Redefining cardiac biomarkers in predicting mortality and adverse outcomes of inpatients with COVID-19

The prognostic power of circulating cardiac biomarkers, their utility and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined. In this multi-centered retrospective study, we enrolled 3,219 patients with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019 to March 4, 2020, to estimate the associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the mixed-effect Cox model, after adjusting for age, gender and comorbidities, the adjusted hazard ratios of 28-day mortality for high-sensitivity cardiac troponin I (hs-cTnI) was 7.12 (95%CI, 4.60-11.03; P<0.001), NT-proB-type natriuretic peptide (NT-proBNP) was 5.11 (95%CI, 3.50-7.47; P<0.001), CK-MB was 4.86 (95%CI, 3.33-7.09; P<0.001), myoglobin was 4.50 (95%CI, 3.18-6.36; P < 0.001), and CK was 3.56 (95%CI, 2.53-5.02; P < 0.001). The cutoffs of those cardiac biomarkers for effective prognosis of 28-day mortality of COVID-19 were found to be much lower than for regular heart disease at about 49% of the currently recommended thresholds. Patients with elevated cardiac injury markers above the newly established cutoffs were associated with significantly increased risk of COVID-19 death. In conclusion, cardiac biomarker elevations are significantly associated with 28-day death in patients with COVID-19. The prognostic cutoffs for of these values might be much lower than the current reference standards. These findings can assist better management of COVID-19 patients to improve outcomes. Importantly, the newly established cutoff levels of COVID-19 associated cardiac biomarkers may serve as useful criteria for the future prospective studies and clinical trials

Redefining Cardiac Biomarkers in Predicting Mortality of Inpatients With COVID-19

The prognostic power of circulating cardiac biomarkers, their utility, and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined. In this multicentered retrospective study, we enrolled 3219 patients with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019 to March 4, 2020, to estimate the associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the mixed-effects Cox model, after adjusting for age, sex, and comorbidities, the adjusted hazard ratio of 28-day mortality for hs-cTnI (high-sensitivity cardiac troponin I) was 7.12 ([95% CI, 4.60-11.03] P\u3c0.001), (NT-pro)BNP (N-terminal pro-B-type natriuretic peptide or brain natriuretic peptide) was 5.11 ([95% CI, 3.50-7.47] P\u3c0.001), CK (creatine phosphokinase)-MB was 4.86 ([95% CI, 3.33-7.09] P\u3c0.001), MYO (myoglobin) was 4.50 ([95% CI, 3.18-6.36] P\u3c0.001), and CK was 3.56 ([95% CI, 2.53-5.02] P\u3c0.001). The cutoffs of those cardiac biomarkers for effective prognosis of 28-day mortality of COVID-19 were found to be much lower than for regular heart disease at about 19%-50% of the currently recommended thresholds. Patients with elevated cardiac injury markers above the newly established cutoffs were associated with significantly increased risk of COVID-19 death. In conclusion, cardiac biomarker elevations are significantly associated with 28-day death in patients with COVID-19. The prognostic cutoff values of these biomarkers might be much lower than the current reference standards. These findings can assist in better management of COVID-19 patients to improve outcomes. Importantly, the newly established cutoff levels of COVID-19-associated cardiac biomarkers may serve as useful criteria for the future prospective studies and clinical trials

Sepsis and cardiovascular dysfunction : new therapeutic approaches

Le sepsis, caractérisé par une réponse systémique inadaptée, demeure une des principales causes de mortalité. Les principaux mécanismes des défaillances d’organes induites par le sepsis sont d’étiologie vasculaire et/ou inflammatoire. Notre hypothèse est que la dysfonction vasculaire entraîne une baisse exagérée de la perfusion et de l’oxygénation des organes et ainsi une détérioration de leur fonction, l’ensemble pouvant mener au décès.Dans ce contexte physiopathologique complexe, l’objectif était d’étudier 2 pistes thérapeutiques nouvelles qui modulent, l’une la réponse inflammatoire des organes par l’érythropoïétine (EPO) et l’autre l’un des principaux effecteurs de la dysfonction vasculaire, l’adrénomédulline (ADM). Nos résultats montrent que, lors du sepsis :- l'EPO prévient la réponse inflammatoire et le stress oxydant dans les organes etdans le plasma et a un effet positif sur la mortalité précoce. Cependant, les doses pour obtenir ces effets cytoprotecteurs sont élevées.- l’Adrezicumab (ADZ), anticorps inhibant partiellement l’ADM, restaure une pression artérielle et un débit cardiaque corrects précocement. Si l’ADZ prévient les dysfonctionsvasculaire, métabolique et cardiaque au cours du sepsis et/ou diminue la nécessité de recours aux vasopresseurs, cela ouvrirait des perspectives thérapeutiques majeures.En conclusion, les pistes thérapeutiques testées sont d’intérêt. Pour établir le potentiel chez l’Homme, l’utilisation de dérivés non-hémapoïétiques de l’EPO serait engageante et demande d’autres investigations. L’approche immunologique, telle celle ciblant l’ADM est prometteuse, les effets à long terme sont encore à établir. ,Sepsis, characterized by inadequate systemic response with organ failure, remains amajor cause of death worldwide. The main mechanisms of sepsis-induced organ dysfunctionare from vascular and inflammatory etiologies. Our hypothesis was that vascular dysfunctioninduced a major drop in perfusion and oxygenation of organs and in turn a deterioration offunction, all of which lead to death.In this multifactorial pathophysiological background, our objective was to investigate2 novel therapeutic approaches able to modulate, one the inflammatory response of failingorgans through the use of erythropoietin (EPO) and the other one the key effector ofvascular dysfunction in sepsis, adrenomedullin (ADM).Our results show that during sepsis:- EPO prevents, inflammatory response and oxidative stress in organs and in theplasma and in turn death. The doses for these cytoprotective effects are high.- the Adrezicumab (ADZ) through the partial inhibition of the ADM and themodulation of vasodilation, rapidly improved, during sepsis, blood pressure and cardiacoutput and could thus prevent the onset of organ dysfunction related to sepsis. IfAdrecizumab prevents vascular, metabolic and cardiac dysfunction during sepsis and/orreduces the need for use of vasopressors, it would open major therapeutic perspectives.In conclusion, all together we provide new evidence that on one hand the use of nonhematopoieticderivatives of EPO could be promising but request further investigations andon the other, the immunologic approach such as targetting ADM could be of high interest inthe treatment of sepsis

The Science Underlying COVID-19

The coronavirus disease 2019 (COVID-19) pandemic has affected health and economy worldwide on an unprecedented scale. Patients have diverse clinical outcomes, but those with preexisting cardiovascular disease, hypertension, and related conditions incur disproportionately worse outcome. The high infectivity of severe acute respiratory syndrome coronavirus 2 is in part related to new mutations in the receptor binding domain, and acquisition of a furin cleavage site in the S-spike protein. The continued viral shedding in the asymptomatic and presymptomatic individuals enhances its community transmission. The virus uses the angiotensin converting enzyme 2 receptor for internalization, aided by transmembrane protease serine 2 protease. The tissue localization of the receptors correlates with COVID-19 presenting symptoms and organ dysfunction. Virus-induced angiotensin converting enzyme 2 downregulation may attenuate its function, diminish its anti-inflammatory role, and heighten angiotensin II effects in the predisposed patients. Lymphopenia occurs early and is prognostic, potentially associated with reduction of the CD4+ and some CD8+ T cells. This leads to imbalance of the innate/acquired immune response, delayed viral clearance, and hyperstimulated macrophages and neutrophils. Appropriate type I interferon pathway activation is critical for virus attenuation and balanced immune response. Persistent immune activation in predisposed patients, such as elderly adults and those with cardiovascular risk, can lead to hemophagocytosis-like syndrome, with uncontrolled amplification of cytokine production, leading to multiorgan failure and death. In addition to the airways and lungs, the cardiovascular system is often involved in COVID-19 early, reflected in the release of highly sensitive troponin and natriuretic peptides, which are all extremely prognostic, in particular, in those showing continued rise, along with cytokines such as interleukin-6. Inflammation in the vascular system can result in diffuse microangiopathy with thrombosis. Inflammation in the myocardium can result in myocarditis, heart failure, cardiac arrhythmias, acute coronary syndrome, rapid deterioration, and sudden death. Aggressive support based on early prognostic indicators with expectant management can potentially improve recovery. Appropriate treatment for heart failure, arrhythmias, acute coronary syndrome, and thrombosis remain important. Specific evidence-based treatment strategies for COVID-19 will emerge with ongoing global collaboration on multiple approaches being evaluated. To protect the wider population, antibody testing and effective vaccine will be needed to make COVID-19 history