Evaluation of Women with Peripartum or Dilated Cardiomyopathy and Their First-Degree Relatives: The DCM Precision Medicine Study
Authors: Kransdorf Evan P. , Jain Rashmi , Mead Jonathan O. , Haas Garrie , Hofmeyer Mark , Ewald Gregory A. , Diamond Jamie , Owens Anjali , Lowes Brian , Stoller Douglas , Tang W. H. Wilson , Drazner Mark , Martin Cindy M. , Shah Palak , Tallaj Jose , Katz Stuart , Jimenez Javier , Shore Supriya , Smart Frank , Wang Jessica , Gottlieb Stephen S. , Judge Daniel P. , Huggins Gordon S. , Cowan Jason , Parker Patricia , Cao Jinwen , Hurst Natalie S. , Jordan Elizabeth , Ni Hanyu , Kinnamon Daniel D. , Hershberger Ray E. 
Published: February 2025

AbstractBackgroundPeripartum cardiomyopathy (PPCM) presents substantial risk of maternal mortality, but underlying cause remains unsettled.MethodsWe compared the prevalence of dilated cardiomyopathy (DCM)-relevant genetic variants in 452 female patients (probands) of African and European ancestry (AA, EA) with PPCM or DCM who had been pregnant at least once. Pathogenic and likely pathogenic (P/LP) variants were identified in DCM-associated genes. Risk of DCM or partial DCM, defined as left ventricular enlargement or a left ventricular ejection fraction of <50%, were compared in 665 FDRs of PPCM and DCM probands.ResultsThe estimated prevalences of P/LP findings among 67 probands with PPCM compared to 385 probands with DCM were comparable within ancestry (for AA, 7.8% [95% CI: 0.0%- 15.7%] vs. 7.8% [95% CI: 1.1%-14.4%]; for EA, 29.5% [12.5%-46.5%] vs. 29.8% [15.5%-44.2%]). The risk of DCM/partial DCM was not lower for FDRs of PPCM probands relative to FDRs of DCM probands (HR, 0.77; 95% CI, 0.47 – 1.28). For an FDR of a non-Hispanic EA proband with PPCM, the lowest estimated DCM/partial DCM risk by age 80 was 26.8% (95% CI, 15.0%-45.0%) compared to 33.2% (95% CI, 21.2%-49.5%) for an FDR of a proband with DCM. Further validating PPCM genetic risk by using a set of genes common between studies, the estimated prevalence of P/LP variants among EA PPCM probands (26.6%; 95% CI, 12.6%- 40.6%) was higher than the general population estimate from a UK Biobank study (0.6%), Also, the estimated DCM prevalence among the lowest-risk FDRs of non-Hispanic EA probands with PPCM (7.0% [95% CI, 0%-14.1%] females, 9.0% [95% CI, 1.6%-16.3%] males) was higher than general population estimates from another UK Biobank study (0.30% females, 0.63% males).ConclusionsComparing women with PPCM to those with DCM, a similar prevalence of DCM-relevant genetic variants and similar risk of DCM or partial DCM among their first-degree relatives were observed. These findings, along with comparisons to the general population showing higher prevalence of DCM-relevant genetic variants in women with PPCM and higher DCM prevalence in their FDRs, strengthen evidence for the genetic basis of PPCM and underscore the need for clinical genetic evaluations for PPCM patients.Clinical Trialclinicaltrials.gov,NCT03037632Clinical PerspectiveWhat is new?This is the first study to use familial risk, as shown by DCM and partial DCM phenotypes in first-degree relatives (FDRs) of women with PPCM, to gain insight into the genetics of PPCM.The prevalence of DCM-relevant rare genetic variants was similar between women probands diagnosed with PPCM and DCM within European and African ancestry groups.In PPCM probands of European ancestry, the prevalence of rare variants in DCM-relevant genes was higher than a general population estimate.In the first-degree relatives of women with PPCM and DCM, the familial risk of DCM or a partial phenotype of DCM was similar for PPCM and DCM but higher than a population-based estimate.What are the clinical implications?The genetic findings of this study from PPCM probands and their first-degree relatives strengthens evidence that DCM-related genetics is a key underlying factor in the risk of PPCM.A genetics evaluation is indicated following established guidelines for women with PPCM as is the case for women and men with DCM.