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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.

Objective To summarize data on the rates and predictors of left atrial/left atrial appendage thrombus (LAT/LAAT) detection by transoesophageal echocardiography (TEE) prior to electrical cardioversion (ECV) or catheter ablation (CA) for atrial fibrillation (AF). Methods EMBASE, MEDLINE, and Web of Science were searched to identify all studies providing relevant data and published by October 07, 2020. Random-effects meta-analysis method was used to pool estimates. Results A total of 85 studies were included, reporting data from 56,660 patients with AF. In patients undergoing CA and ECV, the pooled prevalence of LAT/LAAT was respectively 1.8% and 7.5% in those not on oral anticoagulation (OAC), 1.8% and 5.5% in those taking OAC, 1.3% and 4.9% in case of adequate OAC. According to the type of OAC, the prevalence was 2.0% and 7.6% for vitamin K antagonist (VKA), 1.3% and 3.5% for direct oral anticoagulant (DOAC). Predictors of LAT/LAAT detection were non-paroxysmal AF (odds ratio [OR] 3.6, 95% confidence interval 2.4-5.2), hypertension (OR 2.9, 1.2-7.0), previous stroke (OR 3.0, 1.6-5.63), heart failure (OR 4.3, 2.7-6.8) and CHADS2 score ≥ 2 (OR 3.3, 1.9-5.8) for patients undergoing CA; and heart failure (OR 2.8, 1.3-6.2) and the CHA2 DS2 -VASc score (OR 2.55, 1.5-4.5) for those undergoing ECV. Conclusion The prevalence of LAT/LAAT in AF patients undergoing ECV or CA varies widely, mainly due to differences in patient risk profiles and OAC types. Further research should determine whether the predictors of LAT/LAAT detection identified by this study could be used to select patients who require preprocedural TEE. This article is protected by copyright. All rights reserved.

In this study, we sought to estimate the prevalence of concomitant sleep-disordered breathing (SDB) in patients with atrial fibrillation (AF) and to systematically evaluate how SDB is assessed in this population.We searched Medline, Embase and Cinahl databases through August 2020 for studies reporting on SDB in a minimum 100 patients with AF. For quantitative analysis, studies were required to have systematically assessed for SDB in consecutive AF patients. Pooled prevalence estimates were calculated with the use of the random effects model. Weighted mean differences and odds ratios were calculated when possible to assess the strength of association between baseline characteristics and SDB.The search yielded 2758 records, of which 33 studies (n = 23,894 patients) met the inclusion criteria for qualitative synthesis and 13 studies (n = 2660 patients) met the meta-analysis criteria. The pooled SDB prevalence based on an SDB diagnosis cutoff of apnea-hypopnea index (AHI) ≥ 5/h was 78% (95% confidence interval [CI] 70%-86%; P0.001). For moderate-to-severe SDB (AHI ≥ 15/h), the pooled SDB prevalence was 40% (95% CI 32%-48%; P0.001). High degrees of heterogeneity were observed (ISDB is highly prevalent in patients with AF. Wide variation exists in the diagnostic tools and thresholds used to detect concomitant SDB in AF. Prospective systematic testing for SDB in unselected cohorts of AF patients may be required to define the true prevalence of SDB in this population.

Background Atrial fibrillation (AF) is common after pacemaker implantation. However, the impact of pacemaker algorithms in AF prevention is not well understood. Objective The purpose of this study was to evaluate the role of pacing algorithms in preventing AF progression. Methods A systematic search of articles using the PubMed and Embase databases resulted in a total of 754 references. After exclusions, 21 randomized controlled trials (8336 patients) were analyzed, comprising studies reporting ventricular pacing percentage (VP%) (AAI vs DDD, n=1; reducing ventricular pacing [RedVP] algorithms, n=2); and atrial pacing therapies (atrial preference pacing [APP], n=14; atrial antitachycardia pacing [aATP]+APP, n=3; RedVP+APP+aATP, n=1). Results Low VP% ( 10%). APP algorithm reduced premature atrial complexes (PAC) burden (mean difference [MD] –1117.74; 95% CI –1852.36 to –383.11; P = .003; I2 = 67%) but did not decrease AF burden (MD 8.20; 95% CI –5.39 to 21.80; P = .24; I2 = 17%) or AF episodes (MD 0.00; 95% CI –0.24 to 0.25; P = .98; I2 = 0%). Similarly, aATP+APP programming showed no significant difference in AF progression (odds ratio 0.65; 95% CI 0.36–1.14; P = .13; I2 = 61%). No serious adverse events related to algorithm were reported. Conclusion This meta-analysis of randomized controlled trials demonstrated that algorithms to reduce VP% can be considered safe. Low burden VP% did not significantly suppress AF progression. The atrial pacing therapy algorithms could suppress PAC burden but did not prevent AF progression.

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.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.A total of 32 studies (n = 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; P0.001). 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 = 0.01). Analysis of the studies that investigated the association between CV risk factors and LTL (n = 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 = 0.039).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.

Objective: To summarize data on atrial fibrillation (AF) detection rates and predictors across different rhythm monitoring strategies in patients with cryptogenic stroke (CS) or embolic stroke of undetermined source (ESUS). Methods: MEDLINE, Embase, and Web of Science were searched to identify all published studies providing relevant data through July 6, 2020. Random-effects meta-analysis method was used to pool estimates. Results: We included 47 studies reporting on a pooled population of 8,215 patients with CS or ESUS. Using implantable cardiac monitor (ICM), the pooled rate of AF was 12.2% (95% CI 9.4–15.0) at 3 months, 16.0% (95% CI 13.2–18.8) at 6 months, 18.7% (95% CI 15.7–21.7) at 12 months, 22.8% (95% CI 19.1–26.5) at 24 months, and 28.5% (95% CI 17.6–39.3) at 36 months. AF rates were significantly higher in patients with ESUS vs CS (22.0% vs 14.2%; p

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 anti-arrhythmic 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.

The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has led to 47 m infected cases and 1. 2 m (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 TNFα. 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.

The coronavirus pandemic has reportedly infected over 31.5 million individuals and caused over 970,000 deaths worldwide (as of 22nd Sept 2020). 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.

Background Although physical activity (PA) is an important component of cardiovascular disease prevention and treatment, its role in atrial fibrillation (AF) risk is less well established. Objective The purpose of this study was to systematically summarize the evidence pertaining to the relationship of PA and risk of AF. Methods We searched the PubMed and Embase databases for prospective cohort studies reporting the risk of AF associated with a specific PA volume through March 2020. From each study, we extracted the risk associated with a given PA level, in comparison with insufficiently active ("inactive") individuals. The reported risk was normalized to metabolic equivalent of task (MET)-minutes per week. A random-effects meta-analysis was used to compare AF risk between those who met and those who did not meet PA recommendations (450 MET-minutes per week), and a dose-response analysis between the level of PA and the risk of AF was performed. Results Fifteen studies reporting data from 1,464,539 individuals (median age 55.3 years; 51.7% female) were included. Individuals achieving guideline-recommended level of PA had a significantly lower risk of AF (hazard ratio 0.94; 95% confidence interval 0.90–0.97; P = .001). Dose-response analysis showed that PA levels up to 1900 MET-minutes per week were associated with a lower risk of AF, with less certainty beyond that level. Conclusion PA at guideline-recommended levels and above are associated with a significantly lower AF risk. However, at 2000 MET-minutes per week and beyond, the benefit is less clear.

Atrial fibrillation (AF) and carotid stenosis (CS) can coexist and this association has been reported to result in a higher risk of stroke than attributed to either condition alone. Here we aimed to summarize the data on the association of CS and AF. MEDLINE and Embase were searched to identify all published studies providing relevant data through February 27, 2020. Random-effects meta-analysis method was used to pool estimates of prevalence. Heterogeneity was assessed by mean I-squared statistic. Forty-eight studies were included, 20 reporting on the prevalence of carotid disease in a pooled population of 49,070 AF patients, and 28 on the prevalence of AF in a total of 2,288,265 patients with carotid disease. The pooled prevalence of CS in AF patients was 12.4% (95% confidence interval [CI] 8.7 to 16.0, I2 93%; n = 3,919), ranging from 4.4% to 24.3%. The pooled prevalence of carotid plaque was 48.4% (95% CI 35.2 to 61.7, I2 = 99%; n = 4292). The prevalence of AF in patients with CS was 9.3% (95% CI 8.7 to 10.0, I2 99%; n = 2,286,518), ranging from 3.6% to 10.0%. This prevalence was much higher (p 0.05). In conclusion, AF and CS frequently coexist, with about one in ten patients with AF having CS, and vice versa. In addition, nonstenotic carotid disease is present in about half of AF patients. These findings have important implications for AF screening in patients with CS, stroke prevention, and the opportunities to intervene on common risk factors.

Background Ablation index (AI) and Lesion Size Index (LSI) are novel parameters that incorporates contact force, time, and power in a weighted formula. Recent studies have shown that such indices predict lesion size and durability of pulmonary vein isolation (PVI). However, the outcomes of ablation guided by indices of force-time-power, such as PV reconnections and atrial fibrillation recurrence, have not been well characterised. Objectives To determine the association between indices of force-time-power and acute PV reconnections, procedure and fluoroscopy time and AF recurrence in patients undergoing radiofrequency PVI. Methods PUBMED and EMBASE were searched using the terms "catheter ablation" AND "Ablation index" OR "Contact force" OR "Force time integral" OR "lesion size" from inception through 22 May 2019. Studies reporting the procedure time, ablation time, fluoroscopy time, and incidence of AI acute and late reconnection and AF recurrence were included. Result Six studies were included in this study with 530 patients, which n = 416 were paroxysmal AF and 114 non-paroxysmal AF. All procedural characteristics (procedure, radiofrequency, and fluoroscopy times) were similar between AI guided and non-AI guided ablation (p > 0.05). Two studies comparing mean PV reconnections in AI guided vs. AI Blinded. Two studies compared minimum AI in reconnected vs. non-reconnected PV segments. Acute PV segment reconnection was associated with a lower minimum AI vs. non-reconnection. In 3 studies reporting AI guided vs. AI blinded ablations, AI was associated with an increased freedom from AF after average follow-up of 12 months. Conclusions Radiofrequency ablation guided by AI/LSI was associated with lower acute PV reconnection rates and improved AF freedom after PVI. There was no difference in fluoroscopy, ablation or procedure time with the use of these novel parameters. Abstract Figure.

Although electrocardiography (ECG) is a cost-effective and convenient tool for routine screening of left ventricular hypertrophy (LVH), its performance has been shown to be poor. The Peguero-Lo Presti, a novel voltage criterion, was found to be potentially better than the most commonly used criteria. We conducted a systematic review and meta-analysis of its diagnostic accuracy compared to Cornell and Sokolow-Lyon voltage criteria. Bibliographic databases were searched to identify relevant articles. Pooled sensitivity, specificity, diagnostic odds ratio (DOR), and summary receiver operating characteristic (ROC) curves were performed for comparison. Ten studies reporting data from 5984 individuals were included in the meta-analysis. Peguero-Lo Presti had the highest pooled sensitivity (43.0%, 95% confidence interval [CI]: 30.2-56.9) followed by Cornell (26.1%; 95% CI: 16.9-37.9) and Sokolow Lyon (22.0%; 95% CI: 14.1-32.7). However, Peguero-Lo Presti had the lesser pooled specificity (90.5%; 95% CI: 86.3-93.5) and Cornell the highest (94.9%; 95% CI: 90.3-97.3). The pooled DOR was 6.63 (95% CI: 3.95-11.13), 5.50 (95% CI: 3.64-8.30), and 2.94 (95% CI: 2.20-3.92) for Peguero-Lo Presti, Cornell, and Sokolow-Lyon, respectively. Peguero-Lo Presti had the best accuracy according to summary ROC curves, with an area under the curve of 0.827 compared to 0.715 for Cornell, and 0.623 for Sokolow-Lyon. In conclusion, according to this meta-analysis, Peguero-Lo Presti has a better diagnostic performance than Cornell and Sokolow-Lyon and might be more useful in routine clinical practice as a screening tool for LVH.

OBJECTIVES: The aims of the study were to characterize: 1) electrical and electroanatomical remodeling in patients with atrial fibrillation (AF) with obesity; and 2) the impact of epicardial fat depots on adjacent atrial tissue. BACKGROUND: Obesity is associated with an increased risk of AF. METHODS: A total of 115 patients with AF who underwent AF ablation were screened. After exclusion, 26 patients were divided into 2 groups (obese: body mass index [BMI] ≥27 kg/m2 and reference: BMI

Background Obesity-mediated epicardial adipose tissue (EAT) expansion drives fat cell infiltration which forms the unique substrate for atrial fibrillation (AF). The LEGACY study showed the benefits of weight loss but an attenuated response with weight fluctuation. How fluxes in weight impacts the atrial substrate in not known. Objective To investigate EAT and the atrial substrates due to weight fluctuation, with comparison to stable obesity. Methods We studied 24 sheep in 3 equal groups over 80 weeks: 1. Obesity induced by high calorie diet fed ad libitum; 2. Weight fluctuation induced by 20-week cycle of weight gain/loss (20:20:20:20); and 3. Lean controls fed quality hay to maintain baseline weight. All sheep underwent: daily weight measurement; haemodynamic and imaging assessments (cardiac MRI; dual-energy X-ray absorptiometry; and matrix assisted laser desorption infrared lipid imaging); electrophysiological studies and electroanatomic mapping; histological and structural analysis. Evaluations included: atrial voltage, conduction velocity, and refractoriness (7 sites, 2 cycle lengths), electrogram fractionation, EAT volume, fibro-fatty infiltration, myolysis of myocytes, and spatial distribution of intra-atrial lipids. Results The Table shows the group differences. Compared to reference controls, obesity demonstrated: Increased atrial volume and pressure, abnormal atrial electrical properties, expanded EAT and ensuing fibro-fatty infiltrations, and myolysis of myocytes. Despite comparable weight and EAT with controls, weight fluctuation resulted in extensive and severe fibro-fatty infiltrations, and twofold greater myolysis that persisted. Moreover, characteristic profiles and abundance of lipid species in the atrial myocardium were noted on further evaluation. More importantly, EAT and fibro-fatty infiltrates strongly correlated with increased atrial volume and pressure; with only fibro-fatty infiltrates correlating with fractionated electrograms (r=0.71, p Conclusions Obesity induces fibro-fatty replacement of atrial myocytes and deterioration of contractile units, which may drive impaired electrical remodeling. Despite final weight loss, weight fluctuation demonstrates residual electro-structural, fibro-fatty and contractile substrates.

Introduction Obesity and enhanced inflammatory response are two independent risk factors involved in the pathogenesis of atrial fibrillation (AF). Components of the NLRP3 inflammasome have been found to be expressed in cardiomyocytes and cardiac fibroblasts and that increased inflammasome activation contributes to the pathogenesis of AF. The NLRP3 inflammasome is a multi-protein signaling complex that is activated in two steps: 1st) a priming event that includes a NFκB-activating stimuli which increases the expression of pro-inflammatory cytokines, and 2nd) a triggering event that includes the assembly of the inflammasome complex and activation of caspase-1 which promotes the production of pro-inflammatory cytokines like interleukin 1 beta (IL-1b). Purpose We used a sheep model of sustained obesity to characterize the association between atrial myocardial fat infiltration, atrial activation of the NLRP3 inflammasome and the development of an atrial arrhythmogenic substrate for AF. Methods Eight sheep were fed ad libitum calorie-dense diet over 40 weeks to gain weight and were maintained in this state of sustained obesity for another 40 weeks. Eight lean, weight-controlled and aged-matched sheep served as control. Atrial fat infiltration was determined by oil-red staining and NLRP3 inflammasome activation was assessed by immunoblot in atrial whole-tissue lysate. Atrial effective refractory periods (aERPs) were evaluated (twice diastolic threshold, cycle length (CL) of 400 ms, S1S2 -protocol). Results Sustained obesity was associated with increased atrial fat infiltration (lean: 0.8±0.3% vs. obese: 2.3±1.2%, p=0.1) and shorter aERP (lean: 169±22ms vs. obese: 138±26ms, p=0.03). Protein levels of caspase-1 and mature IL-1β were significantly enhanced (p=0.04 and p=0.01, respectively). Further shortening of aERP correlated with increasing atrial protein levels of caspase-1 (r=0.59, p=0.02). In contrast, levels of TNFα and NFκB were not significantly changed in atria of sheep with sustained obesity. Conclusions Sustained obesity is associated with increased expression of NLRP3 inflammasome-related proteins and the development of an arrhythmogenic substrate for AF. Our study suggest that the increased activity is due to increased triggering, rather than increased gene transcription. Whether NLRP3 inflammasome activation represents a modifiable target to prevent AF in obesity warrants further study.

Introduction: Recent research has unravelled an increasing list of cardiac conditions and risk factors that may be responsible for the abnormal underlying atrial substrate that predisposes to atrial fibrillation (AF). Atrial fibrosis has been demonstrated as the pivotal structural abnormality underpinning conduction disturbances that promote AF in different disease models. Despite the advancement in our discoveries of the molecular mechanisms involved in the profibrotic milieu, targeted therapeutics against atrial fibrosis remain lacking. Areas covered: This review is focused on detailing the key molecular signalling pathways that contribute to atrial fibrosis including: angiotensin II, transforming growth factor (TGF- s1), connective tissue growth factor (CTGF) and endothelin-1. We also discussed the potential therapeutic options that may be useful in modulating the abnormal atrial substrate. In addition, we examined the new paradigm of AF care in lifestyle and risk factor management that has been shown to arrest and reverse the atrial remodelling process leading to improved AF outcomes. Expert commentary: The future of AF care is likely to require an integrated approach consisting of aggressive risk factor management in addition to the established paradigm of rate and rhythm management and anticoagulation. Translational studies on molecular therapeutics to combat atrial fibrosis is urgently needed.

K. Khokhar, M. Stiles, A. Elliott, R. Mahajan, D. Lau, A. Munawar, A. Thiyagarajah, T. Agbaedeng, C. Gallaghar, P. Sanders