Rare Variant for Inherited Cardiomyopathy Linked to Mortality Risk in Early-Onset AF

Investigators sought to assess the association between rare cardiomyopathy and arrhythmia gene variants in patients with early-onset AF and mortality.

Patients with early-onset atrial fibrillation (AF) and a disease-associated cardiomyopathy or arrhythmia gene variant have a higher risk of all-cause mortality and an increased risk for cardiomyopathy-related death and sudden death, researchers reported in JAMA Cardiology.

The cohort study included participants diagnosed with AF before age 66 years between November 23, 1999, and June 2, 2015. All patients had whole-genome sequencing in the National Heart, Lung and Blood Institute’s Trans-Omics for Precision Medicine Program.

A total of 145 cardiomyopathy and arrhythmia genes from commercial genetic testing panels were chosen for the analysis. The time from AF diagnosis to death or censor date was the primary outcome, and the presence or absence of a disease-associated variant was the primary exposure.

The cohort included 1293 participants (72% men; median age 56.0 years at enrollment [IQR, 48.0-61.0 years]) with early-onset AF, of whom 16.9% died during the follow-up. The median follow-up was 9.9 years (IQR, 6.9-13.2 years) from enrollment and 15.0 years (IQR, 10.3-20.0) from AF diagnosis.

The investigators identified a disease-associated rare variant in 131 patients, of whom 93 had a variant in a dilated cardiomyopathy gene, 43 in a hypertrophic cardiomyopathy gene, and 37 in an arrhythmogenic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy gene.

The presence of disease-associated variants was associated with an increased risk of all-cause mortality (hazard ratio [HR], 1.5; 95% CI, 1.0-2.1; P =.05), according to univariable analysis. In multivariable analysis, a disease-associated variant was associated with a significantly increased risk of all-cause mortality (adjusted survival curve, χ2 = 9.39; P =.009 likelihood ratio test).

A statistically significant interaction between disease-associated variant status and age at AF diagnosis (P =.008 for interaction) was found in the primary multivariable analysis. Male sex (HR, 1.0; 95% CI, 0.7-1.4; P =.98), White race (HR, 1.1; 95% CI, 0.6-2.1; P =.74), increased body mass index (BMI) (HR, 1.4; IQR, 1.2-1.6; P =.001), and lower ventricular ejection fraction (HR, 0.8; 95% CI, 0.7-0.8; P <.001) were associated with an increased mortality risk in the multivariable model.

Older age was associated with an increased risk of death for genotype-positive and genotype-negative male and female participants when the association of age with mortality was analyzed. The relative risk of death was significantly higher for participants who were genotype-positive compared with those who were genotype-negative among those diagnosed with AF at a younger age. When the age at diagnosis began to approach 60 years, this association diminished, when the relative risk of death was higher for genotype-negative participants.

Among the 219 patients that died during follow-up, 33% were cardiomyopathy-related, 18% were sudden deaths, and 5% were stroke-related. The cardiomyopathy-related mortality risk was associated with disease-associated variant status, age at AF diagnosis, and the interaction between disease-associated variant status and age at AF diagnosis (P =.03 for interaction). This model also was adjusted for BMI (HR, 1.2; 95% CI, 1.0-1.5; P =.07), male sex (HR, 1.1; 95% CI, 0.7-1.6; P =.66), and White race (HR, 0.7; 95% CI, 0.3-1.4; P =.28).

Regarding sudden deaths, disease-associated variants (HR, 2.4; 95% CI, 1.1-5.2; P =.03) and age at AF diagnosis (HR, 2.4; 95% CI, 1.4-4.2; P =.002) were associated with a higher mortality risk.

The most prevalent genes that had disease-associated variants were LMNA (OMIM 150330), KCNQ1 (OMIM 607542), MYH6 (OMIM 160710), MYH7 (OMIM 160760), and TTN (OMIM 188840). The number of associated deaths that occurred was 26% for TTN, 33% for MYH7, 22% for LMNA, 0% for KCNQ1,and 0% for MYH6.

The researchers note that the subgroup analyses are underpowered and larger studies are needed to define the risk according to variants for individual syndromes and genes and in racial and ethnic minority groups. Another potential limitation is the accuracy of the cause of death information according to death certificates.

“These data suggest that there is prognostic value for genetic testing in patients with early-onset AF regardless of ejection fraction at the time of presentation,” the investigators wrote.

Disclosure: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Yoneda ZT, Anderson KC, Ye F, et al. Mortality among patients with early-onset atrial fibrillation and rare variants in cardiomyopathy and arrhythmia genes. JAMA Cardiol. Published online May 11, 2022. doi: 10.1001/jamacardio.2022.0810