Familial Patterns of Idiopathic Dilated Cardiomyopathy Becoming Clearer

Approximately 30% of individuals with a diagnosis of idiopathic dilated cardiomyopathy (DCM) may have first-degree relatives at risk for the disease, according to a cross-sectional study of patients from 25 heart failure programs in the United States. Compared with those who were white or Hispanic, Black patients had a higher overall familial prevalence of the disease.

While genetics is believed to play a significant role in idiopathic DCM, there are no hard data as yet to prove it, the study authors say.

“There's substantial risk in these family members, which really supports this whole contention that most of DCM likely has a genetic basis,” senior author Ray E. Hershberger, MD (Ohio State University Wexner Medical Center, Columbus), told TCTMD.

The data, published last week in JAMA, suggest that first-degree relatives of non-Hispanic Black patients with DCM and first-degree relatives of those diagnosed with DCM before age 34 are at particularly high risk of developing the cardiomyopathy or having evidence of a DCM or partial DCM phenotype, in the form of either LVEF < 50% or left ventricular enlargement with no prior evidence of CVD.

The investigators say the reason for the higher rate of familial presence of DCM in Black patients isn’t clear, but one possibility is that their study may have attenuated some of the known effects of social determinants of health by presenting an opportunity for early clinical workup.

“Genetics could be a part of that, too, and we do hope to unearth more in the genetics analysis that we are working on currently,” Hershberger said. “This is an area of huge need for patients and their families.”

In an editorial accompanying the study, Krishna G. Aragam, MD (Massachusetts General Hospital, Boston), says the research is a good first step toward understanding risks and benefits of family-based screening.

“Forthcoming efforts are poised to build on the important findings from this study to change the narrative for DCM from one of ‘diagnose and treat’ to that of ‘preempt and prevent,’ Aragam writes.

Family Connections

For the study, which was led by Gordon S. Huggins, MD (Tufts Medical Center, Boston, MA), researchers enrolled 1,220 DCM proband patients (median age 52.8 years; 43% Black; 44% female) and 1,693 of their first-degree relatives (children, parents, and full siblings) into the DCM Precision Medicine Study.

For each proband enrolled, approximately 28% of their living first-degree relatives were screened. The prevalence of familial DCM was 11.6%. Modeling suggested that if all living relatives of patients with DCM in a typical US advanced heart failure program were similarly screened, the prevalence of familial DCM would be 29.7%. When modeling further expanded the definition of familial DCM to include first-degree relatives with evidence of DCM or partial DCM phenotype, the prevalence of familial DCM increased to 56.9%.

This is an area of huge need for patients and their families. Ray E. Hershberger

Compared with non-Hispanic white patients, the risk of familial DCM for Black probands was higher (HR 1.89; 95% CI 1.26-2.83), with no significant differences seen between Hispanic and non-Hispanic patients or between white and Hispanic patients. Compared with diagnosis at a later age, DCM diagnosis of the proband before age 34 more than doubled the risk of familial DCM (P = 0.02).

While shared lifestyle and environmental factors may contribute to familial DCM, Aragam says the data connecting younger age at diagnosis and higher risk to family members are suggestive of inherited factors. Large-effect variants in more than 100 genes have been linked to the pathogenesis of DCM, as have small-effect genetic variants, although the full extent of their contribution in familial DCM remains to be determined, he writes.

Additionally, Aragam notes that some research suggests there may be differences between Black and white patients in the underlying genetic architecture of DCM.

“Focused studies are, therefore, needed to explore the concept of race-specific differences in DCM risk and, more broadly, whether the social construct of race, underlying genetic ancestry, or particular genetic polymorphisms mediate these potential risk differences,” Aragam observes.

Another big question is what to do about family members identified as being at risk.

“For those who do carry the putative disease-associated variant, you can dial in surveillance to detect earliest disease, and ideally institute appropriate preventive therapies, or if not preventive, at least therapies that will dramatically ameliorate the development of late-phase, advanced DCM where you're looking at heart transplantation,” Hershberger said. “The other big factor here is gene therapy. It's going to happen, I hope, in my lifetime, and . . . we'd love to see a point where we can use that to intervene before the development of end-stage, late-phase disease.”

The current study belongs to a planned series of clinical and genetic family-based investigations into DCM by Hershberger and colleagues under the umbrella of the Dilated Cardiomyopathy Research Project. They hope to follow the family members—potentially adding even more of them—then rescreen them to see what happens. Another part of this research is focusing on how DCM patients should communicate the potential genetic risk to their relatives.