Screening for Dilated Cardiomyopathy in At-Risk First-Degree Relatives

Abstract

Background: Cardiovascular screening is recommended for first-degree relatives (FDRs) of patients with dilated cardiomyopathy (DCM), but the yield of FDR screening is uncertain for DCM patients without known familial DCM, for non-White FDRs, or for DCM partial phenotypes of left ventricular enlargement (LVE) or left ventricular systolic dysfunction (LVSD).

Objectives: This study examined the yield of clinical screening among reportedly unaffected FDRs of DCM patients.

Methods: Adult FDRs of DCM patients at 25 sites completed screening echocardiograms and ECGs. Mixed models accounting for site heterogeneity and intrafamilial correlation were used to compare screen-based percentages of DCM, LVSD, or LVE by FDR demographics, cardiovascular risk factors, and proband genetics results.

Results: A total of 1,365 FDRs were included, with a mean age of 44.8 ± 16.9 years, 27.5% non-Hispanic Black, 9.8% Hispanic, and 61.7% women. Among screened FDRs, 14.1% had new diagnoses of DCM (2.1%), LVSD (3.6%), or LVE (8.4%). The percentage of FDRs with new diagnoses was higher for those aged 45 to 64 years than 18 to 44 years. The age-adjusted percentage of any finding was higher among FDRs with hypertension and obesity but did not differ statistically by race and ethnicity (16.2% for Hispanic, 15.2% for non-Hispanic Black, and 13.1% for non-Hispanic White) or sex (14.6% for women and 12.8% for men). FDRs whose probands carried clinically reportable variants were more likely to be identified with DCM.

Conclusions: Cardiovascular screening identified new DCM-related findings among 1 in 7 reportedly unaffected FDRs regardless of race and ethnicity, underscoring the value of clinical screening in all FDRs.

Keywords: dilated cardiomyopathy; family members; screening.

Conflict of interest statement

Funding Support and Author Disclosures Research reported in this publication was supported by a parent award from the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number R01HL128857, which included a supplement from the National Human Genome Research Institute. The DCM Precision Medicine Study was supported by computational infrastructure provided by The Ohio State University Division of Human Genetics Data Management Platform and the Ohio Supercomputer Center. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

FIGURE 1. Flow Chart of Screened First-Degree Relatives

Information on inclusion and exclusion for the Precision Medicine dilated cardiomyopathy (DCM) study and this analysis. The left boxes describe the enrollment and selection of eligible probands. The right boxes describe the enrollment and selection of eligible first-degree relative (FDR) for the analysis.

FIGURE 2. First-Degree Relatives With DCM, LVE, or LVSD According to Age Group

Blue, red, and gray bars depict percentages of first-degree relatives identified with dilated cardiomyopathy (DCM) and left ventricular enlargement (LVE) or left ventricular systolic dysfunction (LVSD) by clinical screening for the 3 age groups. Error bars denote the 95% CI. Estimates were obtained using generalized estimating-equation type logistic mixed models accounting for site heterogeneity and intrafamily correlation. The percentage of those with DCM was higher for first-degree relatives aged 45 to 64 years than for those aged younger than 45 years (P = 0.02). Percentages of those with LVE or LVSD only or DCM, LVSD, and LVE combined did not differ by age group. Wald P values for differences in these percentages were obtained using the delta method with a standard normal distribution. All comparisons were adjusted by the Bonferroni correction method.

FIGURE 3. First-Degree Relatives With DCM or Partial DCM by DCM-Related Rare Variants

(A) Percentage of first-degree relatives (FDRs) with DCM by probands’ DCM-related rare variants. Blue, red, and gray bars depict percentages of FDRs with DCM for the 3 DCM-related rare variant groups. Age-adjusted percentages were higher for FDRs when their probands carried likely pathogenic/pathogenic (LP/P) or variants of uncertain significance (VUS) only compared with those who did not carry any (P = 0.045 and 0.01, respectively). (B) Percentage of FDRs with LVSD or LVE by probands’ DCM-related rare variants. Blue, red, and gray bars depict percentages of FDRs with LVE or LVSD for the 3 DCM-related rare variant groups. Age-adjusted percentages of those with LVSD or LVE for FDRs when their probands carried LP/P and VUS variants only were not statistically different from those whose probands did not carry any (P = 0.47 and 0.79, respectively). Error bars denote the 95% CI. Abbreviations as in Figure 2.

CENTRAL ILLUSTRATION. Clinical Screening of Reportedly Unaffected First-Degree Relatives of Patients With Dilated Cardiomyopathy

(Top) The progression from a normal heart to dilated cardiomyopathy (DCM) occurs over years. In this progression, a DCM partial phenotype, left ventricular enlargement (LVE), or left ventricular systolic dysfunction (LVSD), is observed before the development of a full asymptomatic DCM phenotype, which eventually presents with symptoms. (Bottom) Probands with DCM had relatives screened according to clinical guidelines and the study protocol. Of enrolled relatives reported to be unaffected, 14.1% had new DCM, LVE, or LVSD detected. Of those with negative screening, surveillance has been recommended to continue at age-defined intervals. Other factors, such as additional genetic variation or lifestyle, may affect disease presentation over time.