Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Short-term effects of ivabradine in patients with chronic stable ischemic heart disease

Introduction: Ivabradine is a novel selective If current inhibitor with anti-ischemic and antianginal activity. Objectives: To assess the effect of the selective If current inhibitor ivabradine on heart rate, angina pectoris, and functional capacity in stable patients with chronic coronary artery disease on maximally tolerated medical therapy. Materials and Methods: Consecutive patients from the out-patient cardiology clinic with stable coronary artery disease documented by coronary angiography were included. Patients had to be on maximally tolerated medical therapy with β-blockers, angiotensin-converting enzyme inhibitors or receptor blockers (ACE-I or ARB), antiplatelets, statins, nitrates, and anti-metabolics with a baseline heart rate of at least 70 beats per minute. All patients underwent assessment of angina (Canadian Cardiovascular Society Angina Class: CCS I to IV) and functional capacity (using a validated self-administered questionnaire), at baseline and after 4 months of ivabradine therapy. Results: Twenty patients were enrolled (mean age 47 ± 7 years, all male, 60% with hypertension, 30% with diabetes mellitus). Patients were on optimal medical regimen of aspirin (100%), β-blocker (100%), statins (100%), clopidogrel (90%), nitrates (35%), anti-metabolics (90%), and ACE-I or ARB (95%). At baseline, the majority of patients (90%) were in CCS class II-IV. All patients were started on ivabradine 5 mg twice daily, and in 12 patients the dose was increased to 7.5 mg twice daily. After 4 months of treatment, the heart rate was significantly reduced from an average of 82 ± 8 to 68 ± 6 bpm ( P < 0.001). The reduction in heart rate was accompanied by a significant improvement in functional capacity (score 3.5 ± 0.9 to 4.7 ± 0.7, P < 0.001) and angina classification; at baseline 10% of the patients were in CCS class I compared to 50% after 4 months of therapy ( P = 0.01). No symptomatic bradycardia was reported with ivabradine. Conclusion: The addition of ivabradine to optimal medical therapy in patients with stable coronary artery disease is associated with significant improvement in anginal symptoms and functional capacity

Congenital aneurysmal right coronary artery with a fistula to the left atrium in an adult

Abstract Background Congenital coronary artery fistula in association with aneurysm of the involved coronary artery in adults is rare. Moreover, the right coronary artery- left atrial fistula is also uncommon. Most of the cases are asymptomatic. However, symptomatic patients need therapeutic interventions. The potential complications associated with this anomaly are life-threatening, therefore, there is a need to explore more on differential diagnosis, investigations, management strategies and prevention of complications. Case presentation We present herewith a 26-year-old male patient with symptoms of chest pain and dyspnea. He was diagnosed with aneurysmal dilatation of the right coronary artery in its entire course which terminated as a fistulous communication into the left atrium. The closure of the fistula was done using autologous pericardial patch under cardiopulmonary bypass. Currently, the patient is being followed up after surgery and receiving anticoagulants. Conclusion The advancement in the diagnostic imaging modalities have made it possible to find similar abnormalities more frequently. Due to rare nature of this anomaly, there is a need to explore and discuss management strategies that include medical management, surgical intervention or percutaneous interventions for a successful outcome

Design and rationale of gulf documentation of ambulatory sick patients with heart failure (Gulf DYSPNEA) registry

Aim: The aim of this study is to describe the clinical characteristics of ambulatory patients with chronic heart failure (HF) in the Arabian Gulf and to examine several aspects including types of HF, causes, and adherence to management guidelines. Methods: Gulf documentation of ambulatory sick patients with HF (Gulf DYSPNEA) registry is a multicenter, cross-sectional study, recruiting adult ambulatory HF patients from 24 hospitals in five Arabian Gulf countries. Consecutive patients are recruited prospectively from participating clinics with no follow-up data collection. Recruitment started on November 07, 2016 and will stop when 3,500 patients are enrolled in this study. Collected data explore demographics, baseline patient characteristics, symptoms, previous medical history, comorbidities, physical signs, presenting electrocardiogram, echocardiographic findings, types of HF, and management. Conclusion: This registry is expected to provide useful data on several important aspects and features of ambulatory patients with chronic HF in Arabian Gulf countries. The trial registration number is “ClinicalTrials.gov number, NCT02793180”