title: 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.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Ian S
authors.initials: IS
authors.lastname: Patten
authors.forename: Sarosh
authors.initials: S
authors.lastname: Rana
authors.forename: Sajid
authors.initials: S
authors.lastname: Shahul
authors.forename: Glenn C
authors.initials: GC
authors.lastname: Rowe
authors.forename: Cholsoon
authors.initials: C
authors.lastname: Jang
authors.forename: Laura
authors.initials: L
authors.lastname: Liu
authors.forename: Michele R
authors.initials: MR
authors.lastname: Hacker
authors.forename: Julie S
authors.initials: JS
authors.lastname: Rhee
authors.forename: John
authors.initials: J
authors.lastname: Mitchell
authors.forename: Feroze
authors.initials: F
authors.lastname: Mahmood
authors.forename: Philip
authors.initials: P
authors.lastname: Hess
authors.forename: Caitlin
authors.initials: C
authors.lastname: Farrell
authors.forename: Nicole
authors.initials: N
authors.lastname: Koulisis
authors.forename: Eliyahu V
authors.initials: EV
authors.lastname: Khankin
authors.forename: Suzanne D
authors.initials: SD
authors.lastname: Burke
authors.forename: Igor
authors.initials: I
authors.lastname: Tudorache
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
authors.forename: Federica
authors.initials: F
authors.lastname: del Monte
authors.forename: Denise
authors.initials: D
authors.lastname: Hilfiker-Kleiner
authors.forename: S Ananth
authors.initials: SA
authors.lastname: Karumanchi
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Arany
mesh_terms: D000818:Animals; D001971:Bromocriptine / Q000494:pharmacology / Q000627:therapeutic use; D009202:Cardiomyopathies / Q000097:blood / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011225:Pre-Eclampsia / Q000503:physiopathology; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000097:blood / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology*; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology / Q000627:therapeutic use; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D001971:Bromocriptine; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1