Cardiac angiogenic imbalance leads to peripartum cardiomyopathy

Ian S. Patten, Sarosh Rana, Sajid Shahul, Glenn C. Rowe, Cholsoon Jang, Laura Liu, Michele R. Hacker, Julie S. Rhee, John Mitchell, Feroze Mahmood, Philip Hess, Caitlin Farrell, Nicole Koulisis, Eliyahu V. Khankin, Suzanne D. Burke, Igor Tudorache, Johann Bauersachs, Federica del Monte, Denise Hilfiker-Kleiner (), S. Ananth Karumanchi and Zoltan Arany ()
Additional contact information
Ian S. Patten: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA
Sarosh Rana: Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA
Sajid Shahul: Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA
Glenn C. Rowe: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA
Cholsoon Jang: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA
Laura Liu: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA
Michele R. Hacker: Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA
Julie S. Rhee: Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA
John Mitchell: Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA
Feroze Mahmood: Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA
Philip Hess: Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA
Caitlin Farrell: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA
Nicole Koulisis: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA
Eliyahu V. Khankin: Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA
Suzanne D. Burke: Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA
Igor Tudorache: Transplantation and Vascular Surgery, Medizinische Hochschule Hannover, Carl-Neuberg Strasse, D-30625 Hannover, Germany
Johann Bauersachs: MedizinischeHochschule Hannover, Carl-Neuberg Strasse, D-30625 Hannover, Germany
Federica del Monte: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA
Denise Hilfiker-Kleiner: MedizinischeHochschule Hannover, Carl-Neuberg Strasse, D-30625 Hannover, Germany
S. Ananth Karumanchi: Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA
Zoltan Arany: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA

Nature, 2012, vol. 485, issue 7398, 333-338

Abstract: 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.

Date: 2012
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DOI: 10.1038/nature11040

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