Emerging research highlights the role of genetic predisposition in the development of secondary cardiomyopathies triggered by environmental stressors such as pregnancy, alcohol use, and cancer therapy. Findings published in JAMA Cardiology suggest that individuals with a genetic risk for nonischemic dilated cardiomyopathy (DCM) may be more susceptible to these secondary forms, underscoring the potential value of genetic screening in clinical risk assessment.
Understanding the Two-Hit Hypothesis
Cardiomyopathies associated with peripartum states, alcohol consumption, and cancer therapies are traditionally viewed as distinct clinical entities. However, recent studies support a “two-hit” hypothesis: a latent genetic susceptibility to DCM may be activated by physiological or environmental stressors, leading to overt disease.
Dr. Dimitri J. Maamari and colleagues from UT Southwestern Medical Center explain that rare monogenic variants linked to DCM are disproportionately found in individuals with secondary cardiomyopathies, suggesting a shared genetic architecture.
Study Design and Cohort Analysis
To explore this connection, researchers conducted a retrospective analysis using data from the Mass General Brigham Biobank (mean age: 56 years; 58% women), supplemented by three additional cohorts: UK Biobank, FinnGen, and the Veterans Affairs’ Million Veteran Program.
Across these cohorts, 3,414 individuals were identified with secondary cardiomyopathy:
- Peripartum cardiomyopathy: 70 cases
- Alcohol-related cardiomyopathy: 2,281 cases
- Cancer therapy-related cardiomyopathy: 1,063 cases
Key Genetic Findings
A higher polygenic score for nonischemic DCM was significantly associated with increased risk for all three secondary cardiomyopathies:
- Peripartum cardiomyopathy: OR per SD = 1.82 (95% CI: 1.43–2.3; P < .001)
- Alcohol-related cardiomyopathy: OR per SD = 1.56 (95% CI: 1.34–1.82; P < .001)
- Cancer therapy-related cardiomyopathy: OR per SD = 1.64 (95% CI: 1.24–2.15; P < .001)
These associations were consistent across cohorts, except for peripartum cardiomyopathy in the UK Biobank and FinnGen datasets.
Additionally, TTN truncating variants, a known monogenic risk factor for DCM, were strongly associated with all three secondary cardiomyopathies in the Mass General Brigham cohort:
- Peripartum: OR = 27.22
- Alcohol-related: OR = 9.5
- Cancer therapy-related: OR = 13.9
Other monogenic variants linked to DCM were not observed in these secondary cases.
Clinical Implications
Notably, a substantial proportion of patients lacked traditional clinical risk factors at the time of diagnosis:
- Peripartum cardiomyopathy: 57.1% had no known risk factors
- Alcohol-related cardiomyopathy: 28.9%
- Cancer therapy-related cardiomyopathy: 81.2%
This suggests that genetic screening could play a pivotal role in identifying at-risk individuals who might otherwise go undetected.
Looking Ahead
The study’s authors advocate for further research, ideally in prospective cohorts, to determine whether individuals with known genetic risk benefit from tailored monitoring during high-risk periods, such as pregnancy or chemotherapy. Polygenic risk scoring may offer a more scalable and practical approach to risk stratification compared to monogenic testing alone.
