Cardiac angiogenic imbalance leads to peripartum cardiomyopathy.

Abstract

Peripartum cardiomyopathy (PPCM) is an often fatal disease that affects pregnant women who are near delivery, and it occurs more frequently in women with pre-eclampsia and/or multiple gestation. The aetiology of PPCM, and why it is associated with pre-eclampsia, remain unknown. Here we show that PPCM is associated with a systemic angiogenic imbalance, accentuated by pre-eclampsia. Mice that lack cardiac PGC-1α, a powerful regulator of angiogenesis, develop profound PPCM. Importantly, the PPCM is entirely rescued by pro-angiogenic therapies. In humans, the placenta in late gestation secretes VEGF inhibitors like soluble FLT1 (sFLT1), and this is accentuated by multiple gestation and pre-eclampsia. This anti-angiogenic environment is accompanied by subclinical cardiac dysfunction, the extent of which correlates with circulating levels of sFLT1. Exogenous sFLT1 alone caused diastolic dysfunction in wild-type mice, and profound systolic dysfunction in mice lacking cardiac PGC-1α. Finally, plasma samples from women with PPCM contained abnormally high levels of sFLT1. These data indicate that PPCM is mainly a vascular disease, caused by excess anti-angiogenic signalling in the peripartum period. The data also explain how late pregnancy poses a threat to cardiac homeostasis, and why pre-eclampsia and multiple gestation are important risk factors for the development of PPCM.

Authors

Patten, Ian S; Rana, Sarosh; Shahul, Sajid; Rowe, Glenn C; Jang, Cholsoon; Liu, Laura; Hacker, Michele R; Rhee, Julie S; Mitchell, John; Mahmood, Feroze; Hess, Philip; Farrell, Caitlin; Koulisis, Nicole; Khankin, Eliyahu V; Burke, Suzanne D; Tudorache, Igor; Bauersachs, Johann; del Monte, Federica; Hilfiker-Kleiner, Denise; Karumanchi, S Ananth; Arany, Zoltan;

Keywords

  • Animals
  • Bromocriptine/ pharmacology
  • Bromocriptine/ therapeutic use
  • Cardiomyopathies/ blood
  • Cardiomyopathies/ drug therapy
  • Cardiomyopathies/ etiology
  • Cardiomyopathies/ physiopathology
  • Disease Models, Animal
  • Female
  • Heart/ drug effects
  • Heart/ physiopathology
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Mice
  • Mice, Knockout
  • Myocytes, Cardiac/ drug effects
  • Myocytes, Cardiac/ metabolism
  • Neovascularization, Pathologic/ complications
  • Neovascularization, Pathologic/ drug therapy
  • Neovascularization, Pathologic/ physiopathology
  • Neovascularization, Physiologic/ drug effects
  • Neovascularization, Physiologic/ physiology
  • Pre-Eclampsia/ physiopathology
  • Pregnancy
  • Pregnancy Complications, Cardiovascular/ blood
  • Pregnancy Complications, Cardiovascular/ drug therapy
  • Pregnancy Complications, Cardiovascular/ etiology
  • Pregnancy Complications, Cardiovascular/ physiopathology
  • Trans-Activators/ deficiency
  • Trans-Activators/ genetics
  • Trans-Activators/ metabolism
  • Transcription Factors
  • Vascular Endothelial Growth Factor A/ pharmacology
  • Vascular Endothelial Growth Factor A/ therapeutic use
  • Vascular Endothelial Growth Factor Receptor-1/ blood
  • Vascular Endothelial Growth Factor Receptor-1/ genetics
  • Vascular Endothelial Growth Factor Receptor-1/ metabolism
  • Vascular Endothelial Growth Factor Receptor-1/ pharmacology

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