Cardiovascular Institute, and Penn Muscle Institute, Department of Medicine (R.G., J.L., J. Brandimarto, Q.M., K.B.M., T.P.C., Z.A.), Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Maternal and Child Health Research Center, Department of Obstetrics and Gynecology (L.D.L., V.R.), Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Circulation. 2021 May 11;143(19):1852-1862. doi: 10.1161/CIRCULATIONAHA.120.052395. Epub 2021 Apr 20.
Peripartum cardiomyopathy (PPCM) occurs in ≈1:2000 deliveries in the United States and worldwide. The genetic underpinnings of PPCM remain poorly defined. Approximately 10% of women with PPCM harbor truncating variants in (TTNtvs). Whether mutations in other genes can predispose to PPCM is not known. It is also not known if the presence of TTNtvs predicts clinical presentation or outcomes. Nor is it known if the prevalence of TTNtvs differs in women with PPCM and preeclampsia, the strongest risk factor for PPCM.
Women with PPCM were retrospectively identified from several US and international academic centers, and clinical information and DNA samples were acquired. Next-generation sequencing was performed on 67 genes, including , and evaluated for burden of truncating and missense variants. The impact of TTNtvs on the severity of clinical presentation, and on clinical outcomes, was evaluated.
Four hundred sixty-nine women met inclusion criteria. Of the women with PPCM, 10.4% bore TTNtvs (odds ratio=9.4 compared with 1.2% in the reference population; Bonferroni-corrected [*]=1.2×10). We additionally identified overrepresentation of truncating variants in FLNC (odds ratio=24.8, *=7.0×10), DSP (odds ratio=14.9, *=1.0×10), and BAG3 (odds ratio=53.1, *=0.02), genes not previously associated with PPCM. This profile is highly similar to that found in nonischemic dilated cardiomyopathy. Women with TTNtvs had lower left ventricular ejection fraction on presentation than did women without TTNtvs (23.5% versus 29%, =2.5×10), but did not differ significantly in timing of presentation after delivery, in prevalence of preeclampsia, or in rates of clinical recovery.
This study provides the first extensive genetic and phenotypic landscape of PPCM and demonstrates that predisposition to heart failure is an important risk factor for PPCM. The work reveals a degree of genetic similarity between PPCM and dilated cardiomyopathy, suggesting that gene-specific therapeutic approaches being developed for dilated cardiomyopathy may also apply to PPCM, and that approaches to genetic testing in PPCM should mirror those taken in dilated cardiomyopathy. Last, the clarification of genotype/phenotype associations has important implications for genetic counseling.
围产期心肌病（PPCM）在美国和全球范围内约占每 2000 次分娩中的 1 例。PPCM 的遗传基础仍未得到明确界定。大约 10%的 PPCM 妇女存在截断变异（TTNtvs）。其他基因突变是否会导致 PPCM 尚不清楚。也不知道 TTNtvs 是否能预测临床表现或结果。也不知道 TTNtvs 在 PPCM 和子痫前期（PPCM 的最强危险因素）妇女中的患病率是否存在差异。
从美国和国际多个学术中心回顾性地确定了 PPCM 妇女，并获取了临床信息和 DNA 样本。对 67 个基因进行了下一代测序，包括 TTN，并评估了截断和错义变异的负担。评估了 TTNtvs 对临床表现严重程度和临床结局的影响。
469 名妇女符合纳入标准。在 PPCM 妇女中，10.4%携带 TTNtvs（优势比=9.4，与参考人群的 1.2%相比；Bonferroni 校正[]=1.2×10）。我们还发现截断变异在 FLNC（优势比=24.8，=7.0×10）、DSP（优势比=14.9，=1.0×10）和 BAG3（优势比=53.1，=0.02）中的过度表达，这些基因以前与 PPCM 无关。该图谱与非缺血性扩张型心肌病非常相似。与无 TTNtvs 的妇女相比，携带 TTNtvs 的妇女在就诊时的左心室射血分数较低（23.5%比 29%，=2.5×10），但在产后出现的时间、子痫前期的患病率或临床恢复率方面没有显著差异。
本研究首次提供了 PPCM 的广泛遗传和表型图谱，并证明心力衰竭易感性是 PPCM 的一个重要危险因素。这项工作揭示了 PPCM 和扩张型心肌病之间存在一定程度的遗传相似性，这表明正在为扩张型心肌病开发的特定基因治疗方法也可能适用于 PPCM，并且 PPCM 中的基因检测方法应与扩张型心肌病中的方法相似。最后，基因型/表型相关性的明确对遗传咨询具有重要意义。
