Polygenic risk score and coronary artery disease:A meta-analysis of 979,286 participant data

BACKGROUND AND AIMS: Coronary artery disease (CAD) is a complex disease with a strong genetic basis. While previous studies have combined common single-nucleotide polymorphisms (SNPs) into a polygenic risk score (PRS) to predict CAD risk, this association is poorly characterised. We performed a meta-analysis to estimate the effect of PRS on the risk of CAD. METHODS: Online databases were searched for studies reporting PRS and CAD. PRS computation was based on log-odds (PRSLN), pruning or clumping and thresholding (PRSP/C + T), Lassosum regression (PRSLassosum), LDpred (PRSLDpred), or metaGRS (PRSmetaGRS). The reported odds ratio (OR), hazard ratio (HR), C-indexes and their corresponding 95% confidence interval (95% CI) were pooled in a random-effects meta-analysis. RESULTS: Forty-nine studies were included (979,286 individuals). There was a significant association between 1-standard deviation [SD] increment in PRS and adjusted risks of both incident and prevalent CAD (OR [95% CI]: 1.67 [1.57-1.77] for PRSmetaGRS, 1.46 [1.26-1.68] for PRSLDpred). The risk of incident CAD was highest for PRSP/C + T (HR [95% CI]: 1.49 [1.26-1.78]), PRSmetaGRS (1.37 [1.27-1.47]), and PRSLDpred (1.36 [1.31-1.42]). Analysis of model performance demonstrated that PRS predicted incident CAD with C-index of up to 0.71. Importantly, addition of PRS to clinical risk scores resulted in modest but statistically significant improvements in CAD risk prediction, with 1.5% observed for PRSP/C + T (p < 0.001) and 1.6% for PRSLDpred (p < 0.001). CONCLUSIONS: Polygenic risk score is strongly associated with increased risks of CAD. Future prospective studies should explore the usefulness of polygenic risk scores for identifying individuals at a high risk of developing CAD

Vascular Manifestations of COVID-19 -Thromboembolism and Microvascular Dysfunction

The coronavirus pandemic has reportedly infected over 22 million individuals and caused over 778,000 deaths worldwide. This novel coronavirus, officially named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), although primarily causes significant respiratory distress, can have significant deleterious effects on the cardiovascular system. Severe cases of the virus frequently result in respiratory distress requiring mechanical ventilation, often seen, but not confined to, individuals with pre-existing hypertension and cardiovascular disease, potentially due to the fact that the virus can enter the circulation via the lung alveoli. Here the virus can directly infect vascular tissues, via TMPRSS2 spike glycoprotein priming, thereby facilitating ACE-2-mediated viral entry. Clinical manifestations, such as vasculitis, have been detected in a number of vascular beds (e.g. lungs, heart, and kidneys), with thromboembolism being observed in patients suffering from severe coronavirus disease (COVID-19), suggesting the virus perturbs the vasculature, leading to vascular dysfunction. Activation of endothelial cells via the immune-mediated inflammatory response and viral infection of either endothelial cells or cells involved in endothelial homeostasis, are some of the multifaceted mechanisms potentially involved in the pathogenesis of vascular dysfunction within COVID-19 patients. In this review, we examine the evidence of vascular manifestations of SARS-CoV-2, the potential mechanism(s) of entry into vascular tissue and the contribution of endothelial cell dysfunction and cellular crosstalk in this vascular tropism of SARS-CoV-2. Moreover, we discuss the current evidence on hypercoagulability and how it relates to increased microvascular thromboembolic complications in COVID-19

The role of MSC therapy in attenuating the damaging effects of the cytokine storm induced by COVID-19 on the heart and cardiovascular system

The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has led to 47m infected cases and 1.2m (2.6%) deaths. A hallmark of more severe cases of SARS-CoV-2 in patients with acute respiratory distress syndrome (ARDS) appears to be a virally-induced over-activation or unregulated response of the immune system, termed a "cytokine storm", featuring elevated levels of pro-inflammatory cytokines such as IL-2, IL-6, IL-7, IL-22, CXCL10 and TNF?. Whilst the lungs are the primary site of infection for SARS-CoV-2, in more severe cases its effects can be detected in multiple organ systems. Indeed, many COVID-19 positive patients develop cardiovascular complications, such as myocardial injury, myocarditis, cardiac arrhythmia and thromboembolism, which are associated with higher mortality. Drug and cell therapies targeting immunosuppression have been suggested to help combat the cytokine storm. In particular, mesenchymal stromal cells (MSCs), owing to their powerful immunomodulatory ability, have shown promise in early clinical studies to avoid, prevent or attenuate the cytokine storm. In this review, we will discuss the mechanistic underpinnings of the cytokine storm on the cardiovascular system, and how MSCs potentially attenuate the damage caused by the cytokine storm induced by COVID-19. We will also address how MSC transplantation could alleviate the long-term complications seen in some COVID-19 patients, such as improving tissue repair and regeneration

A novel macrophage subpopulation conveys increased genetic risk of coronary artery disease

BACKGROUND: Coronary artery disease (CAD), the leading cause of death worldwide, is influenced by both environmental and genetic factors. Although over 250 genetic risk loci have been identified through genome-wide association studies, the specific causal variants and their regulatory mechanisms are still largely unknown, particularly in disease-relevant cell types like macrophages. METHODS: We utilized single-cell RNA-seq and single-cell multiomics approaches in primary human monocyte–derived macrophages to explore the transcriptional regulatory network involved in a critical pathogenic event of coronary atherosclerosis—the formation of lipid-laden foam cells. The relative genetic contribution to CAD was assessed by partitioning disease heritability across different macrophage subpopulations. Meta-analysis of single-cell RNA-seq data sets from 38 human atherosclerotic samples was conducted to provide high-resolution cross-referencing to macrophage subpopulations in vivo. RESULTS: We identified 18 782 cis-regulatory elements by jointly profiling the gene expression and chromatin accessibility of >5000 macrophages. Integration with CAD genome-wide association study data prioritized 121 CAD-related genetic variants and 56 candidate causal genes. We showed that CAD heritability was not uniformly distributed and was particularly enriched in the gene programs of a novel CD52-hi lipid-handling macrophage subpopulation. These CD52-hi macrophages displayed significantly less lipoprotein accumulation and were also found in human atherosclerotic plaques. We investigated the cis-regulatory effect of a risk variant rs10488763 on FDX1, implicating the recruitment of AP-1 and C/EBP-β in the causal mechanisms at this locus. CONCLUSIONS: Our results provide genetic evidence of the divergent roles of macrophage subsets in atherogenesis and highlight lipid-handling macrophages as a key subpopulation through which genetic variants operate to influence disease. These findings provide an unbiased framework for functional fine-mapping of genome-wide association study results using single-cell multiomics and offer new insights into the genotype-environment interactions underlying atherosclerotic disease

Accelerated biological aging secondary to cardiometabolic risk factors is a predictor of cardiovascular mortality: a systematic review and meta-analysis

Background: Chronological aging is one of the major risk factors of cardiovascular (CV) disease (CVD); however, the effect of biological aging on CVD and outcomes remain poorly understood. Herein, we evaluated the association between leukocyte telomere length (LTL), a marker of biological age, and CV outcomes. Methods: We searched PubMed, Embase, Ovid Medline, and Web of Science Core Collection for the studies on the association between LTL and myocardial infarction (MI), CV death, and/or CVD risk factors from inception to July 2020. Extracted data were pooled in a random-effects meta-analysis and summarized as risk ratio (RR) and corresponding 95% confidence interval (CI) per LTL tertile. Results: A total of 32 studies (n ¼ 144,610 participants) were included. In a pooled analysis of MI and LTL in a multivariate-adjusted model, the shortest LTL was associated with a 39% higher risk of MI (RR, 1.39; 95% CI, 1.16-1.67; P < 0.001). After adjusting for chronological age and traditional covariance, we showed a 28% increased risk of CV death in the shortest tertile of LTL (RR, 1.28; 95% CI, 1.05- 1.56; P ¼ 0.01). Analysis of the studies that investigated the association between CV risk factors and LTL (n ¼ 7) showed that diabetes mellitus is associated with a 46% increased risk of LTL attrition (RR, 1.46; 95% CI, 1.46-2.09; P ¼ 0.039). Conclusions: This study shows a strong association between LTL, a marker of biological aging, and the risk of MI and CV death. Cardiometabolic risk factors contribute to telomere attrition and therefore accelerates biological aging.Mehrdad Emami, MD, Thomas A. Agbaedeng, PhD, Gijo Thomas, PhD, Melissa E. Middeldorp, PhD, Anand Thiyagarajah, MBBS, Christopher X. Wong, MBBS, PhD, Adrian D. Elliott, PhD, Celine Gallagher, PhD, Jeroen M.L. Hendriks, PhD, Dennis H. Lau, MBBS, PhD, and Prashanthan Sanders, MBBS, PhD

Progression and reversibility of stretch induced atrial remodeling: characterization and clinical implications

Atrial fibrillation (AF) is the most common sustained arrhythmia and across the developed nations, it contributes to increasing hospitalizations and healthcare burden. Several comorbidities and risk factors including hypertension, heart failure, obstructive sleep apnoea and obesity are known to play an important role in the initiation and perpetuation of AF and atrial stretch or dilatation may play a central mechanistic role. The impact of atrial stretch in the development of AF can vary dependent on the underlying disease. This review focuses on understanding the substrate for AF in conditions of acute and chronic stretch and in the presence of common co-morbidities or risk factors through the review of findings in both animal and human studies. Additionally, the reversibility of atrial remodeling following stretch release will also be discussed. Identification of clinical conditions associated with increased atrial stretch as well as the treatment or prevention of these conditions may help to prevent AF progression and improve sinus rhythm maintenance

Gut microbiota, dysbiosis and atrial fibrillation. Arrhythmogenic mechanisms and potential clinical implications

Recent preclinical and observational cohort studies have implicated imbalances in gut microbiota composition as a contributor to atrial fibrillation (AF). The gut microbiota is a complex and dynamic ecosystem containing trillions of microorganisms, which produces bioactive metabolites influencing host health and disease development. In addition to host-specific determinants, lifestyle-related factors such as diet and drugs are important determinants of the gut microbiota composition. In this review, we discuss the evidence suggesting a potential bidirectional association between AF and gut microbiota, identifying gut microbiota-derived metabolites as possible regulators of the AF substrate. We summarize the effect of gut microbiota on the development and progression of AF risk-factors, including heart failure, hypertension, obesity and coronary artery disease. We also discuss the potential antiarrhythmic effects of pharmacological and diet-induced modifications of gut microbiota composition, which may modulate and prevent the progression to AF. Finally, we highlight important gaps in knowledge and areas requiring future investigation. Although data supporting a direct relationship between gut microbiota and AF are very limited at the present time, emerging preclinical and clinical research dealing with mechanistic interactions between gut microbiota and AF is important as it may lead to new insights into AF pathophysiology and the discovery of novel therapeutic targets for AF