Prevalence and Cumulative Risk of Familial Idiopathic Dilated Cardiomyopathy

Abstract

Importance: Idiopathic dilated cardiomyopathy (DCM) aggregates in families, and early detection in at-risk family members can provide opportunity to initiate treatment prior to late-phase disease. Most studies have included only White patients, yet Black patients with DCM have higher risk of heart failure-related hospitalization and death.

Objective: To estimate the prevalence of familial DCM among DCM probands and the age-specific cumulative risk of DCM in first-degree relatives across race and ethnicity groups.

Design, setting, and participants: A family-based, cross-sectional study conducted by a multisite consortium of 25 US heart failure programs. Participants included patients with DCM (probands), defined as left ventricular systolic dysfunction and left ventricular enlargement after excluding usual clinical causes, and their first-degree relatives. Enrollment commenced June 7, 2016; proband and family member enrollment concluded March 15, 2020, and April 1, 2021, respectively.

Exposures: The presence of DCM in a proband.

Main outcomes and measures: Familial DCM defined by DCM in at least 1 first-degree relative; expanded familial DCM defined by the presence of DCM or either left ventricular enlargement or left ventricular systolic dysfunction without known cause in at least 1 first-degree relative.

Results: The study enrolled 1220 probands (median age, 52.8 years [IQR, 42.4-61.8]; 43.8% female; 43.1% Black and 8.3% Hispanic) and screened 1693 first-degree relatives for DCM. A median of 28% (IQR, 0%-60%) of living first-degree relatives were screened per family. The crude prevalence of familial DCM among probands was 11.6% overall. The model-based estimate of the prevalence of familial DCM among probands at a typical US advanced heart failure program if all living first-degree relatives were screened was 29.7% (95% CI, 23.5% to 36.0%) overall. The estimated prevalence of familial DCM was higher in Black probands than in White probands (difference, 11.3% [95% CI, 1.9% to 20.8%]) but did not differ significantly between Hispanic probands and non-Hispanic probands (difference, -1.4% [95% CI, -15.9% to 13.1%]). The estimated prevalence of expanded familial DCM was 56.9% (95% CI, 50.8% to 63.0%) overall. Based on age-specific disease status at enrollment, estimated cumulative risks in first-degree relatives at a typical US advanced heart failure program reached 19% (95% CI, 13% to 24%) by age 80 years for DCM and 33% (95% CI, 27% to 40%) for expanded DCM inclusive of partial phenotypes. The DCM hazard was higher in first-degree relatives of non-Hispanic Black probands than non-Hispanic White probands (hazard ratio, 1.89 [95% CI, 1.26 to 2.83]).

Conclusions and relevance: In a US cross-sectional study, there was substantial estimated prevalence of familial DCM among probands and modeled cumulative risk of DCM among their first-degree relatives.

Trial registration: ClinicalTrials.gov Identifier: NCT03037632.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Kinnamon reported receiving grants from the National Heart, Lung, and Blood Institute (NHLBI). Dr Haas reported receiving grants from the National Institutes of Health (NIH). Dr Morris reported receiving grants from the NHLBI. Dr Owens reported receiving consulting fees from Bristol Myers Squibb, Cytokinetics, and Pfizer. Dr Lowes reported receiving grants from the NIH. Dr Tang reported receiving grants from the NIH and personal fees from Sequana Medical AG, Owkin Inc, Relypsa Inc, preCARDIA Inc, Cardiol Therapeutics, Genomics PLC, Springer Nature, and the American Board of Internal Medicine Examination. Dr Trachtenberg reported receiving grants from the NIH. Dr Shah reported receiving grants from the NIH, Merck, Abbott, Roche, and Bayer and personal fees from Merck and Procyrion. Dr Wheeler reported receiving grants from Pfizer, Bristol Myers Squibb, and Novartis. Dr Wilcox reported receiving speaking honoraria from Amgen and Novartis and consulting fees from Abbott and serving on the advisory board for Cytokinetics and Abiomed. She has a patent for LMNA-related dilated cardiomyopathy. Dr Katz reported receiving personal fees from Salubris Bio. Dr Smart reported receiving grants from the NIH and The Ohio State University. Dr Judge reported receiving grants from the NIH and personal fees from 4D Molecular Therapeutics, ADRx, Cytokinetics, Pfizer, and Tenaya Therapeutics. Dr Ni reported receiving grants from the NIH. Dr Hershberger reported receiving financial support for a clinical trial from Pfizer/Array and Myocardia/Bristol Myers Squibb. No other disclosures were reported.

Figures

Figure.. Model-Based Estimates of Age-Specific Cumulative Risk in First-degree Relatives of Patients With Dilated Cardiomyopathy (DCM)

A Weibull proportional hazards model for age-specific cumulative risk was fit to cross-sectional data on disease status at enrollment from first-degree relatives. Each panel presents marginally standardized age-specific cumulative risks derived from this model fit that apply to first-degree relatives of patients seen at a typical US advanced heart failure program, defined as a program at the mean or mode of the random effects distribution describing the population of such programs. Marginally standardized age-specific cumulative risks were calculated by obtaining conditional estimates at a typical US advanced heart failure program in each first-degree relative subpopulation defined by a combination of the covariates and then taking the weighted average according to an assumed covariate distribution described for each panel. A, Each patient subpopulation defined by race and ethnicity was assumed to be balanced across the 16 possible sex (first-degree relative and proband) and proband DCM diagnosis age quartile combinations. These subpopulations, in turn, were represented in proportion to 2019 US Census population estimates (0.99% Hispanic Black, 13.97% non-Hispanic Black, 18.06% Hispanic White, 66.98% non-Hispanic White) in the overall marginally standardized age-specific cumulative risk. Bands represent delta method pointwise 95% CIs. Numbers of individuals within age strata by phenotype are provided in the table below the figure. B, Each patient subpopulation defined by race and ethnicity was assumed to be balanced across the 16 possible sex (first-degree relative and proband) and proband DCM diagnosis age quartile combinations. C, Each subpopulation of first-degree relatives defined by proband DCM diagnosis age quartile, race, and ethnicity was assumed to be balanced across the 4 possible sex (first-degree relative and proband) combinations. Marginally standardized estimates for a particular subpopulation defined by proband DCM diagnosis age quartile were then obtained by weighting race and ethnicity groups in proportion to 2019 US Census population estimates (0.99% Hispanic Black, 13.97% non-Hispanic Black, 18.06% Hispanic White, 66.98% non-Hispanic White). LVE indicates left ventricular enlargement; LVSD, left ventricular systolic dysfunction.