Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery

iPSC-cardiomyocyte models of Brugada syndrome : achievements, challenges and future perspectives

Brugada syndrome (BrS) is an inherited cardiac arrhythmia that predisposes to ventricular fibrillation and sudden cardiac death. It originates from oligogenic alterations that affect cardiac ion channels or their accessory proteins. The main hurdle for the study of the functional effects of those variants is the need for a specific model that mimics the complex environment of human cardiomyocytes. Traditionally, animal models or transient heterologous expression systems are applied for electrophysiological investigations, each of these models having their limitations. The ability to create induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), providing a source of human patient-specific cells, offers new opportunities in the field of cardiac disease modelling. Contemporary iPSC-CMs constitute the best possible in vitro model to study complex cardiac arrhythmia syndromes such as BrS. To date, thirteen reports on iPSC-CM models for BrS have been published and with this review we provide an overview of the current findings, with a focus on the electrophysiological parameters. We also discuss the methods that are used for cell derivation and data acquisition. In the end, we critically evaluate the knowledge gained by the use of these iPSC-CM models and discuss challenges and future perspectives for iPSC-CMs in the study of BrS and other arrhythmias

Editor-in-Chief's Picks From 2014: Part One

As I spent countless hours pouring over hundreds of manuscripts to select those that rose to the top over the past year, I became incredibly excited about being part of a Journal that produces such wonderfully rich and diverse content each year. I have personally selected the papers (both original investigations and review articles) from 13 distinct specialties for your review. There are approximately 150 articles selected across this 2-part series, which represents less than 3% of the papers submitted to JACC in 2014. In order to present the full breadth of this important research in a consumable fashion, we will present these manuscripts over the course of 2 issues of JACC.Part One includes the sections: Congenital Heart Disease, Coronary Disease & Interventions, Genetics, Omics, & Tissue Regeneration, CV Prevention & Health Promotion, Cardiac Failure, and Cardiomyopathies (1–70). Part Two includes the sections: Hypertension, Imaging, Metabolic Disorders & Lipids, Neurovascular & Neurodegenerative Disorders, Rhythm Disorders, Valvular Heart Disease, and Vascular Medicine

Genetic basis of cardiovascular diseases

Cardiovascular diseases are a major global health issue. This thesis focusses on the genetic basis of three cardiovascular conditions: atrial fibrillation (AF), heart failure (HF), and mitral valve prolapse (MVP). AF is widespread and mainly manifests in an irregular heartbeat, HF is a complex condition that occurs when the heart fails to pumps blood effectively, and MVP is a heart valve disorder. Genome-wide association studies (GWAS) have been instrumental in understanding the genetic basis of cardiovascular diseases. Extensive research was conducted for AF, HF, and MVP by utilizing large international consortia and analyzing data from various biobanks and cohorts. First, 250 new AF-related genetic regions were discovered in the largest genetic study for AF to date. Second, rare deleterious variants within the gene TTN, were linked to AF susceptibility. Additionally, we increased the number of HF cases studied from 6.8k to 47k, uncovering 10 new genetic regions. We expanded our analysis on MVP from 1.4k cases to 4.8k, identifying 12 new genetic regions. We carefully evaluated potential effector genes at GWAS locations by generating new functional data and using existing datasets. Overall, this research identified potential effector genes for AF and MVP and shed light on interesting biological pathways. Additionally, we developed improved and new genetic risk scores for AF and MVP, using state of the art computational methods. Although we didn't pinpoint the exact pathophysiology between every genetic variant and AF, our work demonstrated the value of genetic risk profiles in predicting disease risk, offering an improvement over clinical risk factors alone