Disease-Associated Cardiomyopathy Variants May Increase Mortality Risk in Early-Onset AF

M. Benjamin Shoemaker, MD

The presence of disease-associated rare variants for an inherited cardiomyopathy or arrhythmia syndrome may have associations with an increased risk of mortality among patients with early-onset atrial fibrillation (AF), according to new findings.

Data show an approximately 1.5-fold higher risk of mortality over 10 years among this patient population, with higher relative risk when AF was diagnosed at a younger age.

“These data suggest that genetic testing may identify patients with a subtype of early-onset AF who are at higher risk of mortality, relative risk associated with a disease-associated variant may be higher when AF is diagnosed at a younger age, and relative risk may be associated predominantly with variants in [cardiomyopathy] related genes,” wrote study author M. Benjamin Shoemaker, MD, Division of Cardiovascular Medicine, Vanderbilt University Medical Center.

Shoemaker noted the effect of rare genetic variants on clinical outcomes and long-term prognosis in patients with early-onset AF has remained undefined. The current study assessed a cohort of 1293 patients with early-onset AF who underwent whole-genome sequencing.

It included participants enrolled in the Vanderbilt Atrial Fibrillation Registry or Vanderbilt AF Ablation Registry from November 1999 - June 2015. Eligible patients were diagnosed with AF before 66 years of age and underwent whole-genome sequencing through the National Heart, Lung and Blood Institute’s Trans-Omics for Precision Medicine Program.

A total of 145 cardiomyopathy and arrhythmia genes included in commercial genetic testing panels were selected. The primary study outcome was time to death, with data analyzed from February - September 2021.

The study enrolled 1293 participants (934 [72%] male; median age at enrollment, 56.0 years) with early-onset AF from 1999 to 2015 who underwent whole-genome sequencing. From a median follow-up of 9.9 years, 219 participants (17%) died.

Investigators detected disease-associated (pathogenic or likely pathogenic) rare variants in 131 patients (10%). In univariable analysis, data show disease-associated variants were associated with an increased risk of mortality (hazard ratio, [HR], 1.5; 95% confidence interval [CI], 1.0 - 2.1; P = .05).

The team noted the association remained significant in multivariable modeling, following adjustments for age at AF diagnosis, sex, race, body mass index, left ventricular ejection fraction, and an interaction term between disease-associated variant status and age at AF diagnosis.

Moreover, the primary multivariable analysis found a statistically significant interaction between disease-associated variant status and age at AF diagnosis (P = .008 for interaction). Both higher body mass index (HR, 1.4; 95% CI, 1.2 - 1.6; P <.001) and lower left ventricular ejection fraction (HR, 0.8; 95% CI, 0.7 - 0.8; P <.001) had an association with higher mortality risk.

From the 219 deaths observed, 73 were cardiomyopathy-related (33%), 40 were sudden deaths (18%), and 10 were stroke related (5%).

Data show the most prevalent genes with disease-associated variants were TTN, MYH7, MYH6, LMNA, and KCNQI. Mortality rates among these genes were observed to be 26% (10 of 38 patients) for TTN, 33% (6 of 18) for MYH7, 22% (2 of 9) for LMNA, 0% (0 of 10) for MYH6, and 0% (0 of 8) for KCNQ1.

Shoemaker noted that future studies may be necessary to define whether genetic testing improved clinical outcomes in patients with early-onset AF.

The study, “Mortality Among Patients With Early-Onset Atrial Fibrillation and Rare Variants in Cardiomyopathy and Arrhythmia Genes,” was published in JAMA Cardiology.