Molecular Basis Of Atrial Fibrillation Research Articles

HiPSC-derived cardiomyocytes as a model to study the role of small-conductance Ca2+-activated K+ (SK) ion channel variants associated with atrial fibrillation.

Atrial fibrillation (AF), the most common arrhythmia, has been associated with different electrophysiological, molecular, and structural alterations in atrial cardiomyocytes. Therefore, more studies are required to elucidate the genetic and molecular basis of AF. Various genome-wide association studies (GWAS) have strongly associated different single nucleotide polymorphisms (SNPs) with AF. One of these GWAS identified the rs13376333 risk SNP as the most significant one from the 1q21 chromosomal region. The rs13376333 risk SNP is intronic to the KCNN3 gene that encodes for small conductance calcium-activated potassium channels type 3 (SK3). However, the functional electrophysiological effects of this variant are not known. SK channels represent a unique family of K+ channels, primarily regulated by cytosolic Ca2+ concentration, and different studies support their critical role in the regulation of atrial excitability and consequently in the development of arrhythmias like AF. Since different studies have shown that both upregulation and downregulation of SK3 channels can lead to arrhythmias by different mechanisms, an important goal is to elucidate whether the rs13376333 risk SNP is a gain-of-function (GoF) or a loss-of-function (LoF) variant. A better understanding of the functional consequences associated with these SNPs could influence clinical practice guidelines by improving genotype-based risk stratification and personalized treatment. Although research using native human atrial cardiomyocytes and animal models has provided useful insights, each model has its limitations. Therefore, there is a critical need to develop a human-derived model that represents human physiology more accurately than existing animal models. In this context, research with human induced pluripotent stem cells (hiPSC) and subsequent generation of cardiomyocytes derived from hiPSC (hiPSC-CMs) has revealed the underlying causes of various cardiovascular diseases and identified treatment opportunities that were not possible using in vitro or in vivo studies with animal models. Thus, the ability to generate atrial cardiomyocytes and atrial tissue derived from hiPSCs from human/patients with specific genetic diseases, incorporating novel genetic editing tools to generate isogenic controls and organelle-specific reporters, and 3D bioprinting of atrial tissue could be essential to study AF pathophysiological mechanisms. In this review, we will first give an overview of SK-channel function, its role in atrial fibrillation and outline pathophysiological mechanisms of KCNN3 risk SNPs. We will then highlight the advantages of using the hiPSC-CM model to investigate SNPs associated with AF, while addressing limitations and best practices for rigorous hiPSC studies.

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.

Prevalence and spectrum of GJA5 mutations associated with lone atrial fibrillation

Atrial fibrillation (AF) is the most common form of cardiac arrhythmia observed in clinical practice and a major contributor to cardiovascular morbidity and mortality. Accumulating evidence indicates a substantial genetic basis for AF. However, AF is genetically heterogeneous and the hereditary components responsible for AF remain to be identified in the majority of patients. The cardiac gap junction proteinα5(GJA5) is specifically expressed in atrial myocytes and is associated with the coordinated electrical activation of the atria, providing a rationale to screen GJA5 as a logical candidate gene for AF. A cohort of 310unrelated patients with lone AF and their available relatives were included in this study. A group of 200unrelated healthy individuals matched for age, gender and race were also included as controls. The entire coding region and splice sites of the GJA5 gene were initially sequenced in 310unrelated AF patients. The relatives of mutation carriers and 200controls were subsequently genotyped for the presence of identified mutations. As a result, 4novel heterozygous GJA5 mutations, p.K107R, p.L223M, p.Q236H and p.I257L, were identified in 4 of 310unrelated AF patients, respectively, with a prevalence of ~1.29%. Genetic analysis of the carriers' families showed that in each family the missense mutation was present in all the affected family members. Absent in the 400reference alleles, these mutations altered the amino acids highly conserved among various species, with the exception of p.I257L. In conclusion, this study expands the spectrum of GJA5 mutations associated with AF and provides novel insights into the molecular basis of AF, suggesting potential implications for the improved, gene-specific rhythm control strategies.

New insights into the molecular basis of atrial fibrillation: mechanistic and therapeutic implications

This editorial refers to a collection of nine reviews and nine original articles that are part of this special issue on atrial fibrillation, guest edited by Dobromir Dobrev and Stanley Nattel. Atrial fibrillation (AF), the most common sustained arrhythmia, is associated with substantial cardiovascular morbidity and mortality, with stroke being the most critical complication.1 Present drugs used for AF therapy have major limitations, including incomplete efficacy and risks of life-threatening proarrhythmic events and bleeding complications.1,2 Non-pharmacological ablation procedures are efficient and relatively safe, but the very large size of the patient population allows ablation treatment of only a small number of patients. Therefore, drug therapy remains the mainstay of AF treatment. Maintenance of sinus rhythm (rhythm control) appears preferable, but studies to date have failed to demonstrate tangible advantages of rhythm control. The failure to show benefits in mortality and stroke incidence motivates attempts to identify new therapeutic targets relating to basic mechanisms underlying arrhythmia susceptibility. A better mechanistic understanding of the molecular basis of AF may allow for the development of safer and more effective treatment approaches. The mechanisms underlying AF susceptibility are multiple and incompletely understood. The two major determinants of AF maintenance are reentry and ectopic impulse formation (ectopic activity).3 Reentry induction requires an appropriate arrhythmogenic substrate and a trigger that initiates reentry within the substrate. The likelihood of reentry is determined by the tissue properties of conduction and refractoriness, with slow conduction and short refractoriness making persistence of reentry more likely. Ectopic activity is governed by factors controlling the occurrence of afterdepolarizations, primarily Ca2+ handling abnormalities that can cause early and delayed afterdepolarizations. The changes in atrial structure and function that result from heart disease, and indeed AF itself, constitute atrial remodelling and are key elements of the …

Announcement: Review Focus on New Insights into the Molecular Basis of Atrial Fibrillation: Mechanistic and Therapeutic Implications

Announcement: Review Focus on New Insights into the Molecular Basis of Atrial Fibrillation: Mechanistic and Therapeutic Implications

Announcement: Review Focus on New Insights into the Molecular Basis of Atrial Fibrillation: Mechanistic and Therapeutic Implications

Announcement: Review Focus on New Insights into the Molecular Basis of Atrial Fibrillation: Mechanistic and Therapeutic Implications

Announcement: Review Focus on New Insights into the Molecular Basis of Atrial Fibrillation: Mechanistic and Therapeutic Implications

Announcement: Review Focus on New Insights into the Molecular Basis of Atrial Fibrillation: Mechanistic and Therapeutic Implications

Announcement: Review Focus on New Insights into the Molecular Basis of Atrial Fibrillation: Mechanistic and Therapeutic Implications

Announcement: Review Focus on New Insights into the Molecular Basis of Atrial Fibrillation: Mechanistic and Therapeutic Implications

Announcement: Review Focus on New Insights into the Molecular Basis of Atrial Fibrillation: Mechanistic and Therapeutic Implications

Announcement: Review Focus on New Insights into the Molecular Basis of Atrial Fibrillation: Mechanistic and Therapeutic Implications

Announcement: Review Focus on New Insights into the Molecular Basis of Atrial Fibrillation: Mechanistic and Therapeutic Implications

Announcement: Review Focus on New Insights into the Molecular Basis of Atrial Fibrillation: Mechanistic and Therapeutic Implications

Molecular basis of atrial fibrillation: a dream or a reality?

AF is a difficult disease to treat because of the numerous (ischemic, metabolic, inflammatory, structural) mechanisms contributing to its etiology. AF persistence requires both an adequate tissue substrate for reentrant activity and triggers to initiate the arrhythmia. In a few interesting instances, AF may have a monogenic cause. Although there are common electrophysiologic characteristics of myocytes from a variety of AF models and clinical presentations, it is unrealistic to expect that all patients will respond equally to the same interventions. Thus, patients with AF of an inflammatory etiology may respond better to anti-inflammatory therapies, whereas those with enlarged atria secondary to valvular disease may require surgery. Some may respond better to ablation than others. However, the heterogeneity of the substrate does not negate the value of searching for the underlying molecular mechanisms. As we begin to comprehend these mechanisms in greater detail, the dream of using individualized rational therapies will come closer to reality.