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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bromocriptine / pharmacology
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Bromocriptine / therapeutic use
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Cardiomyopathies / blood
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Cardiomyopathies / drug therapy
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Cardiomyopathies / etiology*
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Cardiomyopathies / physiopathology*
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Disease Models, Animal
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Female
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Heart / drug effects
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Heart / physiopathology
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Humans
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Kaplan-Meier Estimate
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Male
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Mice
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Mice, Knockout
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Myocytes, Cardiac / drug effects
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Myocytes, Cardiac / metabolism
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Neovascularization, Pathologic / complications*
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Neovascularization, Pathologic / drug therapy
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Neovascularization, Pathologic / physiopathology*
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Neovascularization, Physiologic / drug effects
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Neovascularization, Physiologic / physiology
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Pre-Eclampsia / physiopathology
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Pregnancy
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Pregnancy Complications, Cardiovascular / blood
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Pregnancy Complications, Cardiovascular / drug therapy
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Pregnancy Complications, Cardiovascular / etiology*
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Pregnancy Complications, Cardiovascular / physiopathology*
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Trans-Activators / deficiency
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription Factors
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Vascular Endothelial Growth Factor A / pharmacology
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Vascular Endothelial Growth Factor A / therapeutic use
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Vascular Endothelial Growth Factor Receptor-1 / blood
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Vascular Endothelial Growth Factor Receptor-1 / genetics
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Vascular Endothelial Growth Factor Receptor-1 / metabolism
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Vascular Endothelial Growth Factor Receptor-1 / pharmacology
Substances
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Ppargc1a protein, mouse
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Trans-Activators
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Transcription Factors
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Vascular Endothelial Growth Factor A
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Bromocriptine
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FLT1 protein, human
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Vascular Endothelial Growth Factor Receptor-1