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. 2022 Jul 1;7(7):733-741.
doi: 10.1001/jamacardio.2022.0810.

Mortality Among Patients With Early-Onset Atrial Fibrillation and Rare Variants in Cardiomyopathy and Arrhythmia Genes

Zachary T Yoneda  1 , Katherine C Anderson  1 , Fei Ye  2 , Joseph A Quintana  1 , Matthew J O'Neill  3 , Richard A Sims  1 , Lili Sun  2 , Andrew M Glazer  4 , Giovanni Davogustto  1 , Majd El-Harasis  1 , James L Laws  1 , Brittany N Saldivar  1 , Diane M Crawford  1 , Thomas Stricker  5 , Quinn Wells  1   4   6   7 , Dawood Darbar  8 , Gregory F Michaud  1 , Lynne W Stevenson  1 , Steven A Lubitz  9   10 , Patrick T Ellinor  9   10 , Dan M Roden  1   4   6   7 , M Benjamin Shoemaker  1
Affiliations

Mortality Among Patients With Early-Onset Atrial Fibrillation and Rare Variants in Cardiomyopathy and Arrhythmia Genes

Zachary T Yoneda et al. JAMA Cardiol. .

Abstract

Importance: Patients with early-onset atrial fibrillation (AF) are enriched for rare variants in cardiomyopathy and arrhythmia genes. The clinical significance of these rare variants in patients with early-onset AF is unknown.

Objective: To assess the association between rare variants in cardiomyopathy and arrhythmia genes detected in patients with early-onset AF and time to death.

Design, setting, and participants: This prospective cohort study included participants with AF diagnosed before 66 years of age who underwent whole-genome sequencing through the National Heart, Lung and Blood Institute's Trans-Omics for Precision Medicine program. Participants were enrolled from November 23, 1999, to June 2, 2015. Data were analyzed from February 26 to September 19, 2021.

Exposures: Rare variants identified in a panel of 145 genes that are included in cardiomyopathy and arrhythmia panels used by commercial clinical genetic testing laboratories.

Main outcomes and measures: The primary study outcome was time to death and was adjudicated from medical records and the National Death Index. Multivariable Cox proportional hazards regression was used to evaluate the association of disease-associated variants with risk of death after adjustment for age at AF diagnosis, sex, race, body mass index, left ventricular ejection fraction, and an interaction term of age at AF diagnosis and disease-associated variant status.

Results: Among 1293 participants (934 [72%] male; median age at enrollment, 56.0 years; IQR, 48.0-61.0 years), disease-associated (pathogenic or likely pathogenic) rare variants were found in 131 (10%). During a median follow-up of 9.9 years (IQR, 6.9-13.2 years), 219 participants (17%) died. In univariable analysis, disease-associated variants were associated with an increased risk of mortality (hazard ratio, [HR], 1.5; 95% CI, 1.0-2.1; P = .05); the association remained significant in multivariable modeling when adjusted 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. The interaction demonstrated that disease-associated variants were associated with a significantly higher risk of mortality compared with no disease-associated variant when AF was diagnosed at a younger age (P = .008 for interaction). Higher body mass index (per IQR: HR, 1.4; 95% CI, 1.2-1.6; P < .001) and lower left ventricular ejection fraction (per IQR: HR, 0.8; 95% CI, 0.7-0.8; P < .001) were associated with higher mortality risk. There were 73 cardiomyopathy-related deaths, 40 sudden deaths, and 10 stroke-related deaths. Mortality among patients with the most prevalent genes with disease-associated variants was 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.

Conclusions and relevance: The findings suggest that rare variants in cardiomyopathy and arrhythmia genes may be associated with increased risk of mortality among patients with early-onset AF, especially those diagnosed at a younger age. Genetic testing may provide important prognostic information for patients with early-onset AF.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Yoneda reported receiving grants from the American Heart Association (AHA) and the National Institutes of Health (NIH) Clinical Translational Science Award during the conduct of the study. Dr Darbar reported receiving grants from the National Heart, Lung and Blood Institute, NIH during the conduct of the study. Dr Stevenson reported being Chair of the Data, Safety, and Monitoring Board for LivaNova outside the submitted work. Dr Michaud reported receiving consulting fees and honoraria from Boston Scientific, Medtronic, and St Jude Medical and research funding from Boston Scientific and Biosense Webster. Dr Lubitz reported receiving grants from the NIH, the AHA, Invite, BMS/Pfizer, Boehringer Ingelheim, IBM, and Fitbit and receiving personal fees from Blackstone Life Sciences and BMS/Pfizer during the conduct of the study. Dr Ellinor reported receiving grants from Bayer AG and IBM Research and receiving personal fees from Bayer AG, MyKardia, and Novartis during the conduct of the study. Dr Shoemaker reported receiving grants from the AHA during the conduct of the study and receiving grants from the NIH outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Breakdown of Participants According to Genotype Status and Death During Follow-up
CM indicates cardiomyopathy.
Figure 2.
Figure 2.. Adjusted Survival Curve of All-Cause Mortality Among Patients With Early-Onset Atrial Fibrillation (AF) With and Without Disease-Associated Rare Variants in Cardiomyopathy and Arrhythmia Genes and Interaction Between Age at AF Diagnosis and Disease-Associated Variants
Shading indicates 95% CIs.
Figure 3.
Figure 3.. Adjusted Cumulative Incidence of Cardiomyopathy (CM)–Related Death and Adjusted Cumulative Incidence of Sudden Death According to Disease-Associated Rare Variant Status
A, Adjustment was made for age at atrial fibrillation diagnosis, sex, race, body mass index, and the interaction between disease-associated variant status and age at atrial fibrillation diagnosis (P = .009 likelihood ratio test). B, Adjustment was made for age at atrial fibrillation diagnosis.
Figure 4.
Figure 4.. Disease-Associated Variants and Mortality Risk Among Participants
A and B, Shading indicates 95% CIs.
See this image and copyright information in PMC

Comment in

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