Cardiac angiogenic imbalance leads to peripartum cardiomyopathy |
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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 |
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Institution: | Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA. |
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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. |
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