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Background: 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 TTN (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., Methods: 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 TTN , 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., Results: 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 P [ P *]=1.2×10 -46 ). We additionally identified overrepresentation of truncating variants in FLNC (odds ratio=24.8, P *=7.0×10 -8 ), DSP (odds ratio=14.9, P *=1.0×10 -8 ), and BAG3 (odds ratio=53.1, P *=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%, P =2.5×10 -4 ), but did not differ significantly in timing of presentation after delivery, in prevalence of preeclampsia, or in rates of clinical recovery., Conclusions: 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.

Aims: Peripartum cardiomyopathy (PPCM) is a life-threatening heart disease occurring in previously heart-healthy women. A common pathomechanism in PPCM involves the angiostatic 16 kDa-prolactin (16 kDa-PRL) fragment, which via NF-κB-mediated up-regulation of microRNA-(miR)-146a induces vascular damage and heart failure. We analyse whether the plasminogen activator inhibitor-1 (PAI-1) is involved in the pathophysiology of PPCM., Methods and Results: In healthy age-matched postpartum women (PP-Ctrl, n = 53, left ventricular ejection fraction, LVEF > 55%), PAI-1 plasma levels were within the normal range (21 ± 10 ng/mL), but significantly elevated (64 ± 38 ng/mL, P < 0.01) in postpartum PPCM patients at baseline (BL, n = 64, mean LVEF: 23 ± 8%). At 6-month follow-up (n = 23), PAI-1 levels decreased (36 ± 14 ng/mL, P < 0.01 vs. BL) and LVEF (49 ± 11%) improved. Increased N-terminal pro-brain natriuretic peptide and Troponin T did not correlate with PAI-1. C-reactive protein, interleukin (IL)-6 and IL-1β did not differ between PPCM patients and PP-Ctrl. MiR-146a was 3.6-fold (P < 0.001) higher in BL-PPCM plasma compared with PP-Ctrl and correlated positively with PAI-1. In BL-PPCM serum, 16 kDa-PRL coprecipitated with PAI-1, which was associated with higher (P < 0.05) uPAR-mediated NF-κB activation in endothelial cells compared with PP-Ctrl serum. Cardiac biopsies and dermal fibroblasts from PPCM patients displayed higher PAI-1 mRNA levels (P < 0.05) than healthy controls. In PPCM mice (due to a cardiomyocyte-specific-knockout for STAT3, CKO), cardiac PAI-1 expression was higher than in postpartum wild-type controls, whereas a systemic PAI-1-knockout in CKO mice accelerated peripartum cardiac fibrosis, inflammation, heart failure, and mortality., Conclusion: In PPCM patients, circulating and cardiac PAI-1 expression are up-regulated. While circulating PAI-1 may add 16 kDa-PRL to induce vascular impairment via the uPAR/NF-κB/miR-146a pathway, experimental data suggest that cardiac PAI-1 expression seems to protect the PPCM heart from fibrosis. Thus, measuring circulating PAI-1 and miR-146a, together with an uPAR/NF-κB-activity assay could be developed into a specific diagnostic marker assay for PPCM, but unrestricted reduction of PAI-1 for therapy may not be advised., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background: Percutaneous mechanical circulatory support (MCS), such as the Impella heart pump is a valuable option for cardiogenic shock (CS), although the use of Impella in CS due to peripartum cardiomyopathy (PPCM) is limited., Objective: To assess outcomes in women with PPCM supported with an Impella device from the global catheter-based ventricular assist device (cVAD) Registry., Methods and Results: A total of 15 women with PPCM supported with Impella devices between November 2008 and October 2015 were included. Of the 15 women, five were treated at Hannover medical school and have been reported previously, the rest were managed at various US hospitals. The mean age was 30.0 ± 7.34 years, eight women were Caucasian, and seven were African-American. The occurrence of PPCM was post-delivery in eight (53.3%), at delivery in one (6.7%), and during gestation in four women (26.7%). At admission, all women had severe heart failure with a mean ejection fraction of 14.7 ± 6% and 13 women (86.7%) presented with CS. Prior to Impella, 100% were mechanically ventilated, 79% received inotropes/vasopressors, 20% supported with IABP, and 27% received veno-arterial extracorporeal membrane oxygenation (VA ECMO) during Impella support. Two women (13.3%) died, and 13 (87.7%) survived to discharge. Eight women (53.3%) had a recovery of native heart function and six (40%) were bridged to durable left ventricular assist device (LVAD)., Conclusion: MCS with Impella devices can be successfully used as a bridge to early improvement, heart recovery, or successful implantation of durable LVAD in women with PPCM complicated by severe LV dysfunction., (© 2019 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

Objective: Peripartum cardiomyopathy (PPCM) can present during pregnancy and up to months post-delivery. Most large-scale epidemiologic studies have reported on cases occurring during pregnancy or the first few days postpartum (termPPCM). Limited information is available on PPCM in the later postpartum period (latePPCM). We studied the incidence, predictors, and hospital outcome of peripartum cardiomyopathy (PPCM) in the prepartum and immediate post delivery period versus up to 3 months post-delivery., Methods: We performed a secondary analysis of the 2013 Nationwide Readmissions Database, and compared the incidence, patient characteristics and in-hospital outcomes of PPCM during the peripartum and three-month postpartum period. All women with a discharge diagnosis of PPCM during a hospitalization for childbirth were included in the termPPCM group and those re-hospitalized within 3 month post-delivery with a new diagnosis of PPCM comprised the latePPCM group., Results: There were 568 cases of PPCM, indicating an incidence of 1 per 2187 deliveries. Two thirds of those were latePPCM, and 75% of latePPCM cases occurred within 10 days of discharge. LatePPCM incidence was 1 per 208 deliveries in the highest risk group (age > 35, gestation diabetes and preeclampsia). Patients with termPPCM were more likely to be co-diagnosed with preeclampsia, to be anemic, and to be delivered by C-section., Conclusions: Most cases of PPCM were diagnosed during a readmission, rather than during pregnancy or childbirth-related index hospitalization. It may be possible to identify latePPCM cases by pre-discharge screening in high risk women and institute early management to potentially decrease morbidity/mortality., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Objectives: The goal of this study was to systematically review the peripartum cardiomyopathy (PPCM) literature and determine the prevalence of pre-eclampsia (PE) in women with PPCM. Secondary analyses included evaluation of the prevalence of hypertensive disorders, multiple gestations, and multiparity., Background: PPCM is a significant cause of maternal and infant morbidity and mortality worldwide, yet its etiology remains unknown. PE is often cited as a risk factor for the development of PPCM and recent research suggests that PE and PPCM share mechanisms that contribute to their pathobiology. No comprehensive evaluation of the relationship between PE and PPCM exists., Methods: A systematic predetermined search strategy was performed in multiple databases to identify studies describing ≥3 women with PPCM. Prevalence rates of PE, hypertension, multiple gestations, and multiparity were pooled., Results: Data from 22 studies (n = 979) were included in this analysis. The pooled prevalence of 22% (95% confidence interval [CI]: 16% to 28%) was more than quadruple the 5% average worldwide background rate of PE in pregnancy (p < 0.001). There were no geographic or racial differences detected in the prevalence of PE in women with PPCM. The rates of hypertension during pregnancy (37% [95% CI: 29% to 45%]) and multiple gestations (9% [95% CI: 7% to 11%]) were also elevated., Conclusions: The prevalence of PE, hypertensive disorders, and multiple gestations in women with PPCM is markedly higher than that in the general population. These findings support the concept of a shared pathogenesis between PE and PPCM and highlight the need for awareness of the overlap between these 2 diseases., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)