Phenotyping and outcome on contemporary management in a German cohort of patients with peripartum cardiomyopathy

Denise Hilfiker-Kleiner,S Labidi,J Jordan,R Lichtinghagen,N Bovy,D Fischer,J Bauersachs,A Haghikia,E Libhaber,D Tsikas,I Struman,K Sliwa,C S Kaisenberg,E Podewski,P Roentgen

doi:10.1007/s00395-013-0366-9

Abstract

Peripartum cardiomyopathy (PPCM) is a life-threatening heart disease developing towards the end of pregnancy or in the months following delivery in previously healthy women in terms of cardiac disease. Enhanced oxidative stress and the subsequent cleavage of the nursing hormone Prolactin into an anti-angiogenic 16 kDa subfragment emerged as a potential causal factor of the disease. We established a prospective registry with confirmed PPCM present in 115 patients (mean baseline left ventricular ejection fraction, LVEF: 27 ± 9 %). Follow-up data (6 ± 3 months) showed LVEF improvement in 85 % and full recovery in 47 % while 15 % failed to recover with death in 2 % of patients. A positive family history of cardiomyopathy was present in 16.5 %. Pregnancy-associated hypertension was associated with a better outcome while a baseline LVEF ≤ 25 % was associated with a worse outcome. A high recovery rate (96 %) was observed in patients obtaining combination therapy with beta-blocker, angiotensin-converting enzyme (ACE) inhibitors/angiotensin-receptor-blockers (ARBs) and bromocriptine. Increased serum levels of Cathepsin D, the enzyme that generates 16 kDa Prolactin, miR-146a, a direct target of 16 kDa Prolactin, N-terminal-pro-brain-natriuretic peptide (NT-proBNP) and asymmetric dimethylarginine (ADMA) emerged as biomarkers for PPCM. In conclusion, low baseline LVEF is a predictor for poor outcome while pregnancy-induced hypertensive disorders are associated with a better outcome in this European PPCM cohort. The high recovery rate in this collective is associated with a treatment concept using beta-blockers, ACE inhibitors/ARBs and bromocriptine. Increased levels of Cathepsin D activity, miR-146a and ADMA in serum of PPCM patients support the pathophysiological role of 16 kDa Prolactin for PPCM and may be used as a specific diagnostic marker profile.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-013-0366-9) contains supplementary material, which is available to authorized users.

Highlights

Peripartum cardiomyopathy (PPCM) is the major cause of pregnancy-induced heart failure and is associated with high morbidity and mortality [16, 19, 21, 24].The true incidence of PPCM is unknown, as clinical presentation varies
Advances have been achieved in understanding some underlying molecular cascades deregulated in PPCM pointing to an important role of an angiogenic imbalance caused by angiostatic and pro-apoptotic 16 kDa Prolactin fragment and the soluble VEGF receptor 1 which leads to massive endothelial damage and myocardial dysfunction [9, 10, 15]. 16 kDa Prolactin seems to mediate a large part of its antiangiogenic effects by the induction of microRNA-146a [9]
We recently reported that 16 kDa Prolactin induces miR-146a expression in endothelial cells and showed that it is up-regulated in a small collective of PPCM patients [9]

Summary

Introduction

Peripartum cardiomyopathy (PPCM) is the major cause of pregnancy-induced heart failure and is associated with high morbidity and mortality [16, 19, 21, 24].The true incidence of PPCM is unknown, as clinical presentation varies. Advances have been achieved in understanding some underlying molecular cascades deregulated in PPCM pointing to an important role of an angiogenic imbalance caused by angiostatic and pro-apoptotic 16 kDa Prolactin fragment and the soluble VEGF receptor 1 (sFlt1) which leads to massive endothelial damage and myocardial dysfunction [9, 10, 15]. 16 kDa Prolactin promotes shedding of miR-146a loaded exosomes from endothelial cells that are absorbed by cardiomyocytes where they impair metabolic activity [9], a feature that is further supported by observations showing that endothelial microparticles are increased in acute PPCM [26]. Genetic factors may contribute to the susceptibility to PPCM in patients with positive family history of cardiomyopathy, who typically have a more severe course of disease [14, 25]

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