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
Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH.
medRxiv. 2025 Feb 21:2025.02.18.25322501. doi: 10.1101/2025.02.18.25322501.
Peripartum cardiomyopathy (PPCM) presents substantial risk of maternal mortality, but underlying cause remains unsettled.
We 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.
The 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).
Comparing 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.
clinicaltrials.gov, NCT03037632.
围产期心肌病（PPCM）存在较高的孕产妇死亡风险，但其潜在病因仍未明确。
我们比较了452名非洲和欧洲血统（AA、EA）的女性患者（先证者）中扩张型心肌病（DCM）相关基因变异的患病率，这些患者患有PPCM或DCM且至少怀孕过一次。在DCM相关基因中鉴定出致病和可能致病（P/LP）变异。比较了665名PPCM和DCM先证者的一级亲属中DCM或部分DCM（定义为左心室扩大或左心室射血分数<50%）的风险。
与385名DCM先证者相比，67名PPCM先证者中P/LP发现的估计患病率在不同血统中具有可比性（AA组，7.8% [95% CI：0.0%-15.7%] 对7.8% [95% CI：1.1%-14.4%]；EA组，29.5% [12.5%-46.5%] 对29.8% [15.5%-44.2%]）。PPCM先证者的一级亲属发生DCM/部分DCM的风险并不低于DCM先证者的一级亲属（HR，0.77；95% CI，0.47 - 1.28）。对于一名非西班牙裔EA血统的PPCM先证者的一级亲属，到80岁时估计的最低DCM/部分DCM风险为26.8%（95% CI，15.0%-45.0%），而DCM先证者的一级亲属为33.2%（95% CI，21.2%-49.5%）。通过使用研究间共有的一组基因进一步验证PPCM的遗传风险，EA血统的PPCM先证者中P/LP变异的估计患病率（26.6%；95% CI，12.6%-40.6%）高于英国生物银行研究中的一般人群估计值（0.6%）。此外，非西班牙裔EA血统的PPCM先证者中风险最低的一级亲属的DCM估计患病率（女性为7.0% [95% CI，0%-14.1%]，男性为9.0% [95% CI，1.6%-16.3%]）高于另一项英国生物银行研究中的一般人群估计值（女性为0.30%，男性为0.63%）。
将PPCM女性与DCM女性进行比较，观察到DCM相关基因变异的患病率相似，且她们的一级亲属中DCM或部分DCM的风险相似。这些发现，以及与一般人群的比较表明PPCM女性中DCM相关基因变异的患病率更高，其一级亲属中DCM患病率更高，强化了PPCM遗传基础的证据，并强调了对PPCM患者进行临床基因评估的必要性。
clinicaltrials.gov，NCT03037632。
