospectively compiled total weekly hospital admissions for stroke and TIA between 31 December 2018 and 21 April 2019 versus 30 December 2019 and 19 April 2020 at five US tertiary academic comprehensive stroke centres in cities with early COVID-19 outbreaks in Boston, New York City, Providence and Seattle.,We collected available data on ED stroke alerts, stroke severity using the National Institutes of Health Stroke Scale (NIHSS) and time from symptom onset to hospital arrival.,Compared with 31 December 2018 to 21 April 2019, a decline in stroke/TIA admissions and ED stroke alerts occurred during 30 December 2019 to 19 April 2020 (p trend <0.001 for each).,The declines coincided with state stay-at-home recommendations in late March.,The greatest decline in hospital admissions was observed between 23 March and 19 April 2020, with a 31% decline compared with the corresponding weeks in 2019.,Three of the five centres with 2019 and 2020 stroke alert data had a 46% decline in ED stroke alerts in late March and April 2020, compared with 2019.,Median baseline NIHSS during these 4 weeks was 10 in 2020 and 7 in 2019.,There was no difference in time from symptom onset to hospital arrival.,At these five large academic US hospitals, admissions for stroke and TIA declined during the COVID-19 pandemic.,There was a trend for fewer ED stroke alerts at three of the five centres with available 2019 and 2020 data.,Acute stroke therapies are time-sensitive, so decreased healthcare access or utilisation may lead to more disabling or fatal strokes, or more severe non-neurological complications related to stroke.,Our findings underscore the indirect effects of this pandemic.,Public health officials, hospital systems and healthcare providers must continue to encourage patients with stroke to seek acute care during this crisis. | The current coronavirus disease 2019 (COVID-19) pandemic represents a global public health crisis, disrupting emergency healthcare services.,We determined whether COVID-19 has resulted in delays in stroke presentation and affected the delivery of acute stroke services in a comprehensive stroke center in Hong Kong.,We retrospectively reviewed all patients with transient ischemic attack and stroke admitted via the acute stroke pathway of Queen Mary Hospital, Hong Kong, during the first 60 days since the first diagnosed COVID-19 case in Hong Kong (COVID-19: January 23, 2020-March 24, 2020).,We compared the stroke onset to hospital arrival (onset-to-door) time and timings of inpatient stroke pathways with patients admitted during the same period in 2019 (pre-COVID-19: January 23, 2019-March 24, 2019).,Seventy-three patients in COVID-19 were compared with 89 patients in pre-COVID-19.,There were no significant differences in age, sex, vascular risk factors, nor stroke severity between the 2 groups (P>0.05).,The median stroke onset-to-door time was ≈1-hour longer in COVID-19 compared with pre-COVID-19 (154 versus 95 minutes, P=0.12), and the proportion of individuals with onset-to-door time within 4.5 hours was significantly lower (55% versus 72%, P=0.024).,Significantly fewer cases of transient ischemic attack presented to the hospital during COVID-19 (4% versus 16%, P=0.016), despite no increase in referrals to the transient ischemic attack clinic.,Inpatient stroke pathways and treatment time metrics nevertheless did not differ between the 2 groups (P>0.05 for all comparisons).,During the early containment phase of COVID-19, we noted a prolongation in stroke onset to hospital arrival time and a significant reduction in individuals arriving at the hospital within 4.5 hours and presenting with transient ischemic attack.,Public education about stroke should continue to be reinforced during the COVID-19 pandemic. | 1 |
The gut microbiota has been linked to cardiovascular diseases.,However, the composition and functional capacity of the gut microbiome in relation to cardiovascular diseases have not been systematically examined.,Here, we perform a metagenome-wide association study on stools from 218 individuals with atherosclerotic cardiovascular disease (ACVD) and 187 healthy controls.,The ACVD gut microbiome deviates from the healthy status by increased abundance of Enterobacteriaceae and Streptococcus spp. and, functionally, in the potential for metabolism or transport of several molecules important for cardiovascular health.,Although drug treatment represents a confounding factor, ACVD status, and not current drug use, is the major distinguishing feature in this cohort.,We identify common themes by comparison with gut microbiome data associated with other cardiometabolic diseases (obesity and type 2 diabetes), with liver cirrhosis, and rheumatoid arthritis.,Our data represent a comprehensive resource for further investigations on the role of the gut microbiome in promoting or preventing ACVD as well as other related diseases.,The gut microbiota may play a role in cardiovascular diseases.,Here, the authors perform a metagenome-wide association study on stools from individuals with atherosclerotic cardiovascular disease and healthy controls, identifying microbial strains and functions associated with the disease. | Gut microbial metabolites have been implicated as novel risk factors for cardiovascular events and premature death.,The strength and consistency of associations between blood concentrations of the gut microbial metabolites, trimethylamine‐N‐oxide (TMAO) and its precursors, with major adverse cardiovascular events (MACE) or death have not been comprehensively assessed.,We quantified associations of blood concentrations of TMAO and its precursors with risks of MACE and mortality.,PubMed and Embase databases were searched up, and a total of 19 prospective studies from 16 publications (n=19 256, including 3315 incident cases) with quantitative estimates of the associations of TMAO with the development of MACE or death were included in our main analysis.,Multivariate‐adjusted relative risks (RRs) were used when these were available.,Elevated concentrations of TMAO were associated with a pooled RR of 1.62 (95% CI, 1.45, 1.80; P heterogeneity=0.2; I2=23.5%) for MACE compared with low TMAO levels, and 1 study of black participants influenced the heterogeneity of the association.,After excluding the data of blacks, the RRs were not different according to body mass index, prevalence of diabetes mellitus, history of cardiovascular diseases, and kidney dysfunction.,Furthermore, elevated TMAO concentrations were associated with a pooled RR of 1.63 (1.36, 1.95) for all‐cause mortality.,Individuals with elevated concentrations of TMAO precursors (l‐carnitine, choline, or betaine) had an approximately 1.3 to 1.4 times higher risk for MACE compared to those with low concentrations.,Elevated concentrations of TMAO and its precursors were associated with increased risks of MACE and all‐cause mortality independently of traditional risk factors. | 1 |
What are the cardiovascular effects in unselected patients with recent coronavirus disease 2019 (COVID-19)?,In this cohort study including 100 patients recently recovered from COVID-19 identified from a COVID-19 test center, cardiac magnetic resonance imaging revealed cardiac involvement in 78 patients (78%) and ongoing myocardial inflammation in 60 patients (60%), which was independent of preexisting conditions, severity and overall course of the acute illness, and the time from the original diagnosis.,These findings indicate the need for ongoing investigation of the long-term cardiovascular consequences of COVID-19.,This cohort study evaluates the presence of myocardial injury in unselected patients recently recovered from coronavirus disease 2019 (COVID-19).,Coronavirus disease 2019 (COVID-19) continues to cause considerable morbidity and mortality worldwide.,Case reports of hospitalized patients suggest that COVID-19 prominently affects the cardiovascular system, but the overall impact remains unknown.,To evaluate the presence of myocardial injury in unselected patients recently recovered from COVID-19 illness.,In this prospective observational cohort study, 100 patients recently recovered from COVID-19 illness were identified from the University Hospital Frankfurt COVID-19 Registry between April and June 2020.,Recent recovery from severe acute respiratory syndrome coronavirus 2 infection, as determined by reverse transcription-polymerase chain reaction on swab test of the upper respiratory tract.,Demographic characteristics, cardiac blood markers, and cardiovascular magnetic resonance (CMR) imaging were obtained.,Comparisons were made with age-matched and sex-matched control groups of healthy volunteers (n = 50) and risk factor-matched patients (n = 57).,Of the 100 included patients, 53 (53%) were male, and the mean (SD) age was 49 (14) years.,The median (IQR) time interval between COVID-19 diagnosis and CMR was 71 (64-92) days.,Of the 100 patients recently recovered from COVID-19, 67 (67%) recovered at home, while 33 (33%) required hospitalization.,At the time of CMR, high-sensitivity troponin T (hsTnT) was detectable (greater than 3 pg/mL) in 71 patients recently recovered from COVID-19 (71%) and significantly elevated (greater than 13.9 pg/mL) in 5 patients (5%).,Compared with healthy controls and risk factor-matched controls, patients recently recovered from COVID-19 had lower left ventricular ejection fraction, higher left ventricle volumes, and raised native T1 and T2.,A total of 78 patients recently recovered from COVID-19 (78%) had abnormal CMR findings, including raised myocardial native T1 (n = 73), raised myocardial native T2 (n = 60), myocardial late gadolinium enhancement (n = 32), or pericardial enhancement (n = 22).,There was a small but significant difference between patients who recovered at home vs in the hospital for native T1 mapping (median [IQR], 1119 [1092-1150] ms vs 1141 [1121-1175] ms; P = .008) and hsTnT (4.2 [3.0-5.9] pg/dL vs 6.3 [3.4-7.9] pg/dL; P = .002) but not for native T2 mapping.,None of these measures were correlated with time from COVID-19 diagnosis (native T1: r = 0.07; P = .47; native T2: r = 0.14; P = .15; hsTnT: r = −0.07; P = .50).,High-sensitivity troponin T was significantly correlated with native T1 mapping (r = 0.33; P < .001) and native T2 mapping (r = 0.18; P = .01).,Endomyocardial biopsy in patients with severe findings revealed active lymphocytic inflammation.,Native T1 and T2 were the measures with the best discriminatory ability to detect COVID-19-related myocardial pathology.,In this study of a cohort of German patients recently recovered from COVID-19 infection, CMR revealed cardiac involvement in 78 patients (78%) and ongoing myocardial inflammation in 60 patients (60%), independent of preexisting conditions, severity and overall course of the acute illness, and time from the original diagnosis.,These findings indicate the need for ongoing investigation of the long-term cardiovascular consequences of COVID-19. | Coronavirus disease 2019 (COVID-19) is a pandemic that has affected more than 1.8 million people worldwide, overwhelmed health care systems owing to the high proportion of critical presentations, and resulted in more than 100,000 deaths.,Since the first data analyses in China, elevated cardiac troponin has been noted in a substantial proportion of patients, implicating myocardial injury as a possible pathogenic mechanism contributing to severe illness and mortality.,Accordingly, high troponin levels are associated with increased mortality in patients with COVID-19.,This brief review explores the available evidence regarding the association between COVID-19 and myocardial injury. | 1 |
We describe the first case of acute cardiac injury directly linked to myocardial localization of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in a 69‐year‐old patient with flu‐like symptoms rapidly degenerating into respiratory distress, hypotension, and cardiogenic shock.,The patient was successfully treated with venous‐arterial extracorporeal membrane oxygenation (ECMO) and mechanical ventilation.,Cardiac function fully recovered in 5 days and ECMO was removed.,Endomyocardial biopsy demonstrated low‐grade myocardial inflammation and viral particles in the myocardium suggesting either a viraemic phase or, alternatively, infected macrophage migration from the lung. | To delineate the clinical characteristics of patients with coronavirus disease 2019 (covid-19) who died.,Retrospective case series.,Tongji Hospital in Wuhan, China.,Among a cohort of 799 patients, 113 who died and 161 who recovered with a diagnosis of covid-19 were analysed.,Data were collected until 28 February 2020.,Clinical characteristics and laboratory findings were obtained from electronic medical records with data collection forms.,The median age of deceased patients (68 years) was significantly older than recovered patients (51 years).,Male sex was more predominant in deceased patients (83; 73%) than in recovered patients (88; 55%).,Chronic hypertension and other cardiovascular comorbidities were more frequent among deceased patients (54 (48%) and 16 (14%)) than recovered patients (39 (24%) and 7 (4%)).,Dyspnoea, chest tightness, and disorder of consciousness were more common in deceased patients (70 (62%), 55 (49%), and 25 (22%)) than in recovered patients (50 (31%), 48 (30%), and 1 (1%)).,The median time from disease onset to death in deceased patients was 16 (interquartile range 12.0-20.0) days.,Leukocytosis was present in 56 (50%) patients who died and 6 (4%) who recovered, and lymphopenia was present in 103 (91%) and 76 (47%) respectively.,Concentrations of alanine aminotransferase, aspartate aminotransferase, creatinine, creatine kinase, lactate dehydrogenase, cardiac troponin I, N-terminal pro-brain natriuretic peptide, and D-dimer were markedly higher in deceased patients than in recovered patients.,Common complications observed more frequently in deceased patients included acute respiratory distress syndrome (113; 100%), type I respiratory failure (18/35; 51%), sepsis (113; 100%), acute cardiac injury (72/94; 77%), heart failure (41/83; 49%), alkalosis (14/35; 40%), hyperkalaemia (42; 37%), acute kidney injury (28; 25%), and hypoxic encephalopathy (23; 20%).,Patients with cardiovascular comorbidity were more likely to develop cardiac complications.,Regardless of history of cardiovascular disease, acute cardiac injury and heart failure were more common in deceased patients.,Severe acute respiratory syndrome coronavirus 2 infection can cause both pulmonary and systemic inflammation, leading to multi-organ dysfunction in patients at high risk.,Acute respiratory distress syndrome and respiratory failure, sepsis, acute cardiac injury, and heart failure were the most common critical complications during exacerbation of covid-19. | 1 |
We assessed the impact of the coronavirus disease 19 (COVID-19) pandemic on code stroke activations in the emergency department, stroke unit admissions, and referrals to the stroke prevention clinic at London’s regional stroke center, serving a population of 1.8 million in Ontario, Canada.,We found a 20% drop in the number of code strokes in 2020 compared to 2019, immediately after the first cases of COVID-19 were officially confirmed.,There were no changes in the number of stroke admissions and there was a 22% decrease in the number of clinic referrals, only after the provincial lockdown.,Our findings suggest that the decrease in code strokes was mainly driven by patient-related factors such as fear to be exposed to the SARS-CoV-2, while the reduction in clinic referrals was largely explained by hospital policies and the Government lockdown. | In order to cope with the exponentially increasing number of patients infected with SARS‐CoV‐2, European countries made enormous efforts to reorganize medical assistance and several diseases, including stroke, were particularly impacted.,We report the experience of stroke neurologists from three European countries (Italy, France and Germany) that faced the pandemic at diverse time points and with different approaches, depending on their resources and healthcare system organization.,Pre‐hospital and in‐hospital acute stroke pathways were reorganized to prioritize COVID‐19 management and, in severely affected regions of Italy and France, stroke care was centralized to a limited number of centers, whereas the remaining stroke units were dedicated to patients with COVID‐19.,Access to acute stroke diagnostics and time‐dependent therapies was limited or delayed because of reduced capacities of emergency services due to the burden of patients with COVID‐19.,A marked reduction in the number of patients presenting with transient ischaemic attack and stroke was noted in the emergency departments of all three countries.,Although we only have preliminary data, these conditions may have affected stroke outcome.,These indirect effects of the COVID‐19 pandemic could negate the efforts of stroke neurologists over the last few years to improve outcome and reduce mortality of stroke patients.,Although the SARS‐CoV‐2 infection rate is slowing down in Europe, the effects of ending lockdown in the next months are unpredictable.,It is important for the European and world stroke community to share what has been learned so far to be plan strategies to ensure stroke care in the future and upcoming challenging times. | 1 |
The novel coronavirus disease (COVID-19) outbreak, caused by SARS-CoV-2, represents the greatest medical challenge in decades.,We provide a comprehensive review of the clinical course of COVID-19, its comorbidities, and mechanistic considerations for future therapies.,While COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome (ARDS), it also affects multiple organs, particularly the cardiovascular system.,Risk of severe infection and mortality increase with advancing age and male sex.,Mortality is increased by comorbidities: cardiovascular disease, hypertension, diabetes, chronic pulmonary disease, and cancer.,The most common complications include arrhythmia (atrial fibrillation, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury [elevated highly sensitive troponin I (hs-cTnI) and creatine kinase (CK) levels], fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation (DIC).,Mechanistically, SARS-CoV-2, following proteolytic cleavage of its S protein by a serine protease, binds to the transmembrane angiotensin-converting enzyme 2 (ACE2) -a homologue of ACE-to enter type 2 pneumocytes, macrophages, perivascular pericytes, and cardiomyocytes.,This may lead to myocardial dysfunction and damage, endothelial dysfunction, microvascular dysfunction, plaque instability, and myocardial infarction (MI).,While ACE2 is essential for viral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis.,Hence, patients should not discontinue their use.,Moreover, renin-angiotensin-aldosterone system (RAAS) inhibitors might be beneficial in COVID-19.,Initial immune and inflammatory responses induce a severe cytokine storm [interleukin (IL)-6, IL-7, IL-22, IL-17, etc.] during the rapid progression phase of COVID-19.,Early evaluation and continued monitoring of cardiac damage (cTnI and NT-proBNP) and coagulation (D-dimer) after hospitalization may identify patients with cardiac injury and predict COVID-19 complications.,Preventive measures (social distancing and social isolation) also increase cardiovascular risk.,Cardiovascular considerations of therapies currently used, including remdesivir, chloroquine, hydroxychloroquine, tocilizumab, ribavirin, interferons, and lopinavir/ritonavir, as well as experimental therapies, such as human recombinant ACE2 (rhACE2), are discussed. | •SARS-CoV-2 may impair host antiviral response, causing subsequent hyperinflammation.,•SARS-CoV-2 likely deranges the renin angiotensin aldosterone system (RAAS).,•Hyperinflammation and RAAS imbalance may drive acute lung injury and coagulopathy.,•RAAS imbalance impairs fibrinolysis, which can result in relative hypofibrinolysis.,•This can lead widespread immunothrombosis, contributing to multi-organ damage.,SARS-CoV-2 may impair host antiviral response, causing subsequent hyperinflammation.,SARS-CoV-2 likely deranges the renin angiotensin aldosterone system (RAAS).,Hyperinflammation and RAAS imbalance may drive acute lung injury and coagulopathy.,RAAS imbalance impairs fibrinolysis, which can result in relative hypofibrinolysis.,This can lead widespread immunothrombosis, contributing to multi-organ damage.,Early clinical evidence suggests that severe cases of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are frequently characterized by hyperinflammation, imbalance of renin-angiotensin-aldosterone system, and a particular form of vasculopathy, thrombotic microangiopathy, and intravascular coagulopathy.,In this paper, we present an immunothrombosis model of COVID-19.,We discuss the underlying pathogenesis and the interaction between multiple systems, resulting in propagation of immunothrombosis, which through investigation in the coming weeks, may lead to both an improved understanding of COVID-19 pathophysiology and identification of innovative and efficient therapeutic targets to reverse the otherwise unfavorable clinical outcome of many of these patients. | 1 |
Coronavirus disease (COVID-19) is a serious illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).,The symptoms of the disease range from asymptomatic to mild respiratory symptoms and even potentially life-threatening cardiovascular and pulmonary complications.,Cardiac complications include acute myocardial injury, arrhythmias, cardiogenic shock and even sudden death.,Furthermore, drug interactions with COVID-19 therapies may place the patient at risk for arrhythmias, cardiomyopathy and sudden death.,In this review, we summarise the cardiac manifestations of COVID-19 infection and propose a simplified algorithm for patient management during the COVID-19 pandemic. | We describe the first case of acute cardiac injury directly linked to myocardial localization of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in a 69‐year‐old patient with flu‐like symptoms rapidly degenerating into respiratory distress, hypotension, and cardiogenic shock.,The patient was successfully treated with venous‐arterial extracorporeal membrane oxygenation (ECMO) and mechanical ventilation.,Cardiac function fully recovered in 5 days and ECMO was removed.,Endomyocardial biopsy demonstrated low‐grade myocardial inflammation and viral particles in the myocardium suggesting either a viraemic phase or, alternatively, infected macrophage migration from the lung. | 1 |
The COVID‐19 pandemic has become an urgent issue in every country.,Based on recent reports, the most severely ill patients present with coagulopathy, and disseminated intravascular coagulation (DIC)‐like massive intravascular clot formation is frequently seen in this cohort.,Therefore, coagulation tests may be considered useful to discriminate severe cases of COVID‐19.,The clinical presentation of COVID‐19‐associated coagulopathy is organ dysfunction primarily, whereas hemorrhagic events are less frequent.,Changes in hemostatic biomarkers represented by increase in D‐dimer and fibrin/fibrinogen degradation products indicate the essence of coagulopathy is massive fibrin formation.,In comparison with bacterial‐sepsis‐associated coagulopathy/DIC, prolongation of prothrombin time, and activated partial thromboplastin time, and decrease in antithrombin activity is less frequent and thrombocytopenia is relatively uncommon in COVID‐19.,The mechanisms of the coagulopathy are not fully elucidated, however.,It is speculated that the dysregulated immune responses orchestrated by inflammatory cytokines, lymphocyte cell death, hypoxia, and endothelial damage are involved.,Bleeding tendency is uncommon, but the incidence of thrombosis in COVID‐19 and the adequacy of current recommendations regarding standard venous thromboembolic dosing are uncertain. | Coronavirus disease 2019 (COVID-19) is a viral infection that can, in severe cases, result in cytokine storm, systemic inflammatory response and coagulopathy that is prognostic of poor outcomes.,While some, but not all, laboratory findings appear similar to sepsis-associated disseminated intravascular coagulopathy (DIC), COVID-19- induced coagulopathy (CIC) appears to be more prothrombotic than hemorrhagic.,It has been postulated that CIC may be an uncontrolled immunothrombotic response to COVID-19, and there is growing evidence of venous and arterial thromboembolic events in these critically ill patients.,Clinicians around the globe are challenged with rapidly identifying reasonable diagnostic, monitoring and anticoagulant strategies to safely and effectively manage these patients.,Thoughtful use of proven, evidence-based approaches must be carefully balanced with integration of rapidly emerging evidence and growing experience.,The goal of this document is to provide guidance from the Anticoagulation Forum, a North American organization of anticoagulation providers, regarding use of anticoagulant therapies in patients with COVID-19.,We discuss in-hospital and post-discharge venous thromboembolism (VTE) prevention, treatment of suspected but unconfirmed VTE, laboratory monitoring of COVID-19, associated anticoagulant therapies, and essential elements for optimized transitions of care specific to patients with COVID-19. | 1 |
High mortality rates have been reported in patients with cerebral venous sinus thrombosis (CVST) due to vaccine‐induced immune thrombotic thrombocytopenia (VITT) after vaccination with adenoviral vector SARS‐CoV‐2 vaccines.,The aim of this study was to evaluate whether the mortality of patients with CVST‐VITT has decreased over time.,The EudraVigilance database of the European Medicines Agency was used to identify cases of CVST with concomitant thrombocytopenia occurring within 28 days of SARS‐CoV‐2 vaccination.,Vaccines were grouped based on vaccine type (adenoviral or mRNA).,Cases with CVST onset until 28 March were compared to cases after 28 March 2021, which was the day when the first scientific paper on VITT was published.,In total, 270 cases of CVST with thrombocytopenia were identified, of which 266 (99%) occurred after adenoviral vector SARS‐CoV‐2 vaccination (ChAdOx1 nCoV‐19, n = 243; Ad26.,COV2.,S, n = 23).,The reported mortality amongst adenoviral cases with onset up to 28 March 2021 was 47/99 (47%, 95% confidence interval 37%-58%) compared to 36/167 (22%, 95% confidence interval 16%-29%) in cases with onset after 28 March (p < 0.001).,None of the four cases of CVST with thrombocytopenia occurring after mRNA vaccination died.,The reported mortality of CVST with thrombocytopenia after vaccination with adenoviral vector‐based SARS‐CoV‐2 vaccines has significantly decreased over time, which may indicate a beneficial effect of earlier recognition and/or improved treatment on outcome after VITT.,The EudraVigilance database of the European Medicines Agency was used to identify cases of cerebral venous sinus thrombosis (CVST) with concomitant thrombocytopenia occurring within 28 days of SARS‐CoV‐2 vaccination.,The reported mortality of CVST with thrombocytopenia after vaccination with adenoviral vector‐based vaccines significantly decreased over time with a mortality rate of 47% (95% confidence interval 37%-58%) in cases with CVST onset prior to 28 March 2021 compared to 22% (95% confidence interval 16%-29%) in cases after 28 March (p < 0.001).,This declining mortality may indicate a beneficial effect of earlier recognition and/or improved treatment on outcome after vaccine‐induced thrombotic thrombocytopenia. | Several cases of unusual thrombotic events and thrombocytopenia have developed after vaccination with the recombinant adenoviral vector encoding the spike protein antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (ChAdOx1 nCov-19, AstraZeneca).,More data were needed on the pathogenesis of this unusual clotting disorder.,We assessed the clinical and laboratory features of 11 patients in Germany and Austria in whom thrombosis or thrombocytopenia had developed after vaccination with ChAdOx1 nCov-19.,We used a standard enzyme-linked immunosorbent assay to detect platelet factor 4 (PF4)-heparin antibodies and a modified (PF4-enhanced) platelet-activation test to detect platelet-activating antibodies under various reaction conditions.,Included in this testing were samples from patients who had blood samples referred for investigation of vaccine-associated thrombotic events, with 28 testing positive on a screening PF4-heparin immunoassay.,Of the 11 original patients, 9 were women, with a median age of 36 years (range, 22 to 49).,Beginning 5 to 16 days after vaccination, the patients presented with one or more thrombotic events, with the exception of 1 patient, who presented with fatal intracranial hemorrhage.,Of the patients with one or more thrombotic events, 9 had cerebral venous thrombosis, 3 had splanchnic-vein thrombosis, 3 had pulmonary embolism, and 4 had other thromboses; of these patients, 6 died.,Five patients had disseminated intravascular coagulation.,None of the patients had received heparin before symptom onset.,All 28 patients who tested positive for antibodies against PF4-heparin tested positive on the platelet-activation assay in the presence of PF4 independent of heparin.,Platelet activation was inhibited by high levels of heparin, Fc receptor-blocking monoclonal antibody, and immune globulin (10 mg per milliliter).,Additional studies with PF4 or PF4-heparin affinity purified antibodies in 2 patients confirmed PF4-dependent platelet activation.,Vaccination with ChAdOx1 nCov-19 can result in the rare development of immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4, which clinically mimics autoimmune heparin-induced thrombocytopenia.,(Funded by the German Research Foundation.) | 1 |
The incidence, characteristics, and prognosis of pulmonary embolism (PE) in Coronavirus disease 2019 (COVID-19) have been poorly investigated.,We aimed to investigate the prevalence and the correlates with the occurrence of PE as well as the association between PE and the risk of mortality in COVID-19.,Retrospective multicenter study on consecutive COVID-19 patients hospitalized at 7 Italian Hospitals.,At admission, all patients underwent medical history, laboratory and echocardiographic evaluation.,The study population consisted of 224 patients (mean age 69 ± 14, male sex 62%); PE was diagnosed in 32 cases (14%).,Patients with PE were hospitalized after a longer time since symptoms onset (7 IQR 3-11 days, 3 IQR 1-6 days; p = 0.001) and showed higher D-dimers level (1819 IQR 568-5017 ng/ml vs 555 IQR 13-1530 ng/ml; p < 0.001) and higher prevalence of myocardial injury (47% vs 28%, p = 0.033).,At multivariable analysis, tricuspid annular plane systolic excursion (TAPSE; HR = 0.84; 95% CI 0.66-0.98; p = 0.046) and systolic pulmonary arterial pressure (sPAP; HR = 1.12; 95% CI 1.03-1.23; p = 0.008) resulted the only parameters independently associated with PE occurrence.,Mortality rates (50% vs 27%; p = 0.010) and cardiogenic shock (37% vs 14%; p = 0.001) were significantly higher in PE as compared with non-PE patients.,At multivariate analysis PE was significant associated with mortality.,PE is relatively common complication in COVID-19 and is associated with increased mortality risk.,TAPSE and sPAP resulted the only parameters independently associated with PE occurrence in COVID-19 patients. | An important feature of severe acute respiratory syndrome coronavirus 2 pathogenesis is COVID-19-associated coagulopathy, characterised by increased thrombotic and microvascular complications.,Previous studies have suggested a role for endothelial cell injury in COVID-19-associated coagulopathy.,To determine whether endotheliopathy is involved in COVID-19-associated coagulopathy pathogenesis, we assessed markers of endothelial cell and platelet activation in critically and non-critically ill patients admitted to the hospital with COVID-19.,In this single-centre cross-sectional study, hospitalised adult (≥18 years) patients with laboratory-confirmed COVID-19 were identified in the medical intensive care unit (ICU) or a specialised non-ICU COVID-19 floor in our hospital.,Asymptomatic, non-hospitalised controls were recruited as a comparator group for biomarkers that did not have a reference range.,We assessed markers of endothelial cell and platelet activation, including von Willebrand Factor (VWF) antigen, soluble thrombomodulin, soluble P-selectin, and soluble CD40 ligand, as well as coagulation factors, endogenous anticoagulants, and fibrinolytic enzymes.,We compared the level of each marker in ICU patients, non-ICU patients, and controls, where applicable.,We assessed correlations between these laboratory results with clinical outcomes, including hospital discharge and mortality.,Kaplan-Meier analysis was used to further explore the association between biochemical markers and survival.,68 patients with COVID-19 were included in the study from April 13 to April 24, 2020, including 48 ICU and 20 non-ICU patients, as well as 13 non-hospitalised, asymptomatic controls.,Markers of endothelial cell and platelet activation were significantly elevated in ICU patients compared with non-ICU patients, including VWF antigen (mean 565% [SD 199] in ICU patients vs 278% [133] in non-ICU patients; p<0·0001) and soluble P-selectin (15·9 ng/mL [4·8] vs 11·2 ng/mL [3·1]; p=0·0014).,VWF antigen concentrations were also elevated above the normal range in 16 (80%) of 20 non-ICU patients.,We found mortality to be significantly correlated with VWF antigen (r = 0·38; p=0·0022) and soluble thrombomodulin (r = 0·38; p=0·0078) among all patients.,In all patients, soluble thrombomodulin concentrations greater than 3·26 ng/mL were associated with lower rates of hospital discharge (22 [88%] of 25 patients with low concentrations vs 13 [52%] of 25 patients with high concentrations; p=0·0050) and lower likelihood of survival on Kaplan-Meier analysis (hazard ratio 5·9, 95% CI 1·9-18·4; p=0·0087).,Our findings show that endotheliopathy is present in COVID-19 and is likely to be associated with critical illness and death.,Early identification of endotheliopathy and strategies to mitigate its progression might improve outcomes in COVID-19.,This work was supported by a gift donation from Jack Levin to the Benign Hematology programme at Yale, and the National Institutes of Health. | 1 |
Coagulopathy is a common abnormality in patients with COVID‐19.,However, the exact incidence of venous thromboembolic event is unknown in anticoagulated, severe COVID‐19 patients.,Systematic assessment of venous thromboembolism (VTE) using complete duplex ultrasound (CDU) in anticoagulated COVID‐19 patients.,We performed a retrospective study in 2 French intensive care units (ICU) where CDU is performed as a standard of care.,A CDU from thigh to ankle at selected sites with Doppler waveforms and images was performed early during ICU stay in patients admitted with COVID‐19.,Anticoagulation dose was left to the discretion of the treating physician based on the individual risk of thrombosis.,Patients were classified as treated with prophylactic anticoagulation or therapeutic anticoagulation.,Pulmonary embolism was systematically searched in patients with persistent hypoxemia or secondary deterioration.,From March 19 to April 11, 2020, 26 consecutive patients with severe COVID‐19 were screened for VTE.,Eight patients (31%) were treated with prophylactic anticoagulation, whereas 18 patients (69%) were treated with therapeutic anticoagulation.,The overall rate of VTE in patients was 69%.,The proportion of VTE was significantly higher in patients treated with prophylactic anticoagulation when compared with the other group (100% vs 56%, respectively, P = .03).,Surprisingly, we found a high rate of thromboembolic events in COVID‐19 patients treated with therapeutic anticoagulation, with 56% of VTE and 6 pulmonary embolisms.,Our results suggest considering both systematic screening of VTE and early therapeutic anticoagulation in severe ICU COVID‐19 patients. | •COVID-19 pneumonia could be associated with an increased risk of venous thrombosis.,•Antiphospholipid antibodies might be involved in thrombosis in COVID-19 patients.,•Prevalence of antiphospholipid antibodies in COVID-19 and venous thrombosis was low.,COVID-19 pneumonia could be associated with an increased risk of venous thrombosis.,Antiphospholipid antibodies might be involved in thrombosis in COVID-19 patients.,Prevalence of antiphospholipid antibodies in COVID-19 and venous thrombosis was low. | 1 |
Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19).,We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19.,In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care.,The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge.,The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation.,Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis).,The median value for organ support-free days was 1 (interquartile range, −1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, −1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%).,The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11).,Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis.,In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis.,(REMAP-CAP, ACTIV-4a, and ATTACC ClinicalTrials.gov numbers, NCT02735707, NCT04505774, NCT04359277, and NCT04372589.) | We recently reported a high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 admitted to the intensive care units (ICUs) of three Dutch hospitals.,In answering questions raised regarding our study, we updated our database and repeated all analyses.,We re-evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction and/or systemic arterial embolism in all COVID-19 patients admitted to the ICUs of 2 Dutch university hospitals and 1 Dutch teaching hospital from ICU admission to death, ICU discharge or April 22nd 2020, whichever came first.,We studied the same 184 ICU patients as reported on previously, of whom a total of 41 died (22%) and 78 were discharged alive (43%).,The median follow-up duration increased from 7 to 14 days.,All patients received pharmacological thromboprophylaxis.,The cumulative incidence of the composite outcome, adjusted for competing risk of death, was 49% (95% confidence interval [CI] 41-57%).,The majority of thrombotic events were PE (65/75; 87%).,In the competing risk model, chronic anticoagulation therapy at admission was associated with a lower risk of the composite outcome (Hazard Ratio [HR] 0.29, 95%CI 0.091-0.92).,Patients diagnosed with thrombotic complications were at higher risk of all-cause death (HR 5.4; 95%CI 2.4-12).,Use of therapeutic anticoagulation was not associated with all-cause death (HR 0.79, 95%CI 0.35-1.8).,In this updated analysis, we confirm the very high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 pneumonia. | 1 |
Infection by the 2019 novel coronavirus (COVID-19) has been reportedly associated with a high risk of thrombotic complications.,So far information is scarce and rapidly emerging.,We conducted a scoping review using a single engine search for studies assessing thrombosis and coagulopathy in COVID-19 patients.,Additional studies were identified by secondary review and alert services.,Studies reported the occurrence of venous thromboembolism and stroke in approximately 20% and 3% of patients, respectively.,A higher frequency seems to be present in severely ill patients, in particular those admitted to intensive care units.,The thrombotic risk is elevated despite the use of anticoagulant prophylaxis but optimal doses of anticoagulation are not yet defined.,Although an increase of biomarkers such as D-dimer has been consistently reported in severely ill COVID-19, the optimal cut-off level and prognostic value are not known.,A number of pressing issues were identified by this review, including defining the true incidence of VTE in COVID patients, developing algorithms to identify those susceptible to develop thrombotic complications and severe disease, determining the role of biomarkers and/or scoring systems to stratify patients' risk, designing adequate and feasible diagnostic protocols for PE, establishing the optimal thromboprophylaxis strategy, and developing uniform diagnostic and reporting criteria.,•Thrombotic events, venous and arterial are frequent in COVID-19, more so in critically ill patients.,•Valid biomarkers to define risk and prognosis are still lacking.,•Anticoagulant prophylaxis is needed in all patients.,•The role of higher doses of anticoagulants in all patients is unclear.,•There is a need to develop standard clinical definitions, common data elements, and standard reporting criteria.,Thrombotic events, venous and arterial are frequent in COVID-19, more so in critically ill patients.,Valid biomarkers to define risk and prognosis are still lacking.,Anticoagulant prophylaxis is needed in all patients.,The role of higher doses of anticoagulants in all patients is unclear.,There is a need to develop standard clinical definitions, common data elements, and standard reporting criteria. | A potential association between the use of angiotensin-receptor blockers (ARBs) and angiotensin-converting-enzyme (ACE) inhibitors and the risk of coronavirus disease 2019 (Covid-19) has not been well studied.,We carried out a population-based case-control study in the Lombardy region of Italy.,A total of 6272 case patients in whom infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was confirmed between February 21 and March 11, 2020, were matched to 30,759 beneficiaries of the Regional Health Service (controls) according to sex, age, and municipality of residence.,Information about the use of selected drugs and patients’ clinical profiles was obtained from regional databases of health care use.,Odds ratios and 95% confidence intervals for associations between drugs and infection, with adjustment for confounders, were estimated by means of logistic regression.,Among both case patients and controls, the mean (±SD) age was 68±13 years, and 37% were women.,The use of ACE inhibitors and ARBs was more common among case patients than among controls, as was the use of other antihypertensive and non-antihypertensive drugs, and case patients had a worse clinical profile.,Use of ARBs or ACE inhibitors did not show any association with Covid-19 among case patients overall (adjusted odds ratio, 0.95 [95% confidence interval {CI}, 0.86 to 1.05] for ARBs and 0.96 [95% CI, 0.87 to 1.07] for ACE inhibitors) or among patients who had a severe or fatal course of the disease (adjusted odds ratio, 0.83 [95% CI, 0.63 to 1.10] for ARBs and 0.91 [95% CI, 0.69 to 1.21] for ACE inhibitors), and no association between these variables was found according to sex.,In this large, population-based study, the use of ACE inhibitors and ARBs was more frequent among patients with Covid-19 than among controls because of their higher prevalence of cardiovascular disease.,However, there was no evidence that ACE inhibitors or ARBs affected the risk of COVID-19. | 1 |
COVID-19, the disease responsible for the devastating pandemic that began at the end of 2019, has been associated with a significantly increased risk of pulmonary thrombosis, even in patients receiving prophylactic anticoagulation.,The predilection for thrombosis in COVID-19 may be driven by at least two distinct, but interrelated, processes: a hypercoagulable state responsible for large-vessel thrombosis and thromboembolism and direct vascular and endothelial injury responsible for in situ microvascular thrombosis.,The presence of pulmonary thrombosis may explain why hypoxemia is out of proportion to impairment in lung compliance in some patients with COVID-19 pneumonia.,Because pulmonary embolism (PE) and COVID-19 pneumonia share many signs and symptoms, diagnosing PE in patients with COVID-19 can be challenging.,Given the high mortality and morbidity associated with severe COVID-19 and the concern that aspects of the disease may be driven by thrombosis, many hospital systems have instituted aggressive anticoagulation protocols above standard VTE prophylaxis.,In this review, the epidemiologic and pathophysiologic features, diagnosis, and treatment of COVID-19 pulmonary thrombosis and thromboembolism are discussed. | Progressive respiratory failure is seen as a major cause of death in severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection.,Relatively little is known about the associated morphologic and molecular changes in the circulation of these patients.,In particular, platelet and erythrocyte pathology might result in severe vascular issues, and the manifestations may include thrombotic complications.,These thrombotic pathologies may be both extrapulmonary and intrapulmonary and may be central to respiratory failure.,Previously, we reported the presence of amyloid microclots in the circulation of patients with coronavirus disease 2019 (COVID-19).,Here, we investigate the presence of related circulating biomarkers, including C-reactive protein (CRP), serum ferritin, and P-selectin.,These biomarkers are well-known to interact with, and cause pathology to, platelets and erythrocytes.,We also study the structure of platelets and erythrocytes using fluorescence microscopy (using the markers PAC-1 and CD62PE) and scanning electron microscopy.,Thromboelastography and viscometry were also used to study coagulation parameters and plasma viscosity.,We conclude that structural pathologies found in platelets and erythrocytes, together with spontaneously formed amyloid microclots, may be central to vascular changes observed during COVID-19 progression, including thrombotic microangiopathy, diffuse intravascular coagulation, and large-vessel thrombosis, as well as ground-glass opacities in the lungs.,Consequently, this clinical snapshot of COVID-19 strongly suggests that it is also a true vascular disease and considering it as such should form an essential part of a clinical treatment regime. | 1 |
Hypertension is a common comorbidity in hospitalized patients with COVID-19 infection.,This study aimed to estimate the risks of adverse events associated with in-hospital blood pressure (BP) control and the effects of angiotensin II receptor blocker (ARB) prescription in COVID-19 patients with concomitant hypertension.,In this retrospective cohort study, the anonymized medical records of COVID-19 patients were retrieved from an acute field hospital in Wuhan, China.,Clinical data, drug prescriptions, and laboratory investigations were collected for individual patients with diagnosed hypertension on admission.,Cox proportional hazards models were used to estimate the risks of adverse outcomes associated with BP control during the hospital stay.,Of 803 hypertensive patients, 67 (8.3%) were admitted to the ICU, 30 (3.7%) had respiratory failure, 26 (3.2%) had heart failure, and 35 (4.8%) died.,After adjustment for confounders, the significant predictors of heart failure were average systolic blood pressure (SBP) (hazard ratio (HR) per 10 mmHg 1.89, 95% confidence interval (CI): 1.15, 3.13) and pulse pressure (HR per 10 mmHg 2.71, 95% CI: 1.39, 5.29).,The standard deviations of SBP and diastolic BP were independently associated with mortality and ICU admission.,The risk estimates of poor BP control were comparable between patients receiving ARBs and those not receiving ARBs, with the only exception of a high risk of heart failure in the non-ARB group.,Poor BP control was independently associated with higher risks of adverse outcomes of COVID-19.,ARB drugs did not increase the risks of adverse events in hypertensive patients. | In a large Israeli dataset of 14 520 individuals tested for SARS-CoV-2, angiotension-converting enzyme inhibitors and angiotensin-receptor blockers were not found to be associated with increased SARS-CoV-2 infection after adjusting for major confounders.,Patients on these medications should not stop their medication prophylactically. | 1 |
Critically ill patients with coronavirus disease 2019 (COVID-19) have been observed to be hypercoagulable, but the mechanisms for this remain poorly described.,Factor VIII is a procoagulant factor that increases during inflammation and is cleaved by activated protein C.,To our knowledge, there is only 1 prior study of factor VIII and functional protein C activity in critically ill patients with COVID-19.,Here, we present a case series of 10 critically ill patients with COVID-19 who had severe elevations in factor VIII activity and low normal functional protein C activity, which may have contributed to hypercoagulability. | Little evidence of increased thrombotic risk is available in COVID-19 patients.,Our purpose was to assess thrombotic risk in severe forms of SARS-CoV-2 infection.,All patients referred to 4 intensive care units (ICUs) from two centers of a French tertiary hospital for acute respiratory distress syndrome (ARDS) due to COVID-19 between March 3rd and 31st 2020 were included.,Medical history, symptoms, biological data and imaging were prospectively collected.,Propensity score matching was performed to analyze the occurrence of thromboembolic events between non-COVID-19 ARDS and COVID-19 ARDS patients.,150 COVID-19 patients were included (122 men, median age 63 [53; 71] years, SAPSII 49 [37; 64] points).,Sixty-four clinically relevant thrombotic complications were diagnosed in 150 patients, mainly pulmonary embolisms (16.7%). 28/29 patients (96.6%) receiving continuous renal replacement therapy experienced circuit clotting.,Three thrombotic occlusions (in 2 patients) of centrifugal pump occurred in 12 patients (8%) supported by ECMO.,Most patients (> 95%) had elevated D-dimer and fibrinogen.,No patient developed disseminated intravascular coagulation.,Von Willebrand (vWF) activity, vWF antigen and FVIII were considerably increased, and 50/57 tested patients (87.7%) had positive lupus anticoagulant.,Comparison with non-COVID-19 ARDS patients (n = 145) confirmed that COVID-19 ARDS patients (n = 77) developed significantly more thrombotic complications, mainly pulmonary embolisms (11.7 vs.,2.1%, p < 0.008).,Coagulation parameters significantly differed between the two groups.,Despite anticoagulation, a high number of patients with ARDS secondary to COVID-19 developed life-threatening thrombotic complications.,Higher anticoagulation targets than in usual critically ill patients should therefore probably be suggested.,The online version of this article (10.1007/s00134-020-06062-x) contains supplementary material, which is available to authorized users. | 1 |
Supplemental Digital Content is available in the text.,The full spectrum of coronavirus disease 2019 (COVID-19) infection ranges from asymptomatic to acute respiratory distress syndrome, characterized by hyperinflammation and thrombotic microangiopathy.,The pathogenic mechanisms are poorly understood, but emerging evidence suggest that excessive neutrophil extracellular trap (NET) formation plays a key role in COVID-19 disease progression.,Here, we evaluate if circulating markers of NETs are associated with COVID-19 disease severity and clinical outcome, as well as to markers of inflammation and in vivo coagulation and fibrinolysis.,One hundred six patients with COVID-19 with moderate to severe disease were enrolled shortly after hospital admission and followed for 4 months.,Acute and convalescent plasma samples as well as plasma samples from 30 healthy individuals were assessed for markers of NET formation: citrullinated histone H3, cell-free DNA, NE (neutrophil elastase).,We found that all plasma levels of NET markers were elevated in patients with COVID-19 relative to healthy controls, that they were associated with respiratory support requirement and short-term mortality, and declined to those found in healthy individuals 4 months post-infection.,The levels of the NET markers also correlated with white blood cells, neutrophils, inflammatory cytokines, and C-reactive protein, as well as to markers of in vivo coagulation, fibrinolysis, and endothelial damage.,Our findings suggest a role of NETs in COVID-19 disease progression, implicating their contribution to an immunothrombotic state.,Further, we observed an association between circulating markers of NET formation and clinical outcome, demonstrating a potential role of NET markers in clinical decision-making, as well as for NETs as targets for novel therapeutic interventions in COVID-19. | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets multiple organs and causes severe coagulopathy.,Histopathological organ changes might not only be attributable to a direct virus-induced effect, but also the immune response.,The aims of this study were to assess the duration of viral presence, identify the extent of inflammatory response, and investigate the underlying cause of coagulopathy.,This prospective autopsy cohort study was done at Amsterdam University Medical Centers (UMC), the Netherlands.,With informed consent from relatives, full body autopsy was done on 21 patients with COVID-19 for whom autopsy was requested between March 9 and May 18, 2020.,In addition to histopathological evaluation of organ damage, the presence of SARS-CoV-2 nucleocapsid protein and the composition of the immune infiltrate and thrombi were assessed, and all were linked to disease course.,Our cohort (n=21) included 16 (76%) men, and median age was 68 years (range 41-78).,Median disease course (time from onset of symptoms to death) was 22 days (range 5-44 days).,In 11 patients tested for SARS-CoV-2 tropism, SARS-CoV-2 infected cells were present in multiple organs, most abundantly in the lungs, but presence in the lungs became sporadic with increased disease course.,Other SARS-CoV-2-positive organs included the upper respiratory tract, heart, kidneys, and gastrointestinal tract.,In histological analyses of organs (sampled from nine to 21 patients per organ), an extensive inflammatory response was present in the lungs, heart, liver, kidneys, and brain.,In the brain, extensive inflammation was seen in the olfactory bulbs and medulla oblongata.,Thrombi and neutrophilic plugs were present in the lungs, heart, kidneys, liver, spleen, and brain and were most frequently observed late in the disease course (15 patients with thrombi, median disease course 22 days [5-44]; ten patients with neutrophilic plugs, 21 days [5-44]).,Neutrophilic plugs were observed in two forms: solely composed of neutrophils with neutrophil extracellular traps (NETs), or as aggregates of NETs and platelets..,In patients with lethal COVID-19, an extensive systemic inflammatory response was present, with a continued presence of neutrophils and NETs.,However, SARS-CoV-2-infected cells were only sporadically present at late stages of COVID-19.,This suggests a maladaptive immune response and substantiates the evidence for immunomodulation as a target in the treatment of severe COVID-19.,Amsterdam UMC Corona Research Fund. | 1 |
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