Highlight
– Individuals with peripartum cardiomyopathy (PPCM), alcohol-induced cardiomyopathy (ACM), and cancer therapy–related cardiomyopathy (CCM) show enrichment for both rare monogenic DCM variants and a high polygenic risk score for DCM.
– In multi-cohort analyses (Mass General Brigham Biobank with replication in UK Biobank, FinnGen, and the VA Million Veteran Program), a 1-SD higher DCM polygenic score was associated with adjusted odds ratios of ~1.6–1.8 for secondary cardiomyopathies; high polygenic scores conferred roughly 3-fold increased odds in medical-record reviewed cases.
– Most affected individuals lacked clear antecedent clinical risk factors, supporting a model in which inherited myocardial vulnerability interacts with diverse environmental triggers to produce clinically manifest cardiomyopathy.
Background
Nonischemic dilated cardiomyopathy (DCM) is a heterogeneous myocardial disorder with both monogenic and complex polygenic contributions. Rare pathogenic variants in established cardiomyopathy genes (for example, TTN, LMNA, BAG3) explain a substantial fraction of familial and idiopathic DCM. Separately, environmental stressors including pregnancy, alcohol excess, and cardiotoxic cancer therapies can precipitate clinically overt cardiomyopathy in a subset of exposed individuals. Whether those “secondary” cardiomyopathies arise purely from environmental toxicity or from interaction between environmental triggers and genetic susceptibility has important implications for screening, prevention, and counseling.
Study design
Maamari et al. conducted a retrospective genetic association analysis anchored in the Mass General Brigham (MGB) Biobank (n = 42,137) with replication in three large population cohorts: UK Biobank (n = 295,160), FinnGen (n = 417,950), and the Veterans Affairs Million Veteran Program (n = 516,066). Secondary cardiomyopathy cases were ascertained using coded data and, for the MGB subset, by manual medical-record review to confirm case definitions and identify antecedent clinical risk factors. The exposures of interest were (1) a polygenic risk score (PRS) for DCM derived from genome-wide association data and (2) rare, putatively pathogenic monogenic variants in DCM genes. Primary outcomes were associations between the DCM PRS and three secondary cardiomyopathies—PPCM, ACM, and CCM—and the prevalence and interplay of monogenic and polygenic susceptibilities among cases.
Key findings
Population and case counts: Across the four cohorts the authors identified 3,414 individuals with secondary cardiomyopathy: 70 with PPCM, 2,281 with ACM, and 1,063 with CCM. Case ascertainment and review were most detailed in the MGB subset, where 113 cardiomyopathy cases underwent chart review for antecedent exposures and genetic findings.
Association of DCM polygenic score with secondary cardiomyopathies
The DCM polygenic score was associated with higher odds of each secondary cardiomyopathy across cohorts. Reported effect sizes (per standard deviation increase in PRS) were:
- PPCM: odds ratio (OR) 1.82 per SD (95% CI, 1.43–2.30)
- ACM: OR 1.56 per SD (95% CI, 1.34–1.82)
- CCM: OR 1.64 per SD (95% CI, 1.24–2.15)
All associations were statistically significant (P < .001 for primary analyses), and findings replicated across cohorts with differing ancestry compositions and ascertainment strategies, increasing confidence in the robustness of the signal.
Monogenic variant enrichment and joint contributions
Rare pathogenic or likely pathogenic monogenic DCM variants were enriched among secondary cardiomyopathy cases relative to controls, consistent with prior reports linking TTN truncating variants and other cardiomyopathy genes to PPCM and cardiotoxicity. In the MGB medical-record reviewed subset, monogenic variants were identified in 7 of 113 individuals, whereas 66 of 113 had a high polygenic score. A high PRS was associated with approximately a 3-fold increased odds of cardiomyopathy in this chart-reviewed cohort.
Antecedent clinical risk factors and penetrance
Remarkably, most individuals with cardiomyopathy lacked clear antecedent clinical risk factors beyond the triggering exposure (for example, heavy alcohol use, pregnancy, or cardiotoxic chemotherapy). This observation supports a model in which inherited genetic vulnerability (rare or polygenic) lowers the myocardial reserve or resilience such that otherwise common exposures produce disproportionate cardiac injury.
Expert commentary and biological plausibility
These data align with mechanistic and clinical intuition. Rare loss-of-function variants—most notably truncating variants in the giant sarcomeric protein titin (TTN)—reduce baseline myocardial structural integrity and functional reserve. When the myocardium is further stressed by hemodynamic load of late pregnancy, direct ethanol toxicity, or anthracycline-mediated oxidative injury, individuals with reduced reserve are more likely to cross the threshold into clinical heart failure. A polygenic score aggregates many common alleles of small effect that together may capture additional pathways related to myocardial structure, intercellular signaling, metabolism, and response to stress, thereby also identifying a subset of individuals at higher risk of decompensation after exposure.
Clinical implications
1. Risk stratification: Combining monogenic screening and DCM polygenic scores could refine identification of individuals at elevated risk before exposure—pregnant persons, patients advised to abstain from heavy alcohol use, or those scheduled for cardiotoxic chemotherapy.
2. Counseling and surveillance: For high-risk individuals, intensified cardiac surveillance (serial echocardiography, biomarkers), preventive measures (dose modification or cardioprotective agents in oncology), and targeted counseling (avoidance of heavy alcohol, informed pregnancy planning) may be warranted. However, the absolute risk and optimal management thresholds remain to be defined.
3. Precision prevention trials: The study supports designing prospective trials to test whether genotype-informed preventive strategies reduce the incidence or severity of secondary cardiomyopathies.
Limitations and caveats
– Case counts for some subgroups were small (especially PPCM with n=70 across cohorts), limiting precision and subgroup analyses.
– The retrospective design and reliance on biobank phenotyping risk misclassification, despite chart review in a subset.
– Polygenic scores have variable performance across ancestry groups because discovery GWAS are often Eurocentric; portability and calibration for underrepresented ancestries need rigorous assessment before clinical use.
– Monogenic variant detection depends on sequencing depth and gene panels used; noncoding or structural variants may be missed.
– The PRS and monogenic variants explain only a fraction of variance in risk; environmental, epigenetic, and stochastic factors remain important determinants of clinical outcomes.
– Clinical utility (does knowledge of PRS alter outcomes?) is unproven; false reassurance or anxiety are potential harms that require study alongside benefit evaluation.
Recommendations and next steps
1. Validation in larger, ancestrally diverse cohorts with prospective phenotyping to estimate absolute risks and to define actionable PRS thresholds.
2. Integrate genetic findings with clinical risk models (age, comorbidities, exposure dose/timing) to develop calibrated risk calculators for specific clinical contexts (pregnancy planning, chemotherapy selection, alcohol counseling).
3. Evaluate utility in interventional trials where genotype-positive individuals are randomized to enhanced surveillance or cardioprotective strategies to determine whether genetic stratification improves clinical outcomes in an evidence-based manner.
4. Ethical, legal, and social implications: develop counseling pathways and protect against genetic discrimination, ensuring informed consent and appropriate follow-up for individuals found to have high genetic risk.
Conclusion
Maamari et al. provide compelling multi-cohort evidence that both rare monogenic DCM variants and higher polygenic risk for DCM are enriched among individuals with peripartum, alcohol-induced, and cancer therapy–related cardiomyopathies. These findings support a shared genetic architecture in which inherited myocardial vulnerability is unmasked by disparate environmental insults. Clinical translation will require larger and more diverse datasets, prospective validation of risk thresholds, and rigorous trials to demonstrate that genotype-informed prevention or surveillance reduces morbidity. Meanwhile, clinicians should recognize the growing evidence that genetic susceptibility matters in secondary cardiomyopathies and consider referral for genetic evaluation when clinical suspicion is high.
Funding and clinicaltrials.gov
Funding sources and trial registration details are reported in the original publication (Maamari DJ et al., JAMA Cardiology 2025). Readers should consult the source article for complete disclosures and funding statements.
References
1. Maamari DJ, Biddinger KJ, Jurgens SJ, et al. Polygenic Susceptibility in Peripartum, Alcohol-Induced, and Cancer Therapy-Related Cardiomyopathies. JAMA Cardiol. 2025 Nov 1;10(11):1138-1146. doi:10.1001/jamacardio.2025.3248.
2. Herman DS, Lam L, Taylor MR, et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Apr 26;366(7):619–628. doi:10.1056/NEJMoa1110186.
3. Khera AV, Chaffin M, Aragam KG, et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet. 2018 Sep;50(9):1219–1224. doi:10.1038/s41588-018-0183-z.
For more detailed methodology, data access queries, and full disclosure statements, see Maamari et al., JAMA Cardiology 2025.