Genetically based atrial fibrillation: Current considerations for diagnosis and management

Abstract

Atrial fibrillation (AF) is the most common atrial arrhythmia and is subcategorized into numerous clinical phenotypes. Given its heterogeneity, investigations into the genetic mechanisms underlying AF have been pursued in recent decades, with predominant analyses focusing on early onset or lone AF. Linkage analyses, genomewide association studies (GWAS), and single gene analyses have led to the identification of rare and common genetic variants associated with AF risk.Significant overlap with genetic variants implicated in dilated cardiomyopathy syndromes, including truncating variants of the sarcomere protein titin, have been identified through these analyses, in addition to other genes associated with cardiac structure and function. Despite this, widespread utilization of genetic testing in AF remains hindered by the unclear impact of genetic risk identification on clinical outcomes and the high prevalence of variants of unknown significance (VUS).However, genetic testing is a reasonable option for patients with early onset AF and in those with significant family history of arrhythmia. While many knowledge gaps remain, emerging data support genotyping to inform selection of AF therapeutics. In this review, we highlight the current understanding of the complex genetic basis of AF and explore the overlap of AF with inherited cardiomyopathy syndromes. We propose a set of criteria for clinical genetic testing in AF patients and outline future steps for the integration of genetics into AF care.

Myosin-binding protein H-like regulates myosin-binding protein distribution and function in atrial cardiomyocytes

“…Atrial dysfunction is a comorbidity in HCM, DCM, and many other conditions ( 6 , 10 – 12 , 14 , 15 , 17 ). The sarcomeric mediators of atrial dysfunction have not been well understood.…”

“…The shift in atrial relaxation seen in the absence of MyBP-HL could reflect a primary atrial defect from loss of MyBP-HL and/or the increased cMyBP-C content in the atria. Currently, primary atrial myopathies are still a nascent concept, and our understanding of the genes that are highly enriched in atrial cardiomyocytes and their atrial-specific function is incomplete ( 6 , 14 , 16 ). The human atrial sarcomere differs from the ventricular sarcomere in both myosin heavy-chain and light-chain content, which likely impacts how MyBP-HL regulates myofilament function.…”

“…Physiological regulation of striated muscle force generation and relaxation is finely tuned for muscle subtype-specific function by differential expression of sarcomere protein isoforms ( 1 – 5 ). In heart muscle, mutations in genes that encode most of the components of the sarcomere have been linked to cardiomyopathies, most commonly hypertrophic and dilated cardiomyopathy (HCM and DCM, respectively) ( 6 , 7 ). HCM mutations that cause hypercontractile sarcomeres are almost exclusively found in genes that encode sarcomere proteins ( 8 , 9 ).…”

“…In contrast, DCM mutations affect a variety of cellular processes, with sarcomere mutations generally causing a hypocontractile left ventricle ( 7 , 8 ). Mutations that cause cardiomyopathy can also cause atrial dilation and atrial fibrillation ( 6 , 10 ), comorbidities that are associated with a worse prognosis ( 11 , 12 ).…”