Incident Atrial Fibrillation Is Associated With MYH7 Sarcomeric Gene Variation in Hypertrophic Cardiomyopathy

Abstract

Background Although atrial fibrillation (AF) is common in hypertrophic cardiomyopathy (HCM) patients, the relationship between genetic variation and AF has been poorly defined. Characterizing genetic subtypes of HCM and their associations with AF may help to improve personalized medical care. We aimed to investigate the link between sarcomeric gene variation and incident AF in HCM patients. Methods and Results Patients from the multinational Sarcomeric Human Cardiomyopathy Registry were followed for incident AF. Those with likely pathogenic or pathogenic variants in sarcomeric genes were included. The AF incidence was ascertained by review of medical records and electrocardiograms at each investigative site. One thousand forty adult HCM patients, without baseline AF and with likely pathogenic or pathogenic variation in either MYH7 (n=296), MYBPC3 (n=659), or thin filament genes (n=85), were included. Compared with patients with variation in other sarcomeric genes, those with MYH7 variants were younger on first clinical encounter at the Sarcomeric Human Cardiomyopathy Registry site and more likely to be probands than the MYBPC3 variants. During an average follow-up of 7.2 years, 198 incident AF events occurred. Patients with likely pathogenic or pathogenic mutations in MYH7 had the highest incidence of AF after adjusting for age, sex, proband status, left atrial size, maximal wall thickness, and peak pressure gradient (hazard ratio, 1.7; 95% CI, 1.1–2.6; P =0.009). Conclusions During a mean follow-up of 7.2 years, new-onset AF developed in 19% of HCM patients with sarcomeric mutations. Compared with other sarcomeric genes, patients with likely pathogenic or pathogenic variation in MYH7 had a higher rate of incident AF independent of clinical and echocardiographic factors.

Genetic Determinants Of Clinical Phenotype In Hypertrophic Cardiomyopathy

“…Atrial brillation tended to be more prevalent in the MYH7 group in our study. This nding is consistent with previous studies [16,30], which reported a higher incidence of atrial brillation in patients with MYH7 mutation in comparison to other HCM patients. Since the development of atrial brillation was associated with risk factors such as LA enlargement, LV wall thickness, and LV out ow tract obstruction, these results suggest that patients with MYH7 mutation present with a more severe clinical phenotype.…”

Epidemiology and clinical characteristics of atrial fibrillation in patients with inherited heart diseases

“…Patients with identified sarcomere gene variants are, therefore, at an increased risk of developing AF earlier in life. Furthermore, it has been demonstrated that variation in the MYH7 gene is associated with incident AF, independent of established risk factors of AF in the general population, age and LA size 16 . Our results likewise show AF is independently associated with age, LA area, and MYH7 variants compared with MYBPC3 .…”

“…There is marked clinical heterogeneity in HCM, and although variable penetrance and expressivity are hallmarks of the disease, recognition of sarcomere‐positive and nonfamilial forms of disease as distinct subgroups may further explain the observed spectrum of disease 14,15 . There is also emerging data to suggest that a patient's underlying genetics may play an important role in AF development 14,16 . We report the frequency of AF in patients with inherited cardiomyopathies and inherited arrhythmia syndromes, including factors associated with AF in those with sarcomere‐positive HCM.…”

Three perspectives on the molecular basis of hypercontractility caused by hypertrophic cardiomyopathy mutations

“…Thus, these HCM-enriched surface regions are particularly noteworthy of study. Interestingly, recent work [50] showed that incident atrial fibrillation is associated with HCM mutations in β-cardiac myosin, and that the incidence of new-onset atrial fibrillation was considerably higher in those patients with mutations in the HCM-enriched surface regions compared to those with mutations in other regions of myosin.…”