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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.,Canagliflozin is a sodium glucose cotransporter 2 inhibitor that significantly reduces the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in patients with type 2 diabetes mellitus and elevated cardiovascular risk.,The comparative effects among participants with and without a history of cardiovascular disease (secondary versus primary prevention) were prespecified for evaluation.,The CANVAS Program (Canagliflozin Cardiovascular Assessment Study) randomly assigned 10 142 participants with type 2 diabetes mellitus to canagliflozin or placebo.,The primary prevention cohort comprised individuals ≥50 years of age with ≥2 risk factors for cardiovascular events but with no prior cardiovascular event, and the secondary prevention cohort comprised individuals ≥30 years of age with a prior cardiovascular event.,The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.,Secondary outcomes included heart failure hospitalization and a renal composite (40% reduction in estimated glomerular filtration rate, renal replacement therapy, or renal death).,Primary prevention participants (N=3486; 34%) were younger (63 versus 64 years of age), were more often female (45% versus 31%), and had a longer duration of diabetes mellitus (14 versus 13 years) compared with secondary prevention participants (N=6656; 66%).,The primary end point event rate was higher in the secondary prevention group compared with the primary prevention group (36.9 versus 15.7/1000 patient-years, P<0.001).,In the total cohort, the primary end point was reduced with canagliflozin compared with placebo (26.9 versus 31.5/1000 patient-years; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75-0.97; P<0.001 for noninferiority, P=0.02 for superiority) with no statistical evidence of heterogeneity (interaction P value=0.18) between the primary (HR, 0.98; 95% CI, 0.74-1.30) and secondary prevention (HR, 0.82; 95% CI, 0.72-0.95) cohorts.,Renal outcomes (HR, 0.59; 95% CI, 0.44-0.79 versus HR, 0.63; 95% CI, 0.39-1.02; interaction P value=0.73) and heart failure hospitalization (HR, 0.68; 95% CI, 0.51-0.90 versus HR, 0.64; 95% CI, 0.35-1.15; interaction P value=0.91) were similarly reduced in the secondary and primary prevention cohorts, respectively.,Lower extremity amputations were similarly increased in the secondary and primary prevention cohorts (HR, 2.07; 95% CI, 1.43-3.00 versus HR, 1.52; 95% CI, 0.70-3.29; interaction P value=0.63).,Patients with type 2 diabetes mellitus and prior cardiovascular events had higher rates of cardiovascular outcomes compared with the primary prevention patients.,Canagliflozin reduced cardiovascular and renal outcomes with no statistical evidence of heterogeneity of the treatment effect across the primary and secondary prevention groups.,Additional studies will provide further insights into the effects of canagliflozin in these patient populations.,URL: https://www.clinicaltrials.gov.,Unique identifiers: NCT01032629 and NCT01989754. | 1 |
The zebrafish (Danio rerio) has become a popular vertebrate model organism to study organ formation and function due to its optical clarity and rapid embryonic development.,The use of genetically modified zebrafish has also allowed identification of new putative therapeutic drugs.,So far, most studies have relied on broad overexpression of transgenes harboring patient-derived mutations or loss-of-function mutants, which incompletely model the human disease allele in terms of expression levels or cell-type specificity of the endogenous gene of interest.,Most human genetically inherited conditions are caused by alleles carrying single nucleotide changes resulting in altered gene function.,Introduction of such point mutations in the zebrafish genome would be a prerequisite to recapitulate human disease but remains challenging to this day.,We present an effective approach to introduce small nucleotide changes in the zebrafish genome.,We generated four different knock-in lines carrying distinct human cardiovascular-disorder-causing missense mutations in their zebrafish orthologous genes by combining CRISPR/Cas9 with a short template oligonucleotide.,Three of these lines carry gain-of-function mutations in genes encoding the pore-forming (Kir6.1, KCNJ8) and regulatory (SUR2, ABCC9) subunits of an ATP-sensitive potassium channel (KATP) linked to Cantú syndrome (CS).,Our heterozygous zebrafish knock-in lines display significantly enlarged ventricles with enhanced cardiac output and contractile function, and distinct cerebral vasodilation, demonstrating the causality of the introduced mutations for CS.,These results demonstrate that introducing patient alleles in their zebrafish orthologs promises a broad application for modeling human genetic diseases, paving the way for new therapeutic strategies using this model organism.,Summary: By using a single-stranded DNA oligonucleotide template in combination with CRISPR/Cas9 in zebrafish, the authors achieved effective germline-transmissible introduction of patient-specific single-nucleotide changes related to cardiovascular disease. | Whole-genome and exome sequencing efforts are increasingly identifying candidate genetic variants associated with human disease.,However, predicting and testing the pathogenicity of a genetic variant remains challenging.,Genome editing allows for the rigorous functional testing of human genetic variants in animal models.,Congenital heart defects (CHDs) are a prominent example of a human disorder with complex genetics.,An inherited sequence variant in the human PBX3 gene (PBX3 p.A136V) has previously been shown to be enriched in a CHD patient cohort, indicating that the PBX3 p.A136V variant could be a modifier allele for CHDs.,Pbx genes encode three-amino-acid loop extension (TALE)-class homeodomain-containing DNA-binding proteins with diverse roles in development and disease, and are required for heart development in mouse and zebrafish.,Here, we used CRISPR-Cas9 genome editing to directly test whether this Pbx gene variant acts as a genetic modifier in zebrafish heart development.,We used a single-stranded oligodeoxynucleotide to precisely introduce the human PBX3 p.A136V variant in the homologous zebrafish pbx4 gene (pbx4 p.A131V).,We observed that zebrafish that are homozygous for pbx4 p.A131V are viable as adults.,However, the pbx4 p.A131V variant enhances the embryonic cardiac morphogenesis phenotype caused by loss of the known cardiac specification factor, Hand2.,Our study is the first example of using precision genome editing in zebrafish to demonstrate a function for a human disease-associated single nucleotide variant of unknown significance.,Our work underscores the importance of testing the roles of inherited variants, not just de novo variants, as genetic modifiers of CHDs.,Our study provides a novel approach toward advancing our understanding of the complex genetics of CHDs.,Summary: This study uses genome editing in zebrafish to demonstrate that a human DNA sequence variant of unknown significance might contribute to the complex genetics of congenital heart defects. | 1 |
Type 2 Diabetes Mellitus (T2DM) is a well-known comorbidity to COVID-19 and coagulopathies are a common accompaniment to both T2DM and COVID-19.,In addition, patients with COVID-19 are known to develop micro-clots within the lungs.,The rapid detection of COVID-19 uses genotypic testing for the presence of SARS-Cov-2 virus in nasopharyngeal swabs, but it can have a poor sensitivity.,A rapid, host-based physiological test that indicated clotting severity and the extent of clotting pathologies in the individual who was infected or not would be highly desirable.,Platelet poor plasma (PPP) was collected and frozen.,On the day of analysis, PPP samples were thawed and analysed.,We show here that microclots can be detected in the native plasma of twenty COVID-19, as well as ten T2DM patients, without the addition of any clotting agent, and in particular that such clots are amyloid in nature as judged by a standard fluorogenic stain.,Results were compared to ten healthy age-matched individuals.,In COVID-19 plasma these microclots are significantly increased when compared to the levels in T2DM.,This fluorogenic test may provide a rapid and convenient test with 100% sensitivity (P < 0.0001) and is consistent with the recognition that the early detection and prevention of such clotting can have an important role in therapy. | 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 |
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. | COVID-19 is an infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).,Apart from respiratory complications, acute cerebrovascular disease (CVD) has been observed in some patients with COVID-19.,Therefore, we described the clinical characteristics, laboratory features, treatment and outcomes of CVD complicating SARS-CoV-2 infection.,Demographic and clinical characteristics, laboratory findings, treatments and clinical outcomes were collected and analysed.,Clinical characteristics and laboratory findings of patients with COVID-19 with or without new-onset CVD were compared.,Of 219 patients with COVID-19, 10 (4.6%) developed acute ischaemic stroke and 1 (0.5%) had intracerebral haemorrhage.,COVID-19 with new onset of CVD were significantly older (75.7±10.8 years vs 52.1±15.3 years, p<0.001), more likely to present with severe COVID-19 (81.8% vs 39.9%, p<0.01) and were more likely to have cardiovascular risk factors, including hypertension, diabetes and medical history of CVD (all p<0.05).,In addition, they were more likely to have increased inflammatory response and hypercoagulable state as reflected in C reactive protein (51.1 (1.3-127.9) vs 12.1 (0.1-212.0) mg/L, p<0.05) and D-dimer (6.9 (0.3-20.0) vs 0.5 (0.1-20.0) mg/L, p<0.001).,Of 10 patients with ischemic stroke; 6 received antiplatelet treatment with aspirin or clopidogrel; and 3 of them died.,The other four patients received anticoagulant treatment with enoxaparin and 2 of them died.,As of 24 March 2020, six patients with CVD died (54.5%).,Acute CVD is not uncommon in COVID-19.,Our findings suggest that older patients with risk factors are more likely to develop CVD.,The development of CVD is an important negative prognostic factor which requires further study to identify optimal management strategy to combat the COVID-19 outbreak. | 1 |
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. | 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 |
To determine the incidence, patient characteristics, and related events associated with new-onset atrial fibrillation (AF) during a national COVID-19 lockdown.,Using nationwide Danish registries, we included all patients, aged 18-90 years, receiving a new-onset AF diagnosis during the first 3 months of 2019 and 2020.,The main comparison was between patients diagnosed during lockdown (12 March 12-1 April 2020) and patients diagnosed in the corresponding period 1 year previously.,We found a lower incidence of new-onset AF during the 3 weeks of lockdown compared with the corresponding weeks in 2019 [incidence rate ratios with 95% confidence intervals (CIs) for the 3 weeks: 0.66 (0.56-0.78), 0.53 (0.45-0.64), and 0.41 (0.34-0.50)].,There was a 47% drop in total numbers (562 vs.,1053).,Patients diagnosed during lockdown were younger and with a lower CHA2DS2-VASc score, while history of cancer, heart failure, and vascular disease were more prevalent.,During lockdown, 30 (5.3%) patients with new-onset AF suffered an ischaemic stroke and 15 (2.7%) died, compared with 45 (4.3%) and 14 (1.3%) patients during the corresponding 2019 period, respectively.,The adjusted odds ratio of a related event (ischaemic stroke or all-cause death) during lock-down compared with the corresponding weeks was 1.41 (95% CI 0.93-2.12).,Following a national lockdown in Denmark, a 47% drop in registered new-onset AF cases was observed.,In the event of prolonged or subsequent lockdowns, the risk of undiagnosed AF patients developing complications could potentially translate into poorer outcomes in patients with AF during the COVID-19 pandemic.,Graphical Abstract | •There are anecdotal reports of lower stroke rates during the COVID-19 pandemic.,•Our center confirms a local fall in new acute stroke diagnoses during the pandemic.,•This fall is driven by fewer patients presenting with mild symptoms in our network.,•Mild stroke symptoms ought to not be ignored in community practices.,There are anecdotal reports of lower stroke rates during the COVID-19 pandemic.,Our center confirms a local fall in new acute stroke diagnoses during the pandemic.,This fall is driven by fewer patients presenting with mild symptoms in our network.,Mild stroke symptoms ought to not be ignored in community practices.,Although there is evidence to suggest a high rate of cerebrovascular complications in patients with SARS-CoV-2 infection, anecdotal reports indicate a falling rate of new ischemic stroke diagnoses.,We conducted an exploratory single-center analysis to estimate the change in number of new stroke diagnoses in our region, and evaluate the proximate reasons for this change during the COVID-19 pandemic at a tertiary care center in New Jersey.,A Comprehensive Stroke Center prospective cohort was retrospectively analyzed for the number of stroke admissions, demographic features, and short-term outcomes 5 months prior to 3/1/2020 (pre-COVID-19), and in the 6 weeks that followed (COVID-19 period).,The primary outcome was the number of new acute stroke diagnoses before and during the COVID-19 period, as well as the potential reasons for a decline in the number of new diagnoses.,Of the 328 included patients, 53 (16%) presented in the COVID-19 period.,There was a mean fall of 38% in new stroke diagnoses (mean 1.13/day [SD 1.07] from 1.82/day [SD 1.38], p<0.01), which was related to a 59% decline in the number of daily transfers from referral centers (p<0.01), 25% fewer telestroke consultations (p=0.08), and 55% fewer patients presenting directly to our institution by private vehicle (p<0.01) and 29% fewer patients through emergency services (p=0.09).,There was no significant change in the monthly number of strokes due to large vessel occlusion (LVO), however the proportion of new LVOs nearly doubled in the COVID-19 period (38% vs. 21%, p=0.01).,The observations at our tertiary care center corroborate anecdotal reports that the number of new stroke diagnoses is falling, which seems related to a smaller proportion of patients seeking healthcare services for milder symptoms.,These preliminary data warrant validation in larger, multi-center studies. | 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. | Novel coronavirus disease 2019 (COVID-19) has been associated with an increased risk of arterial and venous thromboembolic (VTE) diseases.,However, there is a limited amount of data regarding the prevention and management of VTE in severe hospitalized COVID-19 patients.,In this article, we review currently available clinical data, and mechanisms for COVID-associated coagulopathy, and propose algorithms for screening, prevention (including extended-duration prophylaxis), and treatment of these patients.,Although these recommendations are subject to change given rapidly evolving data, we provide a framework that can guide clinicians in managing thrombotic complications in this challenging condition. | 1 |
The effect of implantable cardioverter-defibrillator (ICD) therapy in patients with heart failure with reduced ejection fraction (HFrEF) and diabetes is not fully elucidated.,We examined the effect of ICD therapy on sudden cardiac death, cardiovascular death and all-cause mortality, according to diabetes status at baseline in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT).,The outcomes were analyzed by use of cumulative incidence curves and Cox regressions models.,Of the 1676 patients randomized to an ICD or placebo, 540 (32%) had diabetes at baseline.,Patients with diabetes were slightly older (61 vs 58 years) and were more often in NYHA class III (37% vs 28%).,ICD therapy did not reduce the risk of sudden cardiac death in HFrEF patients with diabetes (HR = 0.85; 95% CI 0.52-1.40); even though these patients had a higher risk of sudden cardiac death compared to patients without diabetes (HR = 1.73 95% CI 1.22-2.47).,By contrast, ICD therapy did reduce sudden cardiac death in HFrEF patients without diabetes (HR = 0.26; 95% CI 0.15-0.46); Pinteraction=0.002.,The findings for cardiovascular and all-cause death were similar.,ICD therapy did not reduce the risk of sudden cardiac death (or, as a consequence, all-cause death) in HFrEF patients with diabetes.,Conversely, an ICD reduced the risk of sudden death in patients without diabetes, irrespective of etiology.,The online version of this article (10.1007/s00392-019-01415-z) contains supplementary material, which is available to authorized users. | Supplemental Digital Content is available in the text.,In the EMPA-REG OUTCOME trial (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) in patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease, in comparison with placebo, empagliflozin reduced the risks of 3-point major adverse cardiovascular events (3-point MACE), cardiovascular and all-cause death, and hospitalization for heart failure.,We investigated whether these effects varied across the spectrum of baseline cardiovascular risk.,Cardiovascular death, all-cause mortality, 3-point MACE, and hospitalization for heart failure in the pooled empagliflozin and placebo groups were analyzed in subgroups by prior myocardial infarction and stroke at baseline, and by estimated baseline cardiovascular risk based on the 10-point TIMI (Thrombolysis In Myocardial Infarction) Risk Score for Secondary Prevention.,Of 7020 patients who received the study drug, 65% had a prior myocardial infarction or stroke, and 12%, 40%, 30%, and 18% were at low, intermediate, high, and highest estimated cardiovascular risk according to TIMI Risk Score for Secondary Prevention (≤2, 3, 4, and ≥5 points, respectively).,In the placebo group, 3-point MACE occurred during the trial in 7.3%, 9.4%, 12.6%, and 20.6% of patients at low, intermediate, high, and highest estimated baseline risk, respectively.,Relative reductions in risk of cardiovascular death, all-cause mortality, 3-point MACE and hospitalization for heart failure with empagliflozin versus placebo were consistent in patients with and without prior myocardial infarction and/or stroke and across subgroups by TIMI Risk Score for Secondary Prevention at baseline (P>0.05 for randomized group-by-subgroup interactions).,Despite all patients having atherosclerotic cardiovascular disease, patients in EMPA-REG OUTCOME demonstrated a broad risk spectrum for cardiovascular events.,Reductions in key cardiovascular outcomes and mortality with empagliflozin versus placebo were consistent across the range of cardiovascular risk.,URL: https://www.clinicaltrials.gov.,Unique identifier: NCT01131676. | 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. | 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 |
To investigate the prevalence and prognostic impact of right heart failure and right ventricular-arterial uncoupling in Corona Virus Infectious Disease 2019 (COVID-19) complicated by an Acute Respiratory Distress Syndrome (ARDS).,Ninety-four consecutive patients (mean age 64 years) admitted for acute respiratory failure on COVID-19 were enrolled.,Coupling of right ventricular function to the pulmonary circulation was evaluated by a comprehensive trans-thoracic echocardiography with focus on the tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure (PASP) ratio,The majority of patients needed ventilatory support, which was noninvasive in 22 and invasive in 37.,There were 25 deaths, all in the invasively ventilated patients.,Survivors were younger (62 ± 13 vs. 68 ± 12 years, p = 0.033), less often overweight or usual smokers, had lower NT-proBNP and interleukin-6, and higher arterial partial pressure of oxygen (PaO2)/fraction of inspired O2 (FIO2) ratio (270 ± 104 vs. 117 ± 57 mmHg, p < 0.001).,In the non-survivors, PASP was increased (42 ± 12 vs. 30 ± 7 mmHg, p < 0.001), while TAPSE was decreased (19 ± 4 vs. 25 ± 4 mm, p < 0.001).,Accordingly, the TAPSE/PASP ratio was lower than in the survivors (0.51 ± 0.22 vs.,0.89 ± 0.29 mm/mmHg, p < 0.001).,At univariate/multivariable analysis, the TAPSE/PASP (HR: 0.026; 95%CI 0.01-0.579; p: 0.019) and PaO2/FIO2 (HR: 0.988; 95%CI 0.988-0.998; p: 0.018) ratios were the only independent predictors of mortality, with ROC-determined cutoff values of 159 mmHg and 0.635 mm/mmHg, respectively.,COVID-19 ARDS is associated with clinically relevant uncoupling of right ventricular function from the pulmonary circulation; bedside echocardiography of TAPSE/PASP adds to the prognostic relevance of PaO2/FIO2 in ARDS on COVID-19. | To assess the prevalence, characteristics and prognostic value of pulmonary hypertension (PH) and right ventricular dysfunction (RVD) in hospitalised, non-intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19).,This single-centre, observational, cross-sectional study included 211 patients with COVID-19 admitted to non-ICU departments who underwent a single transthoracic echocardiography (TTE).,Patients with poor acoustic window (n=11) were excluded.,Clinical, imaging, laboratory and TTE findings were compared in patients with versus without PH (estimated systolic pulmonary artery pressure >35 mm Hg) and with versus without RVD (tricuspid annular plane systolic excursion <17 mm or S wave <9.5 cm/s).,The primary endpoint was in-hospital death or ICU admission.,A total of 200 patients were included in the final analysis (median age 62 (IQR 52-74) years, 65.5% men).,The prevalence of PH and RVD was 12.0% (24/200) and 14.5% (29/200), respectively.,Patients with PH were older and had a higher burden of pre-existing cardiac comorbidities and signs of more severe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (radiological lung involvement, laboratory findings and oxygenation status) compared with those without PH.,Conversely, patients with RVD had a higher burden of pre-existing cardiac comorbidities but no evidence of more severe SARS-CoV-2 infection compared with those without RVD.,The presence of PH was associated with a higher rate of in-hospital death or ICU admission (41.7 vs 8.5%, p<0.001), while the presence of RVD was not (17.2 vs 11.7%, p=0.404).,Among hospitalised non-ICU patients with COVID-19, PH (and not RVD) was associated with signs of more severe COVID-19 and with worse in-hospital clinical outcome.,NCT04318366 | 1 |
Specific clinical risk factors linked to transient ischemic attack (TIA) could affect functional ambulatory outcome following thrombolytic therapy in patients having ischemic stroke with a prior TIA (TIA-ischemic stroke).,This issue was investigated in this study.,We retrospectively analyzed data from 6379 ischemic stroke patients of which 1387 presented with an antecedent TIA prior to onset of stroke.,We used logistic regression model to identify demographic and clinical risk factors that are associated with functional ambulatory outcome in patients with TIA-ischemic stroke treated with thrombolytic therapy.,In a population of TIA-ischemic stroke who received recombinant tissue plasminogen activator, patients with a history of stroke (odds ratio [OR] = 3.229, 95% confidence interval [CI] = 1.494-6.98, P = .003) were associated with increasing odds of improvement in functional ambulation, while the female gender (OR = 0.462, 95% CI = 0.223-0.956, P = .037) was associated with reducing odds of improvement.,In the non-TIA group, dyslipidemia (OR = 1.351, 95% CI = 1.026-1.781, P = .032) and blood glucose (OR = 1.003, 95% CI = 1.0-1.005, P = .041) were associated with the increasing odds of improvement while older patients (OR = 0.989, 95% CI = 0.98-0.999, P = .029) with heart failure (OR = 0.513, 95% CI = 0.326-0.808, P = .004) and higher lipid level (OR = 0.834, 95% CI = 0.728-0.955, P = .009) were associated with reducing odds of improvement in ambulation.,In a population of TIA-ischemic stroke with thrombolytic therapy and a clearly defined TIA without focal ischemic injury, regardless of associated clinical risk factors, a TIA prior to a stroke is not associated with reducing odds of improved ambulatory outcome, except in female patients with TIA-ischemic stroke. | Specific clinical risk factors may contribute to improving or worsening neurological functions in acute ischemic stroke (AIS) patients pre-treated with a combined cholesterol reducer and recombinant tissue plasminogen activator (rtPA) therapy.,In this study, clinical risk factors associated with good or poor presenting neurological symptoms in ischemic stroke patients with prior cholesterol reducer use, specifically a statin and rtPA therapy was investigated.,Retrospective data for baseline clinical and demographic data for patients with AIS taking cholesterol reducers prior to rtPA treatment from January 2010 to June 2016 in a regional stroke center was analyzed.,Improving (NIHSS score ≤ 7) or worsening (NIHSS score > 7) of neurologic functions were the determined measures of treatment outcome.,Multivariate logistic regression models identified demographic and clinical factors associated with worsening or improving neurologic functions.,Adjusted multivariate analysis showed that in an AIS population with a combined rtPA and cholesterol reducer medication history, increasing age (OR = 1.032, 95% CI, 1.015-1.048, P < 0.001) and atrial fibrillation (OR = 1.859, 95% CI, 1.098-3.149, P = 0.021) demonstrated a likely association with worsening neurologic functions, while direct admission (OR = 0.411, 95% CI, 0.246-0.686, P = 0.001) and being Caucasian (OR = 0.496, 95% CI, 0.297-0.827, P = 0.007) showed an association with improving or progressing neurologic functions.,A prior cholesterol reducer, namely a statin, plus rtPA combination may be associated with worsening neurological function for elderly AIS patients with atrial fibrillation, while Caucasians directly admitted to a neurology unit are more likely to show an association with progress or improvements in neurologic functions.,While combining statin with rtPA treatment may facilitate worsening neurologic functions in elderly AIS patients with atrial fibrillation, they should not be denied of this therapy.,The decision to combine statin and rtPA for AIS patients with atrial fibrillation can be done after clinical stabilization following appropriate clinical management. | 1 |
Coronavirus disease 2019 (COVID-19) has become a global pandemic, affecting millions of people.,However, the relationship between COVID-19 and acute cerebrovascular diseases is unclear.,We aimed to characterize the incidence, risk factors, clinical-radiological manifestations, and outcome of COVID-19-associated stroke.,Three medical databases were systematically reviewed for published articles on acute cerebrovascular diseases in COVID-19 (December 2019-September 2020).,The review protocol was previously registered (PROSPERO ID = CRD42020185476).,Data were extracted from articles reporting ≥5 stroke cases in COVID-19.,We complied with the PRISMA guidelines and used the Newcastle-Ottawa Scale to assess data quality.,Data were pooled using a random-effect model.,Of 2277 initially identified articles, 61 (2.7%) were entered in the meta-analysis.,Out of 108,571 patients with COVID-19, acute CVD occurred in 1.4% (95%CI: 1.0-1.9).,The most common manifestation was acute ischemic stroke (87.4%); intracerebral hemorrhage was less common (11.6%).,Patients with COVID-19 developing acute cerebrovascular diseases, compared to those who did not, were older (pooled median difference = 4.8 years; 95%CI: 1.7-22.4), more likely to have hypertension (OR = 7.35; 95%CI: 1.94-27.87), diabetes mellitus (OR = 5.56; 95%CI: 3.34-9.24), coronary artery disease (OR = 3.12; 95%CI: 1.61-6.02), and severe infection (OR = 5.10; 95%CI: 2.72-9.54).,Compared to individuals who experienced a stroke without the infection, patients with COVID-19 and stroke were younger (pooled median difference = −6.0 years; 95%CI: −12.3 to −1.4), had higher NIHSS (pooled median difference = 5; 95%CI: 3-9), higher frequency of large vessel occlusion (OR = 2.73; 95%CI: 1.63-4.57), and higher in-hospital mortality rate (OR = 5.21; 95%CI: 3.43-7.90).,Acute cerebrovascular diseases are not uncommon in patients with COVID-19, especially in those whom are severely infected and have pre-existing vascular risk factors.,The pattern of large vessel occlusion and multi-territory infarcts suggests that cerebral thrombosis and/or thromboembolism could be possible causative pathways for the disease. | Supplemental Digital Content is available in the text.,The impact of coronavirus disease 2019 (COVID-19) on the occurrence of ischemic stroke has been the subject of increased speculation but has not been confirmed in large observational studies.,We investigated the association between COVID-19 and stroke.,We performed a cross-sectional study involving patients discharged from a healthcare system in New York State, from January to April 2020.,A mixed-effects logistic regression analysis and a propensity score-weighted analysis were used to control for confounders and investigate the association of COVID-19 with ischemic stroke.,Similar techniques were used to detect the impact of concurrent COVID-19 infection on unfavorable outcomes for patients with stroke.,Among 24 808 discharges, 2513 (10.1%) were diagnosed with COVID-19, and 566 (0.2%) presented with acute ischemic stroke.,Patients diagnosed with COVID-19 were at one-quarter the odds of stroke compared with other patients (odds ratio, 0.25 [95% CI, 0.16-0.40]).,This association was consistent in all age groups.,Our results were robust in sensitivity analyses, including propensity score-weighted regression models.,In patients presenting with stroke, concurrent infection with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) was associated with higher case-fatality (odds ratio, 10.50 [95% CI, 3.54-31.18]) and a trend towards increased occurrence of discharge to rehabilitation (odds ratio, 2.45 [95% CI, 0.81-1.25]).,Using a comprehensive cross-section of patients from a large NY-based healthcare system, we did not identify a positive association between ischemic stroke and COVID-19.,However, patients with stroke with COVID-19 had worse outcomes compared with those without, with over a 9-fold increase in mortality.,Although no definitive conclusions can be reached from our observational study, our data do not support the concerns for an epidemic of stroke in young adults with COVID-19. | 1 |
Some patients with severe COVID-19 develop prothrombotic autoantibodies that are similar to antiphospholipid antibodies found in autoimmune diseases.,Patients with severe COVID-19 are at high risk for occlusion of blood vessels of all sizes.,This prothrombotic phenotype is reminiscent of patients with lupus and antiphospholipid syndrome, who have long-lived circulating antiphospholipid autoantibodies.,In new work, Zuo et al. measured eight types of antiphospholipid antibodies in serum from patients hospitalized with COVID-19 and found at least one antibody in half of patients.,Antibody levels were associated with neutrophil and coagulation pathway activation.,Purified antibodies from some patients activated neutrophils in vitro and potentiated thrombosis when injected into mice.,Together, these findings suggest that autoantibodies are a potential therapeutic target in severe COVID-19.,Patients with COVID-19 are at high risk for thrombotic arterial and venous occlusions.,Lung histopathology often reveals fibrin-based blockages in the small blood vessels of patients who succumb to the disease.,Antiphospholipid syndrome is an acquired and potentially life-threatening thrombophilia in which patients develop pathogenic autoantibodies targeting phospholipids and phospholipid-binding proteins (aPL antibodies).,Case series have recently detected aPL antibodies in patients with COVID-19.,Here, we measured eight types of aPL antibodies in serum samples from 172 patients hospitalized with COVID-19.,These aPL antibodies included anticardiolipin IgG, IgM, and IgA; anti-β2 glycoprotein I IgG, IgM, and IgA; and anti-phosphatidylserine/prothrombin (aPS/PT) IgG and IgM.,We detected aPS/PT IgG in 24% of serum samples, anticardiolipin IgM in 23% of samples, and aPS/PT IgM in 18% of samples.,Antiphospholipid autoantibodies were present in 52% of serum samples using the manufacturer’s threshold and in 30% using a more stringent cutoff (≥40 ELISA-specific units).,Higher titers of aPL antibodies were associated with neutrophil hyperactivity, including the release of neutrophil extracellular traps (NETs), higher platelet counts, more severe respiratory disease, and lower clinical estimated glomerular filtration rate.,Similar to IgG from patients with antiphospholipid syndrome, IgG fractions isolated from patients with COVID-19 promoted NET release from neutrophils isolated from healthy individuals.,Furthermore, injection of IgG purified from COVID-19 patient serum into mice accelerated venous thrombosis in two mouse models.,These findings suggest that half of patients hospitalized with COVID-19 become at least transiently positive for aPL antibodies and that these autoantibodies are potentially pathogenic. | Since the appearance of the first case of coronavirus disease 2019 (COVID-19) a pandemic has emerged affecting millions of people worldwide.,Although the main clinical manifestations are respiratory, an increase in neurological conditions, specifically acute cerebrovascular disease, has been detected.,We present cerebrovascular disease case incidence in hospitalized patients with SARS-CoV-2 infection.,Patients were confirmed by microbiological/serological testing, or on chest CT semiology.,Available data on comorbidity, laboratory parameters, treatment administered, neuroimaging, neuropathological studies and clinical evolution during hospitalization, measured by the modified Rankin scale, were analysed.,A bivariate study was also designed to identify differences between ischaemic and haemorrhagic subtypes.,A statistical model of binary logistic regression and sensitivity analysis was designed to study the influence of independent variables over prognosis.,In our centre, there were 1683 admissions of patients with COVID-19 over 50 days, of which 23 (1.4%) developed cerebrovascular disease.,Within this group of patients, cerebral and chest CT scans were performed in all cases, and MRI in six (26.1%).,Histological samples were obtained in 6/23 cases (two brain biopsies, and four arterial thrombi).,Seventeen patients were classified as cerebral ischaemia (73.9%, with two arterial dissections), five as intracerebral haemorrhage (21.7%), and one leukoencephalopathy of posterior reversible encephalopathy type.,Haemorrhagic patients had higher ferritin levels at the time of stroke (1554.3 versus 519.2, P = 0.004).,Ischaemic strokes were unexpectedly frequent in the vertebrobasilar territory (6/17, 35.3%).,In the haemorrhagic group, a characteristic radiological pattern was identified showing subarachnoid haemorrhage, parieto-occipital leukoencephalopathy, microbleeds and single or multiple focal haematomas.,Brain biopsies performed showed signs of thrombotic microangiopathy and endothelial injury, with no evidence of vasculitis or necrotizing encephalitis.,The functional prognosis during the hospital period was unfavourable in 73.9% (17/23 modified Rankin scale 4-6), and age was the main predictive variable (odds ratio = 1.5; 95% confidence interval 1.012-2.225; P = 0.043).,Our series shows cerebrovascular disease incidence of 1.4% in patients with COVID-19 with high morbidity and mortality.,We describe pathological and radiological data consistent with thrombotic microangiopathy caused by endotheliopathy with a haemorrhagic predisposition. | 1 |
Supplemental Digital Content is available in the text.,Myocarditis has been recognized as a rare complication of coronavirus disease 2019 (COVID-19) mRNA vaccinations, especially in young adult and adolescent males.,According to the US Centers for Disease Control and Prevention, myocarditis/pericarditis rates are ≈12.6 cases per million doses of second-dose mRNA vaccine among individuals 12 to 39 years of age.,In reported cases, patients with myocarditis invariably presented with chest pain, usually 2 to 3 days after a second dose of mRNA vaccination, and had elevated cardiac troponin levels.,ECG was abnormal with ST elevations in most, and cardiac MRI was suggestive of myocarditis in all tested patients.,There was no evidence of acute COVID-19 or other viral infections.,In 1 case, a cardiomyopathy gene panel was negative, but autoantibody levels against certain self-antigens and frequency of natural killer cells were increased.,Although the mechanisms for development of myocarditis are not clear, molecular mimicry between the spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and self-antigens, trigger of preexisting dysregulated immune pathways in certain individuals, immune response to mRNA, and activation of immunologic pathways, and dysregulated cytokine expression have been proposed.,The reasons for male predominance in myocarditis cases are unknown, but possible explanations relate to sex hormone differences in immune response and myocarditis, and also underdiagnosis of cardiac disease in women.,Almost all patients had resolution of symptoms and signs and improvement in diagnostic markers and imaging with or without treatment.,Despite rare cases of myocarditis, the benefit-risk assessment for COVID-19 vaccination shows a favorable balance for all age and sex groups; therefore, COVID-19 vaccination is recommended for everyone ≥12 years of age. | Coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been associated with cardiovascular features of myocardial involvement including elevated serum troponin levels and acute heart failure with reduced ejection fraction.,The cardiac pathological changes in these patients with COVID-19 have yet to be well described.,In an international multicentre study, cardiac tissue from the autopsies of 21 consecutive COVID-19 patients was assessed by cardiovascular pathologists.,The presence of myocarditis, as defined by the presence of multiple foci of inflammation with associated myocyte injury, was determined, and the inflammatory cell composition analysed by immunohistochemistry.,Other forms of acute myocyte injury and inflammation were also described, as well as coronary artery, endocardium, and pericardium involvement.,Lymphocytic myocarditis was present in 3 (14%) of the cases.,In two of these cases, the T lymphocytes were CD4 predominant and in one case the T lymphocytes were CD8 predominant.,Increased interstitial macrophage infiltration was present in 18 (86%) of the cases.,A mild pericarditis was present in four cases.,Acute myocyte injury in the right ventricle, most probably due to strain/overload, was present in four cases.,There was a non-significant trend toward higher serum troponin levels in the patients with myocarditis compared with those without myocarditis.,Disrupted coronary artery plaques, coronary artery aneurysms, and large pulmonary emboli were not identified.,In SARS-CoV-2 there are increased interstitial macrophages in a majority of the cases and multifocal lymphocytic myocarditis in a small fraction of the cases.,Other forms of myocardial injury are also present in these patients.,The macrophage infiltration may reflect underlying diseases rather than COVID-19. | 1 |
The dysfunction of the renin-angiotensin system (RAS) has been observed in coronavirus infection disease (COVID-19) patients, but whether RAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs), are associated with clinical outcomes remains unknown.,COVID-19 patients with hypertension were enrolled to evaluate the effect of RAS inhibitors.,We observed that patients receiving ACEI or ARB therapy had a lower rate of severe diseases and a trend toward a lower level of IL-6 in peripheral blood.,In addition, ACEI or ARB therapy increased CD3 and CD8 T cell counts in peripheral blood and decreased the peak viral load compared to other antihypertensive drugs.,This evidence supports the benefit of using ACEIs or ARBs to potentially contribute to the improvement of clinical outcomes of COVID-19 patients with hypertension. | Severe acute respiratory-syndrome coronavirus-2 (SARS-CoV-2) host cell infection is mediated by binding to angiotensin-converting enzyme 2 (ACE2).,Systemic dysregulation observed in SARS-CoV was previously postulated to be due to ACE2/angiotensin 1-7 (Ang1-7)/Mas axis downregulation; increased ACE2 activity was shown to mediate disease protection.,Because angiotensin II receptor blockers, ACE inhibitors, and mineralocorticoid receptor antagonists increase ACE2 receptor expression, it has been tacitly believed that the use of these agents may facilitate viral disease; thus, they should not be used in high-risk patients with cardiovascular disease.,Based on the anti-inflammatory benefits of the upregulation of the ACE2/Ang1-7/Mas axis and previously demonstrated benefits of lung function improvement in SARS-CoV infections, it has been hypothesized that the benefits of treatment with renin-angiotensin system inhibitors in SARS-CoV-2 may outweigh the risks and at the very least should not be withheld.,•COVID-19 has been associated with cardiac involvement.,SARS-CoV-2 requires binding to ACE2 in the RAS.,•The ACE2/Ang1-7/Mas pathway counterbalances the RAS, which results in activation of anti-inflammatory pathways.,•ACE inhibitors, ARBs, and MRAs upregulate ACE2 activity and expression.,•More data are required to determine if regulation of ACE2 in patients with cardiovascular disease and COVID-19 would help improve clinical outcomes.,COVID-19 has been associated with cardiac involvement.,SARS-CoV-2 requires binding to ACE2 in the RAS.,The ACE2/Ang1-7/Mas pathway counterbalances the RAS, which results in activation of anti-inflammatory pathways.,ACE inhibitors, ARBs, and MRAs upregulate ACE2 activity and expression.,More data are required to determine if regulation of ACE2 in patients with cardiovascular disease and COVID-19 would help improve clinical outcomes. | 1 |
Intestinal ischemia-reperfusion (I/R) injury is a life-threatening vascular emergency and has long been a disturbing problem for surgeons.,Oxidative stress is considered a vital factor in I/R injury.,Metformin has anti-oxidative properties and protects against I/R injury.,The present study aimed to investigate whether Metformin protects against intestinal I/R injury and reveal the protective mechanism of Metformin.,I/R injury was induced in mice by temporary superior mesenteric artery occlusion, and Caco-2 cells were subjected to OGD/R to establish an in vitro model.,Different doses of Metformin were administered in vivo and in vitro.,We found that I/R injury led to intestinal barrier disruption and cell death by examining histopathological results and the intestinal barrier index, including TER, tight junction proteins and serum biomarkers.,We confirmed the existence of pyroptosis in intestinal I/R injury.,Moreover, we confirmed the role of pyroptosis in intestinal I/R injury by silencing the gasdermin D (GSDMD).,Then, we confirmed that Metformin treatment protected barrier function against intestinal I/R injury and reduced oxidative stress and the inflammatory response.,Importantly, Metformin reduced pyroptosis-related proteins, including NLRP3, cleaved caspase-1, and the N-terminus of GSDMD.,Knocking down the GSDMD could reversed the protective effects of Metformin, which showed pyroptosis was one of the major cell death pathways controlled by Metformin treatment in setting of intestinal I/R injury.,We also discovered that Metformin suppressed the expression of TXNIP and the interaction between TXNIP and NLRP3.,We performed siRNA knockdown and found that the protective effects were abolished, which further confirmed our findings.,In conclusion, we believe that Metformin protects against intestinal I/R injury in a TXNIP-NLRP3-GSDMD-dependent manner.,•Pyroptosis plays an important role in intestinal I/R injury.,•Metformin protects against intestinal I/R injury in mice.,•Metformin protects Caco-2 cells subjected to OGD/R.,•Metformin inhibits pyroptosis, inflammation and oxidative stress during I/R injury.,•Metformin exerts protective effect through TXNIP-NLRP3-GSDMD pathway.,Pyroptosis plays an important role in intestinal I/R injury.,Metformin protects against intestinal I/R injury in mice.,Metformin protects Caco-2 cells subjected to OGD/R.,Metformin inhibits pyroptosis, inflammation and oxidative stress during I/R injury.,Metformin exerts protective effect through TXNIP-NLRP3-GSDMD pathway. | Emodin has recently been reported to have a powerful antiinflammatory effect, protecting the myocardium against ischemia/reperfusion (I/R) injury.,Pyroptosis is a proinflammatory programmed cell death that is related to many diseases.,The present study investigated the effect of emodin on pyroptosis in cardiomyocytes.,Sprague Dawley rats were randomly divided into sham, I/R, and I/R+Emodin groups.,I/R model was subjected to 30 minutes’ ligation of left anterior descending coronary artery, followed by 2 hours of reperfusion.,Cardiomyocytes were exposed to hypoxic conditions for 1 hour and normoxic conditions for 2 hours.,The level of the pyroptosis was detected by Western blot, real-time PCR analysis, and ELISA.,The level of gasdermin D-N domains was upregulated in cardiomyocytes during I/R or hypoxia/reoxygenation (H/R) treatment.,Moreover, emodin increased the rate of cell survival in vitro and decreased the myocardial infarct size in vivo via suppressing the levels of I/R-induced pyroptosis.,Additionally, the expression of TLR4, MyD88, phospho-IκBα, phospho-NF-κB, and the NLRP3 inflammasome was significantly upregulated in cardiomyocytes subjected to H/R treatment, while emodin suppressed the expression of these proteins.,This study confirms that emodin treatment was able to alleviate myocardial I/R injury and inhibit pyroptosis in vivo and in vitro.,The inhibitory effect of emodin on pyroptosis was mediated by suppressing the TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway.,Therefore, emodin may provide an alternative treatment for myocardial I/R injury. | 1 |
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. | 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.,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. | The novel coronavirus disease 2019 (COVID-19) has become a global health emergency.,The cumulative number of new confirmed cases and deaths are still increasing out of China.,Independent predicted factors associated with fatal outcomes remain uncertain.,The goal of the current study was to investigate the potential risk factors associated with fatal outcomes from COVID-19 through a multivariate Cox regression analysis and a nomogram model.,A retrospective cohort of 1,590 hospitalized patients with COVID-19 throughout China was established.,The prognostic effects of variables, including clinical features and laboratory findings, were analyzed by using Kaplan-Meier methods and a Cox proportional hazards model.,A prognostic nomogram was formulated to predict the survival of patients with COVID-19.,In this nationwide cohort, nonsurvivors included a higher incidence of elderly people and subjects with coexisting chronic illness, dyspnea, and laboratory abnormalities on admission compared with survivors.,Multivariate Cox regression analysis showed that age ≥ 75 years (hazard ratio [HR], 7.86; 95% CI, 2.44-25.35), age between 65 and 74 years (HR, 3.43; 95% CI, 1.24-9.5), coronary heart disease (HR, 4.28; 95% CI, 1.14-16.13), cerebrovascular disease (HR, 3.1; 95% CI, 1.07-8.94), dyspnea (HR, 3.96; 95% CI, 1.42-11), procalcitonin level > 0.5 ng/mL (HR, 8.72; 95% CI, 3.42-22.28), and aspartate aminotransferase level > 40 U/L (HR, 2.2; 95% CI, 1.1-6.73) were independent risk factors associated with fatal outcome.,A nomogram was established based on the results of multivariate analysis.,The internal bootstrap resampling approach suggested the nomogram has sufficient discriminatory power with a C-index of 0.91 (95% CI, 0.85-0.97).,The calibration plots also showed good consistency between the prediction and the observation.,The proposed nomogram accurately predicted clinical outcomes of patients with COVID-19 based on individual characteristics.,Earlier identification, more intensive surveillance, and appropriate therapy should be considered in patients at high risk. | 1 |
Vaccination with an adenoviral vector vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can result in the rare development of thrombosis with thrombocytopenia mediated by platelet-activating antibodies against platelet factor 4 (PF4).,This is a life-threating condition that may be accompanied by bleeding due to thrombocytopenia with thrombosis of the cerebral venous sinus or splanchnic vein.,Herein, we describe the first fatal case of thrombosis with thrombocytopenia syndrome in Korea, presenting with intracranial hemorrhage caused by cerebral venous sinus thrombosis.,A 33-year-old Korean man received the first dose of the ChAdOx1 nCoV-19 vaccination.,He developed severe headache with vomiting 9 days after the vaccination.,Twelve days after vaccination, he was admitted to the hospital with neurological symptoms and was diagnosed with cerebral venous sinus thrombosis, which was accompanied by intracranial hemorrhage.,Thrombocytopenia and D-dimer elevation were observed, and the result of the PF4 enzyme-linked immunosorbent assay antibody test was reported to be strongly positive.,Despite intensive treatment, including intravenous immunoglobulin injection and endovascular mechanical thrombectomy, the patient died 19 days after vaccination.,Physicians need to be aware of thrombosis with thrombocytopenia syndrome (TTS) in adenoviral vector-vaccinated patients.,Endovascular mechanical thrombectomy might be a useful therapeutic option for the treatment of TTS with cerebral venous sinus thrombosis. | We describe a 30-year-old woman who developed thrombocytopenia and multiple thromboses after she received the ChAdOx1 nCoV-19 vaccine.A maximum 4T HIT score and a positive immunoassay for anti-PF4 antibodies indicated autoimmune HIT as a potential pathogenic mechanism.,We describe a 30-year-old woman who developed thrombocytopenia and multiple thromboses after she received the ChAdOx1 nCoV-19 vaccine.,A maximum 4T HIT score and a positive immunoassay for anti-PF4 antibodies indicated autoimmune HIT as a potential pathogenic mechanism.,Recently, reports of severe thromboses, thrombocytopenia, and hemorrhage in persons vaccinated with the chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19, AZD1222, Vaxzevria; Oxford/AstraZeneca) against severe acute respiratory syndrome coronavirus 2 have emerged.,We describe an otherwise healthy 30-year-old woman who developed thrombocytopenia, ecchymosis, portal vein thrombosis, and cerebral venous sinus thrombosis the second week after she received the ChAdOx1 nCoV-19 vaccine.,Extensive diagnostic workup for thrombosis predispositions showed heterozygosity for the prothrombin mutation, but no evidence of myeloproliferative neoplasia or infectious or autoimmune diseases.,Her only temporary risk factor was long-term use of oral contraceptive pills (OCPs).,Although both the prothrombin mutation and use of OCPs predispose to portal and cerebral vein thrombosis, the occurrence of multiple thromboses within a short time and the associated pattern of thrombocytopenia and consumption coagulopathy are highly unusual.,A maximum 4T heparin-induced thrombocytopenia (HIT) score and a positive immunoassay for anti-platelet factor 4/heparin antibodies identified autoimmune HIT as a potential pathogenic mechanism.,Although causality has not been established, our case emphasizes the importance of clinical awareness.,Further studies of this potentially new clinical entity have suggested that it should be regarded as a vaccine-induced immune thrombotic thrombocytopenia. | 1 |
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. | 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 |
Cardiovascular and arrhythmic events have been reported in hospitalized COVID-19 patients.,However, arrhythmia manifestations and treatment strategies used in these patients have not been well-described.,We sought to better understand the cardiac arrhythmic manifestations and treatment strategies in hospitalized COVID-19 patients through a worldwide cross-sectional survey.,The Heart Rhythm Society (HRS) sent an online survey (via SurveyMonkey) to electrophysiology (EP) professionals (physicians, scientists, and allied professionals) across the globe.,The survey was active from March 27 to April 13, 2020.,A total of 1197 respondents completed the survey with 50% of respondents from outside the USA, representing 76 countries and 6 continents.,Of respondents, 905 (76%) reported having COVID-19-positive patients in their hospital.,Atrial fibrillation was the most commonly reported tachyarrhythmia whereas severe sinus bradycardia and complete heart block were the most common bradyarrhythmias.,Ventricular tachycardia/ventricular fibrillation arrest and pulseless electrical activity were reported by 4.8% and 5.6% of respondents, respectively.,There were 140 of 631 (22.2%) respondents who reported using anticoagulation therapy in all COVID-19-positive patients who did not otherwise have an indication.,One hundred fifty-five of 498 (31%) reported regular use of hydroxychloroquine/chloroquine (HCQ) + azithromycin (AZM); concomitant use of AZM was more common in the USA.,Sixty of 489 respondents (12.3%) reported having to discontinue therapy with HCQ + AZM due to significant QTc prolongation and 20 (4.1%) reported cases of Torsade de Pointes in patients on HCQ/chloroquine and AZM.,Amiodarone was the most common antiarrhythmic drug used for ventricular arrhythmia management.,In this global survey of > 1100 EP professionals regarding hospitalized COVID-19 patients, a variety of arrhythmic manifestations were observed, ranging from benign to potentially life-threatening.,Observed adverse events related to use of HCQ + AZM included prolonged QTc requiring drug discontinuation as well as Torsade de Pointes.,Large prospective studies to better define arrhythmic manifestations as well as the safety of treatment strategies in COVID-19 patients are warranted.,The online version of this article (10.1007/s10840-020-00789-9) contains supplementary material, which is available to authorized users. | Although mortality due to COVID-19 is, for the most part, robustly tracked, its indirect effect at the population level through lockdown, lifestyle changes, and reorganisation of health-care systems has not been evaluated.,We aimed to assess the incidence and outcomes of out-of-hospital cardiac arrest (OHCA) in an urban region during the pandemic, compared with non-pandemic periods.,We did a population-based, observational study using data for non-traumatic OHCA (N=30 768), systematically collected since May 15, 2011, in Paris and its suburbs, France, using the Paris Fire Brigade database, together with in-hospital data.,We evaluated OHCA incidence and outcomes over a 6-week period during the pandemic in adult inhabitants of the study area.,Comparing the 521 OHCAs of the pandemic period (March 16 to April 26, 2020) to the mean of the 3052 total of the same weeks in the non-pandemic period (weeks 12-17, 2012-19), the maximum weekly OHCA incidence increased from 13·42 (95% CI 12·77-14·07) to 26·64 (25·72-27·53) per million inhabitants (p<0·0001), before returning to normal in the final weeks of the pandemic period.,Although patient demographics did not change substantially during the pandemic compared with the non-pandemic period (mean age 69·7 years [SD 17] vs 68·5 [18], 334 males [64·4%] vs 1826 [59·9%]), there was a higher rate of OHCA at home (460 [90·2%] vs 2336 [76·8%]; p<0·0001), less bystander cardiopulmonary resuscitation (239 [47·8%] vs 1165 [63·9%]; p<0·0001) and shockable rhythm (46 [9·2%] vs 472 [19·1%]; p<0·0001), and longer delays to intervention (median 10·4 min [IQR 8·4-13·8] vs 9·4 min [7·9-12·6]; p<0·0001).,The proportion of patients who had an OHCA and were admitted alive decreased from 22·8% to 12·8% (p<0·0001) in the pandemic period.,After adjustment for potential confounders, the pandemic period remained significantly associated with lower survival rate at hospital admission (odds ratio 0·36, 95% CI 0·24-0·52; p<0·0001).,COVID-19 infection, confirmed or suspected, accounted for approximately a third of the increase in OHCA incidence during the pandemic.,A transient two-times increase in OHCA incidence, coupled with a reduction in survival, was observed during the specified time period of the pandemic when compared with the equivalent time period in previous years with no pandemic.,Although this result might be partly related to COVID-19 infections, indirect effects associated with lockdown and adjustment of health-care services to the pandemic are probable.,Therefore, these factors should be taken into account when considering mortality data and public health strategies.,The French National Institute of Health and Medical Research (INSERM) | 1 |
•RISH harmonization is applicable to multicentre dMRI of elderly subjects with SVD.,•Harmonization removes site-differences in dMRI metrics in matched controls.,•Associations between dMRI metrics and SVD markers in patients are preserved.,•Harmonized scans can be pooled to into a single large dataset to increased power.,RISH harmonization is applicable to multicentre dMRI of elderly subjects with SVD.,Harmonization removes site-differences in dMRI metrics in matched controls.,Associations between dMRI metrics and SVD markers in patients are preserved.,Harmonized scans can be pooled to into a single large dataset to increased power.,Acquisition-related differences in diffusion magnetic resonance imaging (dMRI) hamper pooling of multicentre data to achieve large sample sizes.,A promising solution is to harmonize the raw diffusion signal using rotation invariant spherical harmonic (RISH) features, but this has not been tested in elderly subjects.,Here we aimed to establish if RISH harmonization effectively removes acquisition-related differences in multicentre dMRI of elderly subjects with cerebral small vessel disease (SVD), while preserving sensitivity to disease effects.,Five cohorts of patients with SVD (N = 397) and elderly controls (N = 175) with 3 Tesla MRI on different systems were included.,First, to establish effectiveness of harmonization, the RISH method was trained with data of 13 to 15 age and sex-matched controls from each site.,Fractional anisotropy (FA) and mean diffusivity (MD) were compared in matched controls between sites using tract-based spatial statistics (TBSS) and voxel-wise analysis, before and after harmonization.,Second, to assess sensitivity to disease effects, we examined whether the contrast (effect sizes of FA, MD and peak width of skeletonized MD - PSMD) between patients and controls within each site remained unaffected by harmonization.,Finally, we evaluated the association between white matter hyperintensity (WMH) burden, FA, MD and PSMD using linear regression analyses both within individual cohorts as well as with pooled scans from multiple sites, before and after harmonization.,Before harmonization, significant differences in FA and MD were observed between matched controls of different sites (p < 0.05).,After harmonization these site-differences were removed.,Within each site, RISH harmonization did not alter the effect sizes of FA, MD and PSMD between patients and controls (relative change in Cohen’s d = 4 %) nor the strength of association with WMH volume (relative change in R2 = 2.8 %).,After harmonization, patient data of all sites could be aggregated in a single analysis to infer the association between WMH volume and FA (R2 = 0.62), MD (R2 = 0.64), and PSMD (R2 = 0.60).,We showed that RISH harmonization effectively removes acquisition-related differences in dMRI of elderly subjects while preserving sensitivity to SVD-related effects.,This study provides proof of concept for future multicentre SVD studies with pooled datasets. | To determine whether MRI markers, including diffusion tensor imaging (DTI), can predict cognitive decline and dementia in patients with cerebral small vessel disease (SVD).,In the prospective St George's Cognition and Neuroimaging in Stroke study, multimodal MRI was performed annually for 3 years and cognitive assessments annually for 5 years in a cohort of 99 patients with SVD, defined as symptomatic lacunar stroke and confluent white matter hyperintensities (WMH).,Progression to dementia was determined in all patients.,Progression of WMH, brain volume, lacunes, cerebral microbleeds, and a DTI measure (the normalized peak height of the mean diffusivity histogram distribution) as a marker of white matter microstructural damage were determined.,Over 5 years of follow-up, 18 patients (18.2%) progressed to dementia.,A significant change in all MRI markers, representing deterioration, was observed.,The presence of new lacunes, and rate of increase in white matter microstructural damage on DTI, correlated with both decline in executive function and global functioning.,Growth of WMH and deterioration of white matter microstructure on DTI predicted progression to dementia.,A model including change in MRI variables together with their baseline values correctly classified progression to dementia with a C statistic of 0.85.,This longitudinal prospective study provides evidence that change in MRI measures including DTI, over time durations during which cognitive change is not detectable, predicts cognitive decline and progression to dementia.,It supports the use of MRI measures, including DTI, as useful surrogate biomarkers to monitor disease and assess therapeutic interventions. | 1 |
Coronavirus disease 2019 (COVID-19) may predispose to venous thromboembolism.,We determined factors independently associated with computed tomography pulmonary angiography (CTPA)-confirmed pulmonary embolism (PE) in hospitalised severe COVID-19 patients.,Among all (n=349) patients hospitalised for COVID-19 in a university hospital in a French region with a high rate of COVID-19, we analysed patients who underwent CTPA for clinical signs of severe disease (oxygen saturation measured by pulse oximetry ≤93% or breathing rate ≥30 breaths·min−1) or rapid clinical worsening.,Multivariable analysis was performed using Firth penalised maximum likelihood estimates.,162 (46.4%) patients underwent CTPA (mean±sd age 65.6±13.0 years; 67.3% male (95% CI 59.5-75.5%).,PE was diagnosed in 44 (27.2%) patients.,Most PEs were segmental and the rate of PE-related right ventricular dysfunction was 15.9%.,By multivariable analysis, the only two significant predictors of CTPA-confirmed PE were D-dimer level and the lack of any anticoagulant therapy (OR 4.0 (95% CI 2.4-6.7) per additional quartile and OR 4.5 (95% CI 1.1-7.4), respectively).,Receiver operating characteristic curve analysis identified a D-dimer cut-off value of 2590 ng·mL−1 to best predict occurrence of PE (area under the curve 0.88, p<0.001, sensitivity 83.3%, specificity 83.8%).,D-dimer level >2590 ng·mL−1 was associated with a 17-fold increase in the adjusted risk of PE.,Elevated D-dimers (>2590 ng·mL−1) and absence of anticoagulant therapy predict PE in hospitalised COVID-19 patients with clinical signs of severity.,These data strengthen the evidence base in favour of systematic anticoagulation, and suggest wider use of D-dimer guided CTPA to screen for PE in acutely ill hospitalised patients with COVID-19.,We studied predictors of pulmonary embolism in severe COVID-19 and found that D-dimer level and lack of any anticoagulant therapy were associated with a 17-fold and four-fold increase in PE, respectively, in COVID-19 patients with clinical signs of severityhttps://bit.ly/2ETfAfo | 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 |
Some patients with severe COVID-19 develop prothrombotic autoantibodies that are similar to antiphospholipid antibodies found in autoimmune diseases.,Patients with severe COVID-19 are at high risk for occlusion of blood vessels of all sizes.,This prothrombotic phenotype is reminiscent of patients with lupus and antiphospholipid syndrome, who have long-lived circulating antiphospholipid autoantibodies.,In new work, Zuo et al. measured eight types of antiphospholipid antibodies in serum from patients hospitalized with COVID-19 and found at least one antibody in half of patients.,Antibody levels were associated with neutrophil and coagulation pathway activation.,Purified antibodies from some patients activated neutrophils in vitro and potentiated thrombosis when injected into mice.,Together, these findings suggest that autoantibodies are a potential therapeutic target in severe COVID-19.,Patients with COVID-19 are at high risk for thrombotic arterial and venous occlusions.,Lung histopathology often reveals fibrin-based blockages in the small blood vessels of patients who succumb to the disease.,Antiphospholipid syndrome is an acquired and potentially life-threatening thrombophilia in which patients develop pathogenic autoantibodies targeting phospholipids and phospholipid-binding proteins (aPL antibodies).,Case series have recently detected aPL antibodies in patients with COVID-19.,Here, we measured eight types of aPL antibodies in serum samples from 172 patients hospitalized with COVID-19.,These aPL antibodies included anticardiolipin IgG, IgM, and IgA; anti-β2 glycoprotein I IgG, IgM, and IgA; and anti-phosphatidylserine/prothrombin (aPS/PT) IgG and IgM.,We detected aPS/PT IgG in 24% of serum samples, anticardiolipin IgM in 23% of samples, and aPS/PT IgM in 18% of samples.,Antiphospholipid autoantibodies were present in 52% of serum samples using the manufacturer’s threshold and in 30% using a more stringent cutoff (≥40 ELISA-specific units).,Higher titers of aPL antibodies were associated with neutrophil hyperactivity, including the release of neutrophil extracellular traps (NETs), higher platelet counts, more severe respiratory disease, and lower clinical estimated glomerular filtration rate.,Similar to IgG from patients with antiphospholipid syndrome, IgG fractions isolated from patients with COVID-19 promoted NET release from neutrophils isolated from healthy individuals.,Furthermore, injection of IgG purified from COVID-19 patient serum into mice accelerated venous thrombosis in two mouse models.,These findings suggest that half of patients hospitalized with COVID-19 become at least transiently positive for aPL antibodies and that these autoantibodies are potentially pathogenic. | 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. | 1 |
Supplemental Digital Content is available in the text.,A pandemic of historic impact, coronavirus disease 2019 (COVID-19) has potential consequences on the cardiovascular health of millions of people who survive infection worldwide.,Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can infect the heart, vascular tissues, and circulating cells through ACE2 (angiotensin-converting enzyme 2), the host cell receptor for the viral spike protein.,Acute cardiac injury is a common extrapulmonary manifestation of COVID-19 with potential chronic consequences.,This update provides a review of the clinical manifestations of cardiovascular involvement, potential direct SARS-CoV-2 and indirect immune response mechanisms impacting the cardiovascular system, and implications for the management of patients after recovery from acute COVID-19 infection. | The degree of myocardial injury, as reflected by troponin elevation, and associated outcomes among U.S. hospitalized patients with coronavirus disease-2019 (COVID-19) are unknown.,The purpose of this study was to describe the degree of myocardial injury and associated outcomes in a large hospitalized cohort with laboratory-confirmed COVID-19.,Patients with COVID-19 admitted to 1 of 5 Mount Sinai Health System hospitals in New York City between February 27, 2020, and April 12, 2020, with troponin-I (normal value <0.03 ng/ml) measured within 24 h of admission were included (n = 2,736).,Demographics, medical histories, admission laboratory results, and outcomes were captured from the hospitals’ electronic health records.,The median age was 66.4 years, with 59.6% men.,Cardiovascular disease (CVD), including coronary artery disease, atrial fibrillation, and heart failure, was more prevalent in patients with higher troponin concentrations, as were hypertension and diabetes.,A total of 506 (18.5%) patients died during hospitalization.,In all, 985 (36%) patients had elevated troponin concentrations.,After adjusting for disease severity and relevant clinical factors, even small amounts of myocardial injury (e.g., troponin I >0.03 to 0.09 ng/ml; n = 455; 16.6%) were significantly associated with death (adjusted hazard ratio: 1.75; 95% CI: 1.37 to 2.24; p < 0.001) while greater amounts (e.g., troponin I >0.09 ng/dl; n = 530; 19.4%) were significantly associated with higher risk (adjusted HR: 3.03; 95% CI: 2.42 to 3.80; p < 0.001).,Myocardial injury is prevalent among patients hospitalized with COVID-19; however, troponin concentrations were generally present at low levels.,Patients with CVD are more likely to have myocardial injury than patients without CVD.,Troponin elevation among patients hospitalized with COVID-19 is associated with higher risk of mortality. | 1 |
To describe a novel England-wide electronic health record (EHR) resource enabling whole population research on covid-19 and cardiovascular disease while ensuring data security and privacy and maintaining public trust.,Data resource comprising linked person level records from national healthcare settings for the English population, accessible within NHS Digital’s new trusted research environment.,EHRs from primary care, hospital episodes, death registry, covid-19 laboratory test results, and community dispensing data, with further enrichment planned from specialist intensive care, cardiovascular, and covid-19 vaccination data.,54.4 million people alive on 1 January 2020 and registered with an NHS general practitioner in England.,Confirmed and suspected covid-19 diagnoses, exemplar cardiovascular conditions (incident stroke or transient ischaemic attack and incident myocardial infarction) and all cause mortality between 1 January and 31 October 2020.,The linked cohort includes more than 96% of the English population.,By combining person level data across national healthcare settings, data on age, sex, and ethnicity are complete for around 95% of the population.,Among 53.3 million people with no previous diagnosis of stroke or transient ischaemic attack, 98 721 had a first ever incident stroke or transient ischaemic attack between 1 January and 31 October 2020, of which 30% were recorded only in primary care and 4% only in death registry records.,Among 53.2 million people with no previous diagnosis of myocardial infarction, 62 966 had an incident myocardial infarction during follow-up, of which 8% were recorded only in primary care and 12% only in death registry records.,A total of 959 470 people had a confirmed or suspected covid-19 diagnosis (714 162 in primary care data, 126 349 in hospital admission records, 776 503 in covid-19 laboratory test data, and 50 504 in death registry records).,Although 58% of these were recorded in both primary care and covid-19 laboratory test data, 15% and 18%, respectively, were recorded in only one.,This population-wide resource shows the importance of linking person level data across health settings to maximise completeness of key characteristics and to ascertain cardiovascular events and covid-19 diagnoses.,Although this resource was initially established to support research on covid-19 and cardiovascular disease to benefit clinical care and public health and to inform healthcare policy, it can broaden further to enable a wide range of research. | Although patients with cardiovascular disease face excess risks of severe illness with coronavirus disease-2019 (COVID-19), there may be indirect consequences of the pandemic on this high-risk patient segment.,This study sought to examine longitudinal trends in hospitalizations for acute cardiovascular conditions across a tertiary care health system.,Acute cardiovascular hospitalizations were tracked between January 1, 2019, and March 31, 2020.,Daily hospitalization rates were estimated using negative binomial models.,Temporal trends in hospitalization rates were compared across the first 3 months of 2020, with the first 3 months of 2019 as a reference.,From January 1, 2019, to March 31, 2020, 6,083 patients experienced 7,187 hospitalizations for primary acute cardiovascular reasons.,There were 43.4% (95% confidence interval [CI]: 27.4% to 56.0%) fewer estimated daily hospitalizations in March 2020 compared with March 2019 (p < 0.001).,The daily rate of hospitalizations did not change throughout 2019 (-0.01% per day [95% CI: -0.04% to +0.02%]; p = 0.50), January 2020 (-0.5% per day [95% CI: -1.6% to +0.5%]; p = 0.31), or February 2020 (+0.7% per day [95% CI: -0.6% to +2.0%]; p = 0.27).,There was significant daily decline in hospitalizations in March 2020 (-5.9% per day [95% CI: -7.6% to -4.3%]; p < 0.001).,Length of stay was shorter (4.8 days [25th to 75th percentiles: 2.4 to 8.3 days] vs.,6.0 days [25th to 75th percentiles: 3.1 to 9.6 days]; p = 0.003) and in-hospital mortality was not significantly different (6.2% vs.,4.4%; p = 0.30) in March 2020 compared with March 2019.,During the first phase of the COVID-19 pandemic, there was a marked decline in acute cardiovascular hospitalizations, and patients who were admitted had shorter lengths of stay.,These data substantiate concerns that acute care of cardiovascular conditions may be delayed, deferred, or abbreviated during the COVID-19 pandemic. | 1 |
Is Kawasaki disease (KD) associated with droplet- or contact-transmitted infection?,In this cross-sectional study of 17 235 pediatric patients, the number of admissions for KD showed no significant change (27.4% decrease) during quarantine owing to the COVID-19 pandemic, whereas there were significant decreases in numbers of hospital admissions for droplet-transmitted or contact-transmitted respiratory tract infections (75.3% decrease) and gastrointestinal infections (86.3% decrease).,Thus, the ratio of KD admissions to admissions for these infections increased.,These findings suggest that contact or droplet transmission is not a major route for KD development and that KD may be associated with airborne disease.,This cross-sectional study assesses the role of droplet or contact transmission in the etiopathogenesis of Kawasaki disease.,The development of Kawasaki disease (KD) has been suggested to be associated with droplet- or contact-transmitted infection; however, its triggers and transmission modes remain to be determined.,Under an epidemic of SARS-CoV-2, the COVID-19 state of emergency in Japan served as a nationwide social experiment to investigate the impact of quarantine or isolation on the incidence of KD.,To assess the role of droplet or contact transmission in the etiopathogenesis of KD.,This multicenter, longitudinal, cross-sectional study was conducted from 2015 to 2020 at Fukuoka Children’s Hospital and 5 adjacent general hospitals.,The number of admissions for KD and infectious diseases were analyzed.,Participants were pediatric patients admitted to the participating hospitals for KD or infectious diseases.,Quarantine and isolation owing to the COVID-19 state of emergency.,The primary end points were the ratios of patients with KD to patients with respiratory tract or gastrointestinal infections admitted from April to May in 2015 to 2019 and 2020.,A Poisson regression model was used to analyze them.,The study participants included 1649 patients with KD (median [interquartile range] age, 25 [13-43] months; 901 boys [54.6%]) and 15 586 patients with infectious disease (data on age and sex were not available for these patients).,The number of admissions for KD showed no significant change between April and May in 2015 to 2019 vs the same months in 2020 (mean [SD], 24.8 [5.6] vs 18.0 [4.0] admissions per month; 27.4% decrease; adjusted incidence rate ratio [aIRR], 0.73; 95% CI, 0.48-1.10; P = .12).,However, the number of admissions for droplet-transmitted or contact-transmitted respiratory tract infections (mean [SD], 157.6 [14.4] vs 39.0 [15.0] admissions per month; 75.3% decrease; aIRR, 0.25; 95% CI, 0.17-0.35; P < .001) and gastrointestinal infections (mean [SD], 43.8 [12.9] vs 6.0 [2.0] admissions per month; 86.3% decrease; aIRR, 0.14; 95% CI, 0.04-0.43; P < .001) showed significant decreases between April and May in 2015 to 2019 vs the same months in 2020 (total, 12 254 infections).,Thus, the ratio of KD to droplet- or contact-transmitted respiratory tract and gastrointestinal infections incidence in April and May 2020 was significantly increased (ratio, 0.40 vs 0.12; χ21 = 22.76; P < .001).,In this study, the significantly increased incidence of KD compared with respiratory tract and gastrointestinal infections during the COVID-19 state of emergency suggests that contact or droplet transmission is not a major route for KD development and that KD may be associated with airborne infections in most cases. | Epidemiological studies in Kawasaki disease (KD) have suggested infectious aetiology.,During the COVID-19 pandemic, measures for mitigating SARS-CoV-2 transmission also suppress the circulation of other contagious microorganisms.,The primary objective is to compare the number and incidence of KD before and during the COVID-19 pandemic in Japan, and the secondary objective is to investigate temporal association between the KD epidemiology and activities of SARS-CoV-2 and other viral and bacterial infections.,A retrospective cohort study was conducted between 2016 and 2020 in Kobe, Japan.,We collected information of hospitalised KD children in Kobe.,Child population was identified through the resident registry system.,Activity of COVID-19 and 11 other infectious diseases was derived from a public health monitoring system.,Monthly change of KD incidence was analysed using a difference-in-difference regression model.,Throughout the study period, 1027 KD children were identified.,KD had begun to decline in April 2020, coinciding with the beginning of the COVID-19 pandemic.,The number of KD cases (n=66) between April and December 2020 was 40% of the average in the same period in 2016-2019 (165/year).,Annual KD incidence was 315, 300, 353, 347 and 188/100 000 children aged 0-4 years in 2016-2020, respectively.,The difference-in-difference value of KD incidence was significantly reduced in the fourth quarter in 2020 (−15.8, 95% CI −28.0 to −3.5), compared with that in 2016-2019.,Sentinel surveillance showed a marked decrease of all infectious diseases except exanthema subitum after the beginning of the COVID-19 pandemic.,There were 86 COVID-19 cases aged <10 years and no KD children associated with COVID-19.,This study showed that the number and incidence of KD was dramatically reduced during the COVID-19 pandemic in Japan.,This change was temporally associated with decreased activities of various infectious diseases other than COVID-19, supporting the hypothesis of infection-triggered pathogenesis in KD. | 1 |
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. | 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 |
A 49-year-old man was admitted to his local hospital with left leg pain and breathing difficulties.,He had negative nasopharyngeal polymerase chain reaction tests for severe acute respiratory syndrome coronavirus 2.,Chest X-ray and Computed tomography pulmonary angiogram displayed typical coronavirus disease 2019 (COVID-19) radiological features as ground-glass opacities and bronchovascular thickening.,His respiratory symptoms resolved after four days of supportive treatment, whereas his left leg became more painful and discolored.,He was referred to our center with acute left leg ischemia. computed tomography angiogram revealed eccentric mural thrombus at the aortic bifurcation, extending into left common iliac and an abrupt occlusion of left popliteal, tibioperoneal, and posterior tibial arteries.,He was treated with catheter-directed thrombolysis for 48-hours that achieved successful revascularization of the ischemic limb with no intervention-related complications.,At six-week follow-up, he showed full recovery.,Our case demonstrates that catheter-directed thrombolysis is a successful and safe treatment option in a COVID-19 patient with acute arterial occlusion. | 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 |
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. | Recent studies have reported a high prevalence of thrombotic events in coronavirus disease 2019.,However, the significance of thromboembolic complications has not been widely appreciated.,The purpose of this review is to provide current knowledge of this serious problem.,Narrative review.,Online search of published medical literature through PubMed using the term “COVID-19,” “SARS,” “acute respiratory distress syndrome,” “coronavirus,” “coagulopathy,” “thrombus,” and “anticoagulants.”,Articles were chosen for inclusion based on their relevance to coagulopathy and thrombosis in coronavirus disease 2019, and anticoagulant therapy.,Reference lists were reviewed to identify additional relevant articles.,Coronavirus disease 2019 is associated with a strikingly high prevalence of coagulopathy and venous thromboembolism that may contribute to respiratory deterioration.,Monitoring coagulation variables is important, as abnormal coagulation tests are related to adverse outcomes and may necessitate adjuvant antithrombotic interventions.,In the initial phase of the infection, d-dimer and fibrinogen levels are increased, while activated partial prothrombin time, prothrombin time, and platelet counts are often relatively normal.,Increased d-dimer levels three times the upper limit of normal may trigger screening for venous thromboembolism.,In all hospitalized patients, thromboprophylaxis using low-molecular-weight heparin is currently recommended.,The etiology of the procoagulant responses is complex and thought to be a result of specific interactions between host defense mechanisms and the coagulation system.,Although the coagulopathy is reminiscent of disseminated intravascular coagulation and thrombotic microangiopathy, it has features that are markedly distinct from these entities.,Severe acute respiratory syndrome coronavirus 2/coronavirus disease 2019 frequently induces hypercoagulability with both microangiopathy and local thrombus formation, and a systemic coagulation defect that leads to large vessel thrombosis and major thromboembolic complications, including pulmonary embolism in critically ill hospitalized patients. d-dimers and fibrinogen levels should be monitored, and all hospitalized patients should undergo thromboembolism prophylaxis with an increase in therapeutic anticoagulation in certain clinical situations. | 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. | Few data are available on the rate and characteristics of thromboembolic complications in hospitalized patients with COVID-19.,We studied consecutive symptomatic patients with laboratory-proven COVID-19 admitted to a university hospital in Milan, Italy (13.02.2020-10.04.2020).,The primary outcome was any thromboembolic complication, including venous thromboembolism (VTE), ischemic stroke, and acute coronary syndrome (ACS)/myocardial infarction (MI).,Secondary outcome was overt disseminated intravascular coagulation (DIC).,We included 388 patients (median age 66 years, 68% men, 16% requiring intensive care [ICU]).,Thromboprophylaxis was used in 100% of ICU patients and 75% of those on the general ward.,Thromboembolic events occurred in 28 (7.7% of closed cases; 95%CI 5.4%-11.0%), corresponding to a cumulative rate of 21% (27.6% ICU, 6.6% general ward).,Half of the thromboembolic events were diagnosed within 24 h of hospital admission.,Forty-four patients underwent VTE imaging tests and VTE was confirmed in 16 (36%).,Computed tomography pulmonary angiography (CTPA) was performed in 30 patients, corresponding to 7.7% of total, and pulmonary embolism was confirmed in 10 (33% of CTPA).,The rate of ischemic stroke and ACS/MI was 2.5% and 1.1%, respectively.,Overt DIC was present in 8 (2.2%) patients.,The high number of arterial and, in particular, venous thromboembolic events diagnosed within 24 h of admission and the high rate of positive VTE imaging tests among the few COVID-19 patients tested suggest that there is an urgent need to improve specific VTE diagnostic strategies and investigate the efficacy and safety of thromboprophylaxis in ambulatory COVID-19 patients.,•COVID-19 is characterized by coagulation activation and endothelial dysfunction.,Few data are available on thromboembolic complications.,•We studied symptomatic patients with laboratory-proven COVID-19 admitted to a university hospital in Milan, Italy (13.02-10.04.2020).,•Venous and arterial thromboembolic events occurred in 8% of hospitalized patients (cumulative rate 21.0%) and 50% of events were diagnosed within 24 h of hospital admission.,•Forty-four (11% of total) patients underwent VTE imaging tests; 16 were positive (36% of tests), suggesting underestimation of thromboembolic complications.,•There is an urgent need to investigate VTE diagnostic strategies and the impact of thromboprophylaxis in ambulatory COVID-19 patients.,COVID-19 is characterized by coagulation activation and endothelial dysfunction.,Few data are available on thromboembolic complications.,We studied symptomatic patients with laboratory-proven COVID-19 admitted to a university hospital in Milan, Italy (13.02-10.04.2020).,Venous and arterial thromboembolic events occurred in 8% of hospitalized patients (cumulative rate 21.0%) and 50% of events were diagnosed within 24 h of hospital admission.,Forty-four (11% of total) patients underwent VTE imaging tests; 16 were positive (36% of tests), suggesting underestimation of thromboembolic complications.,There is an urgent need to investigate VTE diagnostic strategies and the impact of thromboprophylaxis in ambulatory COVID-19 patients. | 1 |
The Coronavirus Disease 2019 (COVID-19) is now a global pandemic with millions affected and millions more at risk for contracting the infection.,The COVID-19 virus, SARS-CoV-2, affects multiple organ systems, especially the lungs and heart.,Elevation of cardiac biomarkers, particularly high-sensitivity troponin and/or creatine kinase MB, is common in patients with COVID-19 infection.,In our review of clinical analyses, we found that in 26 studies including 11,685 patients, the weighted pooled prevalence of acute myocardial injury was 20% (ranged from 5% to 38% depending on the criteria used).,The plausible mechanisms of myocardial injury include, 1) hyperinflammation and cytokine storm mediated through pathologic T-cells and monocytes leading to myocarditis, 2) respiratory failure and hypoxemia resulting in damage to cardiac myocytes, 3) down regulation of ACE2 expression and subsequent protective signaling pathways in cardiac myocytes, 4) hypercoagulability and development of coronary microvascular thrombosis, 5) diffuse endothelial injury and ‘endotheliitis’ in several organs including the heart, and, 6) inflammation and/or stress causing coronary plaque rupture or supply-demand mismatch leading to myocardial ischemia/infarction.,Cardiac biomarkers can be used to aid in diagnosis as well as risk stratification.,In patients with elevated hs-troponin, clinical context is important and myocarditis as well as stress induced cardiomyopathy should be considered in the differential, along with type I and type II myocardial infarction.,Irrespective of etiology, patients with acute myocardial injury should be prioritized for treatment.,Clinical decisions including interventions should be individualized and carefully tailored after thorough review of risks/benefits.,Given the complex interplay of SARS-CoV-2 with the cardiovascular system, further investigation into potential mechanisms is needed to guide effective therapies.,Randomized trials are urgently needed to investigate treatment modalities to reduce the incidence and mortality associated with COVID-19 related acute myocardial injury. | The aim of this study was to characterize the echocardiographic phenotype of patients with COVID-19 pneumonia and its relation to biomarkers.,Seventy-four patients (59 ± 13 years old, 78% male) admitted with COVID-19 were included after referral for transthoracic echocardiography as part of routine care.,A level 1 British Society of Echocardiography transthoracic echocardiography was used to assess chamber size and function, valvular disease, and likelihood of pulmonary hypertension.,The chief abnormalities were right ventricle (RV) dilatation (41%) and RV dysfunction (27%).,RV impairment was associated with increased D-dimer and C-reactive protein levels.,In contrast, left ventricular function was hyperdynamic or normal in most (89%) patients. | 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. | 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 |
The COVID-19 pandemic, the result of severe acute respiratory syndrome (SARS)-CoV-2, is a major cause of worldwide mortality with a significant cardiovascular component.,While a number of different cardiovascular histopathologies have been reported at postmortem examination, their incidence is unknown, due to limited numbers of cases in any given study.,A literature review was performed identifying 277 autopsied hearts across 22 separate publications of COVID-19 positive patients.,The median age of the autopsy cohort was 75 and 97.6% had one or more comorbidities.,Initial review of the data indicate that myocarditis was present in 20 hearts (7.2%); however, closer examination of additional reported information revealed that most cases were likely not functionally significant and the true prevalence of myocarditis is likely much lower (<2%).,At least one acute, potentially COVID-19-related cardiovascular histopathologic finding, such as macro or microvascular thrombi, inflammation, or intraluminal megakaryocytes, was reported in 47.8% of cases.,Significant differences in reporting of histopathologic findings occurred between studies indicating strong biases in observations and the need for more consistency in reporting.,In conclusion, across 277 cases, COVID-19-related cardiac histopathological findings, are common, while myocarditis is rare. | We sought to study the impact of COVID‐19 pandemic on the presentation delay, severity, patterns of care, and reasons for delay among patients with ST‐elevation myocardial infarction (STEMI) in a non‐hot‐spot region.,COVID‐19 pandemic has significantly reduced the activations for STEMI in epicenters like Spain.,From January 1, 2020, to April 15, 2020, 143 STEMIs were identified across our integrated 18‐hospital system.,Pre‐ and post‐COVID‐19 cohorts were based on March 23rd, 2020, whenstay‐at‐home orders were initiated in Ohio.,We used presenting heart rate, blood pressure, troponin, new Q‐wave, and left ventricle ejection fraction (LVEF) to assess severity.,Duration of intensive care unit stay, total length of stay, door‐to‐balloon (D2B) time, and radial versus femoral access were used to assess patterns of care.,Post‐COVID‐19 presentation was associated with a lower admission LVEF (45 vs. 50%, p = .015), new Q‐wave, and higher initial troponin; however, these did not reach statistical significance.,Among post‐COVID‐19 patients, those with >12‐hr delay in presentation 31(%) had a longer average D2B time (88 vs. 53 min, p = .033) and higher peak troponin (58 vs.,8.5 ng/ml, p = .03).,Of these, 27% avoided the hospital due to fear of COVID‐19, 18% believed symptoms were COVID‐19 related, and 9% did not want to burden the hospital during the pandemic.,COVID‐19 has remarkably affected STEMI presentation and care.,Patients' fear and confusion about symptoms are integral parts of this emerging public health crisis. | 1 |
Emerging evidence indicates that both innate and adaptive immunity contribute to hypertension.,Efforts to understand mechanisms of immune activation in hypertension are defining not only new mechanisms of disease but also new therapeutic options for its treatment.,Although systemic hypertension affects a large proportion of the population, its etiology remains poorly defined.,Emerging evidence supports the concept that immune cells become activated and enter target organs, including the vasculature and the kidney, in this disease.,Mediators released by these cells, including reactive oxygen species, metalloproteinases, cytokines, and antibodies promote dysfunction of the target organs and cause damage.,In vessels, these factors enhance constriction, remodeling, and rarefaction.,In the kidney, these mediators increase expression and activation of sodium transporters, and cause interstitial fibrosis and glomerular injury.,Factors common to hypertension, including oxidative stress, increased interstitial sodium, cytokine production, and inflammasome activation promote immune activation in hypertension.,Recent data suggest that isolevuglandin-modified self-proteins in antigen-presenting cells are immunogenic, promoting cytokine production by the cells in which they are formed and T cell activation.,Efforts to prevent and reverse immune activation may prove beneficial in preventing the long-term sequelae of hypertension and its related cardiovascular diseases. | Recent studies suggest a role for T lymphocytes in hypertension.,However, whether T cells contribute to renal sodium retention and salt-sensitive hypertension is unknown.,Here we demonstrate that T cells infiltrate into the kidney of salt-sensitive hypertensive animals.,In particular, CD8+ T cells directly contact the distal convoluted tubule (DCT) in the kidneys of DOCA-salt mice and CD8+ T cell-injected mice, leading to up-regulation of the Na-Cl co-transporter NCC, p-NCC and the development of salt-sensitive hypertension.,Co-culture with CD8+ T cells upregulates NCC in mouse DCT cells via ROS-induced activation of Src kinase, up-regulation of the K+ channel Kir4.1, and stimulation of the Cl− channel ClC-K.,The last event increases chloride efflux, leading to compensatory chloride influx via NCC activation at the cost of increasing sodium retention.,Collectively, these findings provide a mechanism for adaptive immunity involvement in the kidney defect in sodium handling and the pathogenesis of salt-sensitive hypertension.,T cells contribute to development of high blood pressure but their role in salt-sensitive hypertension is less clear.,Liu et al. show that CD8+ T cells upregulate and activate Na-Cl co-transporter NCC in distal convoluted tubules via direct cell-cell contact and ROS-Src activation, leading to Na+ retention and salt-sensitive hypertension. | 1 |
Supplemental Digital Content is available in the text.,Coronavirus disease 2019 (COVID-19) has led to over 1 million deaths worldwide and has been associated with cardiac complications including cardiac arrhythmias.,The incidence and pathophysiology of these manifestations remain elusive.,In this worldwide survey of patients hospitalized with COVID-19 who developed cardiac arrhythmias, we describe clinical characteristics associated with various arrhythmias, as well as global differences in modulations of routine electrophysiology practice during the pandemic.,We conducted a retrospective analysis of patients hospitalized with COVID-19 infection worldwide with and without incident cardiac arrhythmias.,Patients with documented atrial fibrillation, atrial flutter, supraventricular tachycardia, nonsustained or sustained ventricular tachycardia, ventricular fibrillation, atrioventricular block, or marked sinus bradycardia (heart rate<40 bpm) were classified as having arrhythmia.,Deidentified data was provided by each institution and analyzed.,Data were collected for 4526 patients across 4 continents and 12 countries, 827 of whom had an arrhythmia.,Cardiac comorbidities were common in patients with arrhythmia: 69% had hypertension, 42% diabetes, 30% had heart failure, and 24% had coronary artery disease.,Most had no prior history of arrhythmia.,Of those who did develop an arrhythmia, the majority (81.8%) developed atrial arrhythmias, 20.7% developed ventricular arrhythmias, and 22.6% had bradyarrhythmia.,Regional differences suggested a lower incidence of atrial fibrillation in Asia compared with other continents (34% versus 63%).,Most patients in North America and Europe received hydroxychloroquine, although the frequency of hydroxychloroquine therapy was constant across arrhythmia types.,Forty-three percent of patients who developed arrhythmia were mechanically ventilated and 51% survived to hospital discharge.,Many institutions reported drastic decreases in electrophysiology procedures performed.,Cardiac arrhythmias are common and associated with high morbidity and mortality among patients hospitalized with COVID-19 infection.,There were significant regional variations in the types of arrhythmias and treatment approaches. | Remote monitoring (RM) has significantly transformed the standard of care for patients with cardiac electronic implantable devices.,It provides easy access to valuable information, such as arrhythmic events, acute decompensation manifestations and device‐related issues, without the need of in‐person visits.,Starting March 1st, 332 patients were introduced to an RM program during the Italian lockdown to limit the risk of in‐hospital exposure to severe acute respiratory syndrome‐coronavirus‐2.,Patients were categorized into two groups based on the modality of RM delivery (home [n = 229] vs. office [n = 103] delivered).,The study aimed at assessing the efficacy of the new follow‐up protocol, assessed as mean RM activation time (AT), and the need for technical support.,In addition, patients' acceptance and anxiety status were quantified via the Home Monitoring Acceptance and Satisfaction Questionnaire and the Generalized Anxiety Disorder 7‐item scale.,AT time was less than 48 h in 93% of patients and 7% of them required further technical support.,Despite a higher number of trans‐telephonic technical support in the home‐delivered RM group, mean AT was similar between groups (1.33 ± 0.83 days in home‐delivered vs 1.28 ± 0.81 days in office‐delivered patients; p = .60).,A total of 28 (2.5%) urgent/emergent in‐person examinations were required.,A high degree of patient satisfaction was reached in both groups whereas anxiety status was higher in the office‐delivered group.,The adoption of RM resulted in high patient satisfaction, regardless of the modality of modem delivery; nonetheless, in‐office modem delivery was associated with a higher prevalence of anxiety symptoms. | 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. | Studies have reminded that cardiovascular metabolic comorbidities made patients more susceptible to suffer 2019 novel corona virus (2019-nCoV) disease (COVID-19), and exacerbated the infection.,The aim of this analysis is to determine the association of cardiovascular metabolic diseases with the development of COVID-19.,A meta-analysis of eligible studies that summarized the prevalence of cardiovascular metabolic diseases in COVID-19 and compared the incidences of the comorbidities in ICU/severe and non-ICU/severe patients was performed.,Embase and PubMed were searched for relevant studies.,A total of six studies with 1527 patients were included in this analysis.,The proportions of hypertension, cardia-cerebrovascular disease and diabetes in patients with COVID-19 were 17.1%, 16.4% and 9.7%, respectively.,The incidences of hypertension, cardia-cerebrovascular diseases and diabetes were about twofolds, threefolds and twofolds, respectively, higher in ICU/severe cases than in their non-ICU/severe counterparts.,At least 8.0% patients with COVID-19 suffered the acute cardiac injury.,The incidence of acute cardiac injury was about 13 folds higher in ICU/severe patients compared with the non-ICU/severe patients.,Patients with previous cardiovascular metabolic diseases may face a greater risk of developing into the severe condition and the comorbidities can also greatly affect the prognosis of the COVID-19.,On the other hand, COVID-19 can, in turn, aggravate the damage to the heart. | 1 |
The COVID-19 pandemic has had a profound effect on general health care.,We aimed to evaluate the effect of a nationwide lockdown in France on admissions to hospital for acute myocardial infarction, by patient characteristics and regional prevalence of the pandemic.,In this registry study, we collected data from 21 centres participating in the ongoing French Cohort of Myocardial Infarction Evaluation (FRENCHIE) registry, which collects data from all patients admitted for ST segment elevation myocardial infarction (STEMI) or non-ST segment elevation myocardial infarction (NSTEMI) within 48 h of symptom onset.,We analysed weekly hospital admissions over 8 weeks: the 4 weeks preceding the institution of the lockdown and the 4 weeks following lockdown.,The primary outcome was the change in the number of hospital admissions for all types of acute myocardial infarction, NSTEMI, and STEMI between the 4 weeks before lockdown and the 4 weeks after lockdown.,Comparisons between categorical variables were made using χ2 tests or Fisher's exact tests.,Comparisons of continuous variables were made using Student's t tests or Mann-Whitney tests.,Poisson regression was used to determine the significance of change in hospital admissions over the two periods, after verifying the absence of overdispersion.,Age category, region, and type of acute myocardial infarction (STEMI or NSTEMI) were used as covariables.,The FRENCHIE cohort is registered with ClinicalTrials.gov, NCT04050956.,Between Feb 17 and April 12, 2020, 1167 patients were consecutively admitted within 48 h of acute myocardial infarction (583 with STEMI, 584 with NSTEMI) and were included in the study.,Admissions for acute myocardial infarction decreased between the periods before and after lockdown was instituted, from 686 before to 481 after lockdown (30% decrease; incidence rate ratio 0·69 [95% CI 0·51-0·70]).,Admissions for STEMI decreased from 331 to 252 (24%; 0·72 [0·62-0·85]), and admissions for NSTEMI decreased from 355 to 229 (35%; 0·64 [0·55-0·76]) following institution of the lockdown, with similar trends according to sex, risk factors, and regional prevalence of hospital admissions for COVID-19.,A marked decrease in hospital admissions was observed following the lockdown, irrespective of patient characteristics and regional prevalence of COVID-19.,Health authorities should be aware of these findings, in order to adapt their message if the COVID-19 pandemic persists or recurs, or in case of future major epidemics.,Recherche Hospitalo-Universitaire en Santé iVasc. | 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 |
Pressure overload induces a transition from cardiac hypertrophy to heart failure, but its underlying mechanisms remain elusive.,Here we reconstruct a trajectory of cardiomyocyte remodeling and clarify distinct cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure, by integrating single-cardiomyocyte transcriptome with cell morphology, epigenomic state and heart function.,During early hypertrophy, cardiomyocytes activate mitochondrial translation/metabolism genes, whose expression is correlated with cell size and linked to ERK1/2 and NRF1/2 transcriptional networks.,Persistent overload leads to a bifurcation into adaptive and failing cardiomyocytes, and p53 signaling is specifically activated in late hypertrophy.,Cardiomyocyte-specific p53 deletion shows that cardiomyocyte remodeling is initiated by p53-independent mitochondrial activation and morphological hypertrophy, followed by p53-dependent mitochondrial inhibition, morphological elongation, and heart failure gene program activation.,Human single-cardiomyocyte analysis validates the conservation of the pathogenic transcriptional signatures.,Collectively, cardiomyocyte identity is encoded in transcriptional programs that orchestrate morphological and functional phenotypes.,The mechanisms underlying the transition from cardiac hypertrophy to heart failure following pressure overload are incompletely understood.,Here the authors identify the gene programs encoding the morphological and functional characteristics of cardiomyocytes during the transition from early hypertrophy to heart failure via single-cell transcriptomics, establishing a key role for p53 signalling. | Cardiac regeneration may revolutionize treatment for heart failure but endogenous progenitor-derived cardiomyocytes in the adult mammalian heart are few and pre-existing adult cardiomyocytes divide only at very low rates.,Although candidate genes that control cardiomyocyte cell cycle re-entry have been implicated, expression heterogeneity in the cardiomyocyte stress-response has never been explored.,Here, we show by single nuclear RNA-sequencing of cardiomyocytes from both mouse and human failing, and non-failing adult hearts that sub-populations of cardiomyocytes upregulate cell cycle activators and inhibitors consequent to the stress-response in vivo.,We characterize these subgroups by weighted gene co-expression network analysis and discover long intergenic non-coding RNAs (lincRNA) as key nodal regulators.,KD of nodal lincRNAs affects expression levels of genes related to dedifferentiation and cell cycle, within the same gene regulatory network.,Our study reveals that sub-populations of adult cardiomyocytes may have a unique endogenous potential for cardiac regeneration in vivo.,Adult mammalian cardiomyocytes are predominantly binucleated and unable to divide.,Using single nuclear RNA-sequencing of cardiomyocytes from mouse and human failing and non-failing adult hearts, See et al. show that some cardiomyocytes respond to stress by dedifferentiation and cell cycle re-entry regulated by lncRNAs. | 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. | 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. | 1 |
Hypertrophic cardiomyopathy-causing mutations disrupt a key regulatory off state of myosin in thick filaments.,Hypertrophic cardiomyopathy (HCM) mutations in β-cardiac myosin and myosin binding protein-C (MyBP-C) lead to hypercontractility of the heart, an early hallmark of HCM.,We show that hypercontractility caused by the HCM-causing mutation R663H cannot be explained by changes in fundamental myosin contractile parameters, much like the HCM-causing mutation R403Q.,Using enzymatic assays with purified human β-cardiac myosin, we provide evidence that both mutations cause hypercontractility by increasing the number of functionally accessible myosin heads.,We also demonstrate that the myosin mutation R403Q, but not R663H, ablates the binding of myosin with the C0-C7 fragment of MyBP-C.,Furthermore, addition of C0-C7 decreases the wild-type myosin basal ATPase single turnover rate, while the mutants do not show a similar reduction.,These data suggest that a primary mechanism of action for these mutations is to increase the number of myosin heads functionally available for interaction with actin, which could contribute to hypercontractility. | Supplemental Digital Content is available in the text.,Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy consumption by the heart and increased patient risks for arrhythmias and heart failure.,Recent studies show that pathogenic missense variants in myosin, the molecular motor of the sarcomere, are clustered in residues that participate in dynamic conformational states of sarcomere proteins.,We hypothesized that these conformations are essential to adapt contractile output for energy conservation and that pathophysiology of HCM results from destabilization of these conformations.,We assayed myosin ATP binding to define the proportion of myosins in the super relaxed state (SRX) conformation or the disordered relaxed state (DRX) conformation in healthy rodent and human hearts, at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic HCM variants.,To determine the relationships between myosin conformations, sarcomere function, and cell biology, we assessed contractility, relaxation, and cardiomyocyte morphology and metabolism, with and without an allosteric modulator of myosin ATPase activity.,We then tested whether the positions of myosin variants of unknown clinical significance that were identified in patients with HCM, predicted functional consequences and associations with heart failure and arrhythmias.,Myosins undergo physiological shifts between the SRX conformation that maximizes energy conservation and the DRX conformation that enables cross-bridge formation with greater ATP consumption.,Systemic hemodynamic requirements, pharmacological modulators of myosin, and pathogenic myosin missense mutations influenced the proportions of these conformations.,Hibernation increased the proportion of myosins in the SRX conformation, whereas pathogenic variants destabilized these and increased the proportion of myosins in the DRX conformation, which enhanced cardiomyocyte contractility, but impaired relaxation and evoked hypertrophic remodeling with increased energetic stress.,Using structural locations to stratify variants of unknown clinical significance, we showed that the variants that destabilized myosin conformations were associated with higher rates of heart failure and arrhythmias in patients with HCM.,Myosin conformations establish work-energy equipoise that is essential for life-long cellular homeostasis and heart function.,Destabilization of myosin energy-conserving states promotes contractile abnormalities, morphological and metabolic remodeling, and adverse clinical outcomes in patients with HCM.,Therapeutic restabilization corrects cellular contractile and metabolic phenotypes and may limit these adverse clinical outcomes in patients with HCM. | 1 |
Since the appearance of the first case of coronavirus disease 2019 (COVID-19) a pandemic has emerged affecting millions of people worldwide.,Although the main clinical manifestations are respiratory, an increase in neurological conditions, specifically acute cerebrovascular disease, has been detected.,We present cerebrovascular disease case incidence in hospitalized patients with SARS-CoV-2 infection.,Patients were confirmed by microbiological/serological testing, or on chest CT semiology.,Available data on comorbidity, laboratory parameters, treatment administered, neuroimaging, neuropathological studies and clinical evolution during hospitalization, measured by the modified Rankin scale, were analysed.,A bivariate study was also designed to identify differences between ischaemic and haemorrhagic subtypes.,A statistical model of binary logistic regression and sensitivity analysis was designed to study the influence of independent variables over prognosis.,In our centre, there were 1683 admissions of patients with COVID-19 over 50 days, of which 23 (1.4%) developed cerebrovascular disease.,Within this group of patients, cerebral and chest CT scans were performed in all cases, and MRI in six (26.1%).,Histological samples were obtained in 6/23 cases (two brain biopsies, and four arterial thrombi).,Seventeen patients were classified as cerebral ischaemia (73.9%, with two arterial dissections), five as intracerebral haemorrhage (21.7%), and one leukoencephalopathy of posterior reversible encephalopathy type.,Haemorrhagic patients had higher ferritin levels at the time of stroke (1554.3 versus 519.2, P = 0.004).,Ischaemic strokes were unexpectedly frequent in the vertebrobasilar territory (6/17, 35.3%).,In the haemorrhagic group, a characteristic radiological pattern was identified showing subarachnoid haemorrhage, parieto-occipital leukoencephalopathy, microbleeds and single or multiple focal haematomas.,Brain biopsies performed showed signs of thrombotic microangiopathy and endothelial injury, with no evidence of vasculitis or necrotizing encephalitis.,The functional prognosis during the hospital period was unfavourable in 73.9% (17/23 modified Rankin scale 4-6), and age was the main predictive variable (odds ratio = 1.5; 95% confidence interval 1.012-2.225; P = 0.043).,Our series shows cerebrovascular disease incidence of 1.4% in patients with COVID-19 with high morbidity and mortality.,We describe pathological and radiological data consistent with thrombotic microangiopathy caused by endotheliopathy with a haemorrhagic predisposition. | •We demonstrate five consecutive cases of predominantly lobar COVID-19-associated intracerebral haemorrhage (ICH).,•Patients were typically relatively young with a severe, prolonged inflammatory prodrome.,•COVID-19-induced endotheliitis/endotheliopathy may underlie associated cerebrovascular events.,•For the clinician, anticoagulation decisions must balance risk of thrombosis with risk of haemorrhage.,We demonstrate five consecutive cases of predominantly lobar COVID-19-associated intracerebral haemorrhage (ICH).,Patients were typically relatively young with a severe, prolonged inflammatory prodrome.,COVID-19-induced endotheliitis/endotheliopathy may underlie associated cerebrovascular events.,For the clinician, anticoagulation decisions must balance risk of thrombosis with risk of haemorrhage. | 1 |
COVID‐19 is a systemic infection with a significant impact on the hematopoietic system and hemostasis.,Lymphopenia may be considered as a cardinal laboratory finding, with prognostic potential.,Neutrophil/lymphocyte ratio and peak platelet/lymphocyte ratio may also have prognostic value in determining severe cases.,During the disease course, longitudinal evaluation of lymphocyte count dynamics and inflammatory indices, including LDH, CRP and IL‐6 may help to identify cases with dismal prognosis and prompt intervention in order to improve outcomes.,Biomarkers, such high serum procalcitonin and ferritin have also emerged as poor prognostic factors.,Furthermore, blood hypercoagulability is common among hospitalized COVID‐19 patients.,Elevated D‐Dimer levels are consistently reported, whereas their gradual increase during disease course is particularly associated with disease worsening.,Other coagulation abnormalities such as PT and aPTT prolongation, fibrin degradation products increase, with severe thrombocytopenia lead to life‐threatening disseminated intravascular coagulation (DIC), which necessitates continuous vigilance and prompt intervention.,So, COVID‐19 infected patients, whether hospitalized or ambulatory, are at high risk for venous thromboembolism, and an early and prolonged pharmacological thromboprophylaxis with low molecular weight heparin is highly recommended.,Last but not least, the need for assuring blood donations during the pandemic is also highlighted. | 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 |
The 2019 novel coronavirus outbreak and its associated disease (coronavirus disease 2019 [COVID-19]) have created a worldwide pandemic.,Early data suggest higher rate of ischemic stroke in severe COVID-19 infection.,We evaluated whether a relationship exists between emergent large vessel occlusion (ELVO) and the ongoing COVID-19 outbreak.,This is a retrospective, observational case series.,Data were collected from all patients who presented with ELVO to the Mount Sinai Health System Hospitals across New York City during the peak 3 weeks of hospitalization and death from COVID-19.,Patients’ demographic, comorbid conditions, cardiovascular risk factors, COVID-19 disease status, and clinical presentation were extracted from the electronic medical record.,Comparison was made between COVID-19 positive and negative cohorts.,The incidence of ELVO stroke was compared with the pre-COVID period.,Forty-five consecutive ELVO patients presented during the observation period.,Fifty-three percent of patients tested positive for COVID-19.,Total patients’ mean (±SD) age was 66 (±17).,Patients with COVID-19 were significantly younger than patients without COVID-19, 59±13 versus 74±17 (odds ratio [95% CI], 0.94 [0.81-0.98]; P=0.004).,Seventy-five percent of patients with COVID-19 were male compared with 43% of patients without COVID-19 (odds ratio [95% CI], 3.99 [1.12-14.17]; P=0.032).,Patients with COVID-19 were less likely to be White (8% versus 38% [odds ratio (95% CI), 0.15 (0.04-0.81); P=0.027]).,In comparison to a similar time duration before the COVID-19 outbreak, a 2-fold increase in the total number of ELVO was observed (estimate: 0.78 [95% CI, 0.47-1.08], P≤0.0001).,More than half of the ELVO stroke patients during the peak time of the New York City’s COVID-19 outbreak were COVID-19 positive, and those patients with COVID-19 were younger, more likely to be male, and less likely to be White.,Our findings also suggest an increase in the incidence of ELVO stroke during the peak of the COVID-19 outbreak. | 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. | 1 |
Supplemental Digital Content is available in the text.,Canagliflozin is a sodium glucose cotransporter 2 inhibitor that significantly reduces the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in patients with type 2 diabetes mellitus and elevated cardiovascular risk.,The comparative effects among participants with and without a history of cardiovascular disease (secondary versus primary prevention) were prespecified for evaluation.,The CANVAS Program (Canagliflozin Cardiovascular Assessment Study) randomly assigned 10 142 participants with type 2 diabetes mellitus to canagliflozin or placebo.,The primary prevention cohort comprised individuals ≥50 years of age with ≥2 risk factors for cardiovascular events but with no prior cardiovascular event, and the secondary prevention cohort comprised individuals ≥30 years of age with a prior cardiovascular event.,The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.,Secondary outcomes included heart failure hospitalization and a renal composite (40% reduction in estimated glomerular filtration rate, renal replacement therapy, or renal death).,Primary prevention participants (N=3486; 34%) were younger (63 versus 64 years of age), were more often female (45% versus 31%), and had a longer duration of diabetes mellitus (14 versus 13 years) compared with secondary prevention participants (N=6656; 66%).,The primary end point event rate was higher in the secondary prevention group compared with the primary prevention group (36.9 versus 15.7/1000 patient-years, P<0.001).,In the total cohort, the primary end point was reduced with canagliflozin compared with placebo (26.9 versus 31.5/1000 patient-years; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75-0.97; P<0.001 for noninferiority, P=0.02 for superiority) with no statistical evidence of heterogeneity (interaction P value=0.18) between the primary (HR, 0.98; 95% CI, 0.74-1.30) and secondary prevention (HR, 0.82; 95% CI, 0.72-0.95) cohorts.,Renal outcomes (HR, 0.59; 95% CI, 0.44-0.79 versus HR, 0.63; 95% CI, 0.39-1.02; interaction P value=0.73) and heart failure hospitalization (HR, 0.68; 95% CI, 0.51-0.90 versus HR, 0.64; 95% CI, 0.35-1.15; interaction P value=0.91) were similarly reduced in the secondary and primary prevention cohorts, respectively.,Lower extremity amputations were similarly increased in the secondary and primary prevention cohorts (HR, 2.07; 95% CI, 1.43-3.00 versus HR, 1.52; 95% CI, 0.70-3.29; interaction P value=0.63).,Patients with type 2 diabetes mellitus and prior cardiovascular events had higher rates of cardiovascular outcomes compared with the primary prevention patients.,Canagliflozin reduced cardiovascular and renal outcomes with no statistical evidence of heterogeneity of the treatment effect across the primary and secondary prevention groups.,Additional studies will provide further insights into the effects of canagliflozin in these patient populations.,URL: https://www.clinicaltrials.gov.,Unique identifiers: NCT01032629 and NCT01989754. | Previous animal studies have shown that glucagon-like peptide-1 receptor agonists (GLP-1RAs) suppress arterial restenosis, a major complication of angioplasty, presumably through their direct action on vascular smooth muscle cells.,However, the contribution of vascular endothelial cells (VECs) to this process remains unknown.,In addition, the potential interference caused by severe hyperglycemia and optimal treatment regimen remain to be determined.,Nine-week-old male C57BL6 (wild-type) and diabetic db/db mice were randomly divided into vehicle or liraglutide treatment groups (Day 1), and subject to femoral artery wire injuries (Day 3).,The injured arteries were collected on Day 29 for morphometric analysis.,Human umbilical vein endothelial cells (HUVECs) were used for in vitro experiments.,One-way ANOVA, followed by Tukey’s test, was used for comparisons.,In wild-type mice, liraglutide treatment (5.7, 17, or 107 nmol/kg/day) dose-dependently reduced the neointimal area (20, 50, and 65%) without inducing systemic effects, and caused an associated decrease in the percentage of vascular proliferating cells.,However, these effects were completely abolished by the nitric oxide synthase (NOS) inhibitor N-omega-nitro-l-arginine methyl ester.,Next, we investigated the optimal treatment regimen.,Early treatment (Days 1-14) was as effective in reducing the neointimal area and vascular cell proliferation as full treatment (Days 1-29), whereas delayed treatment (Days 15-29) was ineffective.,In HUVECs, liraglutide treatment dose-dependently stimulated NO production, which was dependent on GLP-1R, cAMP, cAMP-dependent protein kinase, AMP-activated protein kinase (AMPK), and NOS.,Subsequently, we investigated the role of liver kinase B (LKB)-1 in this process.,Liraglutide increased the phosphorylation of LKB-1, and siRNA-induced LKB-1 knockdown abolished liraglutide-stimulated NO production.,In severe hyperglycemic db/db mice, liraglutide treatment also suppressed neointimal hyperplasia, which was accompanied by reductions in vascular cell proliferation and density.,Furthermore, liraglutide treatment suppressed hyperglycemia-enhanced vascular inflammation 7 days after arterial injury.,We demonstrate that endothelial cells are targets of liraglutide, and suppress restenosis via endothelial NO.,Furthermore, the protective effects are maintained in severe hyperglycemia.,Our findings provide an evidence base for a future clinical trial to determine whether treatment with GLP-1RAs represents potentially effective pharmacological therapy following angioplasty in patients with diabetes.,The online version of this article (doi:10.1186/s12933-017-0603-x) contains supplementary material, which is available to authorized users. | 1 |
The coronavirus disease of 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).,While systemic inflammation and pulmonary complications can result in significant morbidity and mortality, cardiovascular complications may also occur.,This brief report evaluates cardiovascular complications in the setting of COVID-19 infection.,The current COVID-19 pandemic has resulted in over one million infected worldwide and thousands of death.,The virus binds and enters through angiotensin-converting enzyme 2 (ACE2).,COVID-19 can result in systemic inflammation, multiorgan dysfunction, and critical illness.,The cardiovascular system is also affected, with complications including myocardial injury, myocarditis, acute myocardial infarction, heart failure, dysrhythmias, and venous thromboembolic events.,Current therapies for COVID-19 may interact with cardiovascular medications.,Emergency clinicians should be aware of these cardiovascular complications when evaluating and managing the patient with COVID-19. | 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 |
To describe the cardiac abnormalities in patients with COVID-19 and identify the characteristics of patients who would benefit most from echocardiography.,In a prospective international survey, we captured echocardiography findings in patients with presumed or confirmed COVID-19 between 3 and 20 April 2020.,Patient characteristics, indications, findings, and impact of echocardiography on management were recorded.,Multivariable logistic regression identified predictors of echocardiographic abnormalities.,A total of 1216 patients [62 (52-71) years, 70% male] from 69 countries across six continents were included.,Overall, 667 (55%) patients had an abnormal echocardiogram.,Left and right ventricular abnormalities were reported in 479 (39%) and 397 (33%) patients, respectively, with evidence of new myocardial infarction in 36 (3%), myocarditis in 35 (3%), and takotsubo cardiomyopathy in 19 (2%).,Severe cardiac disease (severe ventricular dysfunction or tamponade) was observed in 182 (15%) patients.,In those without pre-existing cardiac disease (n = 901), the echocardiogram was abnormal in 46%, and 13% had severe disease.,Independent predictors of left and right ventricular abnormalities were distinct, including elevated natriuretic peptides [adjusted odds ratio (OR) 2.96, 95% confidence interval (CI) 1.75-5.05) and cardiac troponin (OR 1.69, 95% CI 1.13-2.53) for the former, and severity of COVID-19 symptoms (OR 3.19, 95% CI 1.73-6.10) for the latter.,Echocardiography changed management in 33% of patients.,In this global survey, cardiac abnormalities were observed in half of all COVID-19 patients undergoing echocardiography.,Abnormalities were often unheralded or severe, and imaging changed management in one-third of patients. | Up to one-third of COVID-19 patients admitted to intensive care develop an acute cardiomyopathy, which may represent myocarditis or stress cardiomyopathy.,Further, while mortality in older patients with COVID-19 appears related to multi-organ failure complicating acute respiratory distress syndrome (ARDS), the cause of death in younger patients may be related to acute heart failure.,Cardiac involvement needs to be considered early on in critically ill COVID-19 patients, and even after the acute respiratory phase is passing.,This Statement presents a screening algorithm to better identify COVID-19 patients at risk for severe heart failure and circulatory collapse, while balancing the need to protect health care workers and preserve personal protective equipment (PPE).,The significance of serum troponin levels and the role of telemetry and targeted transthoracic echocardiography (TTE) in patient investigation and management are addressed, as are fundamental considerations in the management of acute heart failure in COVID-19 patients. | 1 |
Children descending from pregnancies complicated by gestational hypertension (GH), preeclampsia (PE) or fetal growth restriction (FGR) have a lifelong cardiovascular risk.,The aim of the study was to verify if pregnancy complications induce postnatal alterations in gene expression of microRNAs associated with cardiovascular/cerebrovascular diseases.,Twenty-nine microRNAs were assessed in peripheral blood, compared between groups, and analyzed in relation to both aspects, the current presence of cardiovascular risk factors and cardiovascular complications and the previous occurrence of pregnancy complications with regard to the clinical signs, dates of delivery, and Doppler ultrasound examination.,The expression profile of miR-21-5p differed between controls and children with a history of uncomplicated pregnancies with abnormal clinical findings.,Abnormal expression profile of multiple microRNAs was found in children affected with GH (miR-1-3p, miR-17-5p, miR-20a-5p, miR-21-5p, miR-23a-3p, miR-26a-5p, miR-29a-3p, miR-103a-3p, miR-125b-5p, miR-126-3p, miR-133a-3p, miR-146a-5p, miR-181a-5p, miR-195-5p, and miR-342-3p), PE (miR-1-3p, miR-20a-5p, miR-20b-5p, miR-103a-3p, miR-133a-3p, miR-342-3p), and FGR (miR-17-5p, miR-126-3p, miR-133a-3p).,The index of pulsatility in the ductus venosus showed a strong positive correlation with miR-210-3p gene expression in children exposed to PE and/or FGR.,Any of changes in epigenome (up-regulation of miR-1-3p and miR-133a-3p) that were induced by pregnancy complications are long-acting and may predispose children affected with GH, PE, or FGR to later development of cardiovascular/cerebrovascular diseases.,Novel epigenetic changes (aberrant expression profile of microRNAs) appeared in a proportion of children that were exposed to GH, PE, or FGR.,Screening of particular microRNAs may stratify a highly risky group of children that might benefit from implementation of early primary prevention strategies. | We investigated the role of microRNAs (miRNA) in endothelial dysfunction in the setting of cardiometabolic disorders represented by type 2 diabetes mellitus (T2DM). miR‐29 was dysregulated in resistance arterioles obtained by biopsy in T2DM patients.,Intraluminal delivery of miR‐29a‐3p or miR‐29b‐3p mimics restored normal endothelium‐dependent vasodilation (EDVD) in T2DM arterioles that otherwise exhibited impaired EDVD.,Intraluminal delivery of anti‐miR‐29b‐3p in arterioles from non‐DM human subjects or rats or targeted mutation of Mir29b‐1/a gene in rats led to impaired EDVD and exacerbation of hypertension in the rats. miR‐29b‐3p mimic increased, while anti‐miR‐29b‐3p or Mir29b‐1/a gene mutation decreased, nitric oxide levels in arterioles.,The mutation of Mir29b‐1/a gene led to preferential differential expression of genes related to nitric oxide including Lypla1.,Lypla1 was a direct target of miR‐29 and could abrogate the effect of miR‐29 in promoting nitric oxide production.,Treatment with Lypla1 siRNA improved EDVD in arterioles obtained from T2DM patients or Mir29b‐1/a mutant rats or treated with anti‐miR‐29b‐3p.,These findings indicate miR‐29 is required for normal endothelial function in humans and animal models and has therapeutic potential for cardiometabolic disorders. | 1 |
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