Mortality in Early-Onset AF and Rare Variants in Cardiomyopathy and Arrhythmia Genes

Quick Takes

  • In this cohort study of 1,293 participants diagnosed with AF before 66 years of age, time to death was significantly associated with a disease-associated variant, age at AF diagnosis, and the interaction between age at AF diagnosis and variant status.
  • Genetic testing may provide important prognostic information for patients with early-onset AF.

Study Questions:

In patients with early-onset atrial fibrillation (AF), are rare variants in cardiomyopathy and arrhythmia genes associated with increased all-cause mortality?


Data on patients who underwent whole-genome sequencing and had AF diagnosed before age 66 years of age were analyzed. The primary outcome was time to death and was adjudicated from medical records and the National Death Index. The main analysis involved multivariable Cox proportional hazards regression.


Among 1,293 participants (median age 56 years), pathogenic or likely pathogenic variants were identified in 131 (10%). During a follow-up of 9.9 years, 219 participants (17%) died. There were 73 cardiomyopathy-related deaths, 40 sudden deaths, and 10 stroke-related deaths. Disease-associated variants were associated with 1.5-fold increased risk of all-cause mortality in multivariable modeling. This interaction was especially strong when AF was diagnosed at a younger age. Higher body mass index and lower left ventricular ejection fraction were also associated with higher mortality risk. Mortality among patients with the most prevalent genes with disease-associated variants was 26% for TTN, 33% for MYH7, 22% for LMNA, and 0% for each MYH6 and KCNQ1.


The findings suggest that among patients with early-onset AF, the presence of a disease-associated rare variant for an inherited cardiomyopathy or arrhythmia syndrome may be associated with an increased risk of mortality.


AF is associated with increased risk of stroke and mortality, especially in older populations. The association between AF and higher risk of mortality in younger patients has also been reported. Early-onset AF may be the first sign of a more serious underlying disease, including cardiomyopathy, especially given the possibility that atrial myopathy may be present in some of these individuals. The current study shows a 1.5-fold increase in all-cause mortality among patients with pathogenic or likely pathogenic mutations. The mortality rate in patients with preserved left ventricular function and a disease-associated variant was very high—18% during mean follow-up of 10 years. The results of this study suggest that genetic testing may identify patients with a subtype of early-onset AF who are at higher risk of mortality, with relative risk of mortality being higher when AF is diagnosed at a younger age and when patients have variants in cardiomyopathy-related genes. Future endeavors will be required to assess whether genetic testing in the early-onset AF population will result in a reduction in mortality.

Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Implantable Devices, EP Basic Science, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Acute Heart Failure

Keywords: Arrhythmias, Cardiac, Atrial Fibrillation, Body Mass Index, Cardiomyopathies, Death, Sudden, Genetic Predisposition to Disease, Genetic Testing, Genetic Variation, Heart Failure, KCNQ1 Potassium Channel, Mutation, Risk, Secondary Prevention, Stroke, Stroke Volume, Ventricular Function, Left, Vascular Diseases

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