By Michael H. Crawford, MD
Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco
SYNOPSIS: An observational study of screening first-degree relatives of patients with dilated cardiomyopathy revealed 14% will show either dilated left ventricles, low left ventricular function, or both. These findings are more common if the relatives have been diagnosed with hypertension or are obese, but their frequency is not altered by sex or race.
SOURCE: Ni H, Jordan E, Kinnamon DD, et al. Screening for dilated cardiomyopathy in at-risk first-degree relatives. J Am Coll Cardiol 2023;81:2059-2071.
It is advantageous to screen patients for early evidence of dilated cardiomyopathy (DCM), including the partial phenotypes of only left ventricular enlargement (LVE) or LV systolic dysfunction (LVSD). Clinicians could conduct family-based clinical and genetic evaluation of first-degree relatives (FDRs). However, the yield of such screening is unclear. The DCM Precision Medicine study, conducted in 25 sites between 2016 and 2021, included 735 adult DCM patients (probands) with at least one FDR without known DCM or partial phenotypes. There were 1,365 FDRs for this analysis. The authors defined LVSD as a LV ejection fraction (EF) of < 50% and LVE as > 95th percentile for age and sex. Clinical evaluation included history, physical exam, electrocardiogram, and an echocardiogram. Researchers used genotyping to analyze 36 genes considered clinically relevant for DCM. Variants were classified as pathogenic, likely pathogenic, or a variant of uncertain significance (VUS), further classified as likely benign or benign.
Among the probands, 46% were women, 34% were Black, and 9% were Hispanic or other ethnicities. The median LVEF was 20%. The mean age of FDRs was 45 years; at screening, 14% were newly diagnosed with DCM (2%), LVSD (4%), or LVE (8%). FDRs who received these new diagnoses were more likely to be age 45-64 years, hypertensive or obese, but did not differ by race or ethnicity. The median EF of FDRs with DCM was 40%. Also, the proportion of probands who showed pathogenic or likely pathogenic genetic variants was 20%, and those with variants of uncertain significance was 42%. FDRs of probands with known genetic profiles associated with DCM recorded a higher age-adjusted incidence of DCM, but not the partial phenotypes. The authors concluded cardiovascular screening of FDRs of DCM patients resulted in new DCM-related abnormalities in one of seven people. New DCM was more common in older FDRs with hypertension or obesity whose proband carried a genetic variant known to be associated with DCM, but did not differ by sex or race/ethnicity.
COMMENTARY
The results of the DCM Precision Medicine study provide data to support the recommendation of screening FDRs. The incidence of DCM in this study was 2%. Is this high enough to justify screening asymptomatic FDRs? If so, since the frequency of finding DCM in FDRs increases with age, how often do we need to screen? Will our healthcare system pay for this screening, which certainly will need to occur more than once for most patients? We know how to treat those in whom DCM is detected, but what do we do with those with only dilated LVs? Which therapies are most effective for asymptomatic FDRs with abnormalities on screening? It is reasonable to suspect factors associated with the development of DCM in general would influence the rate of DCM in the FDRs. Hypertension and obesity raised the rate of DCM in FDRs. Another issue not fully covered in the Precision Medicine study is the role of genetic testing. One goal of the investigators was to help clarify the importance of VUS. They found the age-adjusted percentage of FDRs with DCM whose proband had a VUS was 2.5% vs. 0.6% in those who did not, but VUS did not predict partial phenotypes.
There were several limitations to this work. Since it was cross-sectional, we cannot fully appreciate the effect of time on these findings. For example, it is not clear whether the partial phenotypes will become DCM with time. Also, this study was conducted in heart failure referral centers, as evidenced by the low median LVEF of the probands (20%). Thus, the results might not apply to a primary care population. In addition, the study might be biased, as only about one-third of the FDRs were enrolled, and they might have been more health conscious. The lack of sex or racial differences in the findings is useful for designing screening programs, but the number of individuals in the groups defined was too small for any firm conclusions. I believe this study provides some justification for screening FDRs of DCM patients, but raises more questions than it answers.
