Atrial fibrillation (AF) affects over 33 million individuals worldwide1 and has a complex heritability.2 We conducted the largest meta-analysis of genome-wide association studies for AF to date, consisting of over half a million individuals including 65,446 with AF. In total, we identified 97 loci significantly associated with AF including 67 of which were novel in a combined-ancestry analysis, and 3 in a European specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait loci (eQTL) analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

Abstract. At present, nine adrenoceptor (AR) subtypes have been identified: α 1A -, α 1B -, α 1D -, α 2A -, α 2B -, α 2C -, β 1 -, β 2 -, and β 3 AR. In the human heart, β 1 -and β 2 AR are the most powerful physiologic mechanism to acutely increase cardiac performance. Changes in βAR play an important role in chronic heart failure (CHF). Thus, due to increased sympathetic activity in CHF, βAR are chronically (over)stimulated, and that results in β 1 AR desensitization and alterations of down-stream mechanisms. However, several questions remain open: What is the role of β 2 AR in CHF? What is the role of increases in cardiac G i -protein in CHF? Do increases in G-protein-coupled receptor kinase (GRK)s play a role in CHF? Does βAR-blocker treatment cause its beneficial effects in CHF, at least partly, by reducing GRK-activity? In this review these aspects of cardiac AR pharmacology in CHF are discussed. In addition, new insights into the functional importance of β 1 -and β 2 AR gene polymorphisms are discussed. At present it seems that for cardiovascular diseases, βAR polymorphisms do not play a role as disease-causing genes; however, they might be risk factors, might modify disease, and / or might influence progression of disease. Furthermore, βAR polymorphisms might influence drug responses. Thus, evidence has accumulated that a β 1 AR polymorphism (the Arg389Gly β 1 AR) may affect the response to βAR-blocker treatment.

Background Angiotensin-converting enzyme 2 (ACE2) is an endogenous counter-regulator of the renin–angiotensin hormonal cascade. We assessed whether plasma ACE2 concentrations were associated with greater risk of death or cardiovascular disease events. Methods We used data from the Prospective Urban Rural Epidemiology (PURE) prospective study to conduct a case-cohort analysis within a subset of PURE participants (from 14 countries across five continents: Africa, Asia, Europe, North America, and South America). We measured plasma concentrations of ACE2 and assessed potential determinants of plasma ACE2 levels as well as the association of ACE2 with cardiovascular events. Findings We included 10 753 PURE participants in our study. Increased concentration of plasma ACE2 was associated with increased risk of total deaths (hazard ratio [HR] 1·35 per 1 SD increase [95% CI 1·29–1·43]) with similar increases in cardiovascular and non-cardiovascular deaths. Plasma ACE2 concentration was also associated with higher risk of incident heart failure (HR 1·27 per 1 SD increase [1·10–1·46]), myocardial infarction (HR 1·23 per 1 SD increase [1·13–1·33]), stroke (HR 1·21 per 1 SD increase [1·10–1·32]) and diabetes (HR 1·44 per 1 SD increase [1·36–1·52]). These findings were independent of age, sex, ancestry, and traditional cardiac risk factors. With the exception of incident heart failure events, the independent relationship of ACE2 with the clinical endpoints, including death, remained robust after adjustment for BNP. The highest-ranked determinants of ACE2 concentrations were sex, geographic ancestry, and body-mass index (BMI). When compared with clinical risk factors (smoking, diabetes, blood pressure, lipids, and BMI), ACE2 was the highest ranked predictor of death, and superseded several risk factors as a predictor of heart failure, stroke, and myocardial infarction. Interpretation Increased plasma ACE2 concentration was associated with increased risk of major cardiovascular events in a global study. Funding Canadian Institute of Health Research, Heart & Stroke Foundation of Canada, and Bayer.

BackgroundComorbidities are common in patients with heart failure (HF) and complicate treatment and outcomes. We identified patterns of multimorbidity in Asian patients with HF and their association with patients’ quality of life (QoL) and health outcomes.Methods and findingsWe used data on 6,480 patients with chronic HF (1,204 with preserved ejection fraction) enrolled between 1 October 2012 and 6 October 2016 in the Asian Sudden Cardiac Death in Heart Failure (ASIAN-HF) registry. The ASIAN-HF registry is a prospective cohort study, with patients prospectively enrolled from in- and outpatient clinics from 11 Asian regions (Hong Kong, Taiwan, China, Japan, Korea, India, Malaysia, Thailand, Singapore, Indonesia, and Philippines). Latent class analysis was used to identify patterns of multimorbidity. The primary outcome was defined as a composite of all-cause mortality or HF hospitalization within 1 year. To assess differences in QoL, we used the Kansas City Cardiomyopathy Questionnaire. We identified 5 distinct multimorbidity groups: elderly/atrial fibrillation (AF) (N = 1,048; oldest, more AF), metabolic (N = 1,129; obesity, diabetes, hypertension), young (N = 1,759; youngest, low comorbidity rates, non-ischemic etiology), ischemic (N = 1,261; ischemic etiology), and lean diabetic (N = 1,283; diabetic, hypertensive, low prevalence of obesity, high prevalence of chronic kidney disease). Patients in the lean diabetic group had the worst QoL, more severe signs and symptoms of HF, and the highest rate of the primary combined outcome within 1 year (29% versus 11% in the young group) (p for all <0.001). Adjusting for confounders (demographics, New York Heart Association class, and medication) the lean diabetic (hazard ratio [HR] 1.79, 95% CI 1.46–2.22), elderly/AF (HR 1.57, 95% CI 1.26–1.96), ischemic (HR 1.51, 95% CI 1.22–1.88), and metabolic (HR 1.28, 95% CI 1.02–1.60) groups had higher rates of the primary combined outcome compared to the young group. Potential limitations include site selection and participation bias.ConclusionsAmong Asian patients with HF, comorbidities naturally clustered in 5 distinct patterns, each differentially impacting patients’ QoL and health outcomes. These data underscore the importance of studying multimorbidity in HF and the need for more comprehensive approaches in phenotyping patients with HF and multimorbidity.Trial registrationClinicalTrials.gov NCT01633398

These first prospective multinational data from Asia show that HFpEF affects relatively young patients with a high burden of co-morbidities. Regional differences in types of co-morbidities, cardiac remodelling and outcomes of HFpEF across Asia have important implications for public health measures and global HFpEF trial design.

The sympathetic and parasympathetic nervous system play a powerful role in controlling cardiac function by activating adrenergic and muscarinic receptors. In the human heart there exist alpha1-, beta1- and beta2-adrenoceptors and M2-muscarinic receptors and possibly also (prejunctional) alpha2-adrenoceptors. Beta1- and beta2-adrenoceptors are quite evenly distributed in the human heart while M2-receptors are heterogeneously distributed (more receptors in atria than in ventricles). Stimulation of beta1- and beta2-adrenoceptors causes increases in heart rate and force of contraction while stimulation of M2-receptors decreases heart rate (directly in atria) and force of contraction (indirectly in ventricles). Pathological situations (such as heart failure) or pharmacological interventions (for example, beta-blocker treatment) can alter the distribution of beta1- and beta2-adrenoceptors in the human heart, while M2-receptors are only marginally affected. On the other hand, relatively little is known on distribution and functional role of alpha1- and alpha2-adrenoceptor subtypes in the human heart.

There can be no doubt that beta(1)-, beta(2)- and beta(3)-adrenoceptor genes have genetic polymorphisms. Two single nucleotide polymorphisms have been described for the beta(1)- (Ser49Gly; Gly389Arg), three for the beta(2)- (Arg16Gly; Gln27Glu; Thr164Ile) and one for the beta(3)-adrenoceptor subtype (Trp64Arg) that might be of functional importance. The possibility that changes in expression or properties of the beta-adrenoceptors due to single nucleotide polymorphisms might have phenotypic consequences influencing their cardiovascular or metabolic function or may contribute to the pathophysiology of several disorders like hypertension, congestive heart failure, asthma or obesity is an idea that has attracted much interest during the last 10 years. At present, it appears that these beta-adrenoceptor polymorphisms are very likely not disease-causing genes, but might be risk factors, might modify disease and/or might influence progression of disease. The aim of this review is to provide an overview of the functional consequences of such beta-adrenoceptor polymorphisms in vitro, ex vivo and in vivo.

Rats treated with monocrotaline (MCT) develop pulmonary hypertension. Their right ventricles (RVs) exhibit severe pressure overload-induced hypertrophy, whereas the left ventricles (LVs) are normally loaded. In contrast, enhanced neuroendocrine stimulation during the transition to heart failure affects both ventricles. We assessed gene expression levels of Ca2+-regulating proteins in RVs and LVs of control and MCT rats in transition to heart failure to identify biomechanical load-regulated genes. In MCT RVs, both mRNA and protein levels of the Ca2+-ATPase of the sarcoplasmic/endoplasmic reticulum (SERCA2a) were reduced by 36% (P=0.001) and 17% (P=0.016), respectively, compared with control RVs. Phospholamban and ryanodine receptor mRNA levels likewise were reduced (by 27% [P=0.05] and 21% [P=0.011], respectively) in MCT RVs, whereas sarcolemmal Na+-Ca2+ exchanger expression was not altered. MCT LVs exhibited no significant expression changes compared with control LVs. Isometrically contracting MCT intact RV trabeculae showed enhanced baseline force development. Although control RV preparations exhibited a positive force-frequency relationship, MCT RVs showed a negative force-frequency relationship and blunted postrest potentiation. Contractile function of MCT LV trabeculae was normal. Maximum Ca2+-activated tension was enhanced by 64% in permeabilized RV MCT preparations (P=0.013). beta-Myosin heavy chain protein was upregulated in MCT RVs (P<0.001) but unaltered in MCT LVs. Degradation of troponin T was prominent in MCT RVs, a phenomenon not observed in the LV. Enhanced biomechanical load is necessary to induce the gene expression changes associated with the hypertrophic phenotype of the pressure-overloaded RV. Neuroendocrine factors, which equally affect both chambers, are not sufficient to alter the expression of Ca2+-cycling proteins.