Molecular mechanisms of peripartum cardiomyopathy: A vascular/hormonal hypothesis

Abstract

Peripartum cardiomyopathy (PPCM) is characterized by the development of systolic heart failure in the last month of pregnancy or within the first 5 months postpartum. The disease affects between 1:300 and 1:3000 births worldwide. Heart failure can resolve spontaneously but often does not. Mortality rates, like incidence, vary widely based on location, ranging from 0% to 25%. The consequences of PPCM are thus often devastating for an otherwise healthy young woman and her newborn. The cause of PPCM remains elusive. Numerous hypotheses have been proposed, with mixed supporting evidence. Recent work has suggested that PPCM is a vascular disease, triggered by the profound hormonal changes of late gestation. We focus here on these new mechanistic findings, and their potential implication for understanding and treating PPCM.

Fig

PPCM as a hormonal and vascular disease: The peripartum period causes secretion of hormones from the pituitary (e.g., prolactin (PRL)) and placenta (e.g., sFlt1). PRL is converted to 16-kD Vasoinhibin by CathepsinD (CathD) secreted from cardiomyocytes. Vasoinhibin then both triggers endothelial cell (EC) apoptosis and the secretion from ECs of miRNA146a encapsulated in exosomes. These exosomes are internalized by cardiomyocytes, where miRNA146s targets the ErbB4 pathway and others, causing dysfunction and apoptosis. At the same time, sFlt1 binds to and inhibits VEGF signaling, leading to EC dysfunction and apoptosis. Ultimately, dwindling vascular support leads to metabolic insufficiency in cardiomyocytes and cardiomyopathy.