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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-1?, 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-1?. 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.

SUBMITTER: Patten IS

PROVIDER: S-EPMC3356917 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Cardiac angiogenic imbalance leads to peripartum cardiomyopathy.

Patten Ian S IS Rana Sarosh S Shahul Sajid S Rowe Glenn C GC Jang Cholsoon C Liu Laura L Hacker Michele R MR Rhee Julie S JS Mitchell John J Mahmood Feroze F Hess Philip P Farrell Caitlin C Koulisis Nicole N Khankin Eliyahu V EV Burke Suzanne D SD Tudorache Igor I Bauersachs Johann J del Monte Federica F Hilfiker-Kleiner Denise D Karumanchi S Ananth SA Arany Zoltan Z

Nature 20120509 7398

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 ...[more]

PMID: 22596155

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Project description:BackgroundIn peripartum cardiomyopathy, the prevalence of focal myocardial damage detected by late gadolinium enhancement (LGE) cardiovascular magnetic resonance is important to elucidate mechanisms of myocardial injury and cardiac dysfunction. LGE equates irreversible myocardial injury, but LGE prevalence in peripartum cardiomyopathy is uncertain.Methods and resultsAmong 100 women enrolled within the Investigations of Pregnancy Associated Cardiomyopathy cohort, we recruited 40 women at 13 centers to undergo LGE cardiovascular magnetic resonance, enrolled within the first 13 weeks postpartum. Follow-up scans occurred at 6 months postpartum, and death/transplant rates at 12 months. Baseline characteristics did not differ significantly in the parent cohort according to cardiovascular magnetic resonance enrollment except for mechanical circulatory support. LGE was noted only in 2 women (5%) at baseline. While left ventricular dysfunction with enlargement was prevalent at baseline cardiovascular magnetic resonance scans (eg, ejection fraction 38% [Q1-Q3 31-50%], end diastolic volume index=108 mL/m2 [Q1-Q3 83-134 mL/m2]), most women demonstrated significant improvements at 6 months, consistent with a low prevalence of LGE. LGE was not related to baseline clinical variables, ejection fraction, New York Heart Association heart failure class, or mortality. Neither of the 2 women who died exhibited LGE. LGE was inversely associated with persistent left ventricular ejection fraction at 6 months (P=0.006).ConclusionsFactors other than focal myocardial damage detectable by LGE explain the initial transient depressions in baseline left ventricular ejection fraction, yet focal myocardial damage may contribute to persistent myocardial dysfunction and hinder recovery in a small minority. Most women exhibit favorable changes in ventricular function over 6 months.Clinical trial registrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT01085955.

Dataset Information

Cardiac angiogenic imbalance leads to peripartum cardiomyopathy.

Publications

Cardiac angiogenic imbalance leads to peripartum cardiomyopathy.

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