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. 2012 May 9;485(7398):333-8.
doi: 10.1038/nature11040.

Cardiac angiogenic imbalance leads to peripartum cardiomyopathy

Ian S Patten  1 , 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, Zoltan Arany
Affiliations

Cardiac angiogenic imbalance leads to peripartum cardiomyopathy

Ian S Patten et al. Nature. .

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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Conflict of interest statement

COMPETING FINANCIAL INTERESTS

S.A.K is a co-inventor on multiple patents held by the Beth Israel Deaconess Medical Center that is related to the use of angiogenic proteins for diagnosis and treatment of pre-eclampsia. S.A.K. has financial interest in Aggamin Therapeutics. All other authors report no competing financial interests.

Figures

Figure 1
Figure 1. Mice lacking cardiac PGC-1α develop peri-partum cardiomyopathy
a, Kaplan-Meier survival curve in female αMHC-Cre: PGC-1αlox/lox mice (F HKO), versus HKO males or control mice of either gender (M/F CT). b, Hematoxylin and Eosin and Masson Trichrome stains of hearts from post-partum HKO mice (PP HKO), versus CT mice (PP CT). c–d, Heart weight (c) and heart weight/tibial length ratios (d) of nulliparous CT and HKO mice, and after two pregnancies (PP). e, Sample M-mode echocardiograms of PP HKO mice, and control mice containing the αMHC-Cre transgene alone (PP CRE). f–i, Echocardiographic measures in mice of the indicated genotypes, either nulliparous or post-partum (PP). n≥5 for all groups. *p<0.05
Figure 2
Figure 2. PGC-1α regulates an angiogenic program in cardiomyocytes
a–b, Relative expression of mitochondrial genes (cycs and cox5b) and angiogenic genes (vegfa, pdgfb, bfgf) in neonatal rat ventricular myocytes (NRVMs) infected with adenovirus expressing PGC-1α versus GFP (a), or siPGC-1α versus siCtrl (b). c–d, PGC-1α expression in NRVMs induces the migration of adjacent endothelial cells, and the migration is blocked by sFlt1. Representative images (c) show phalloidin-stained endothelial cells that have migrated towards the NRVMs. Experimental procedure is schematized in bottom panel. Data are quantified in (d). e, Knockdown of PGC-1α inhibits the migration of endothelial cells. Error bars are +/− SE. *p<0.05 versus control. †p<0.05 versus cells not treated with sFlt1.
Figure 3
Figure 3. Mice lacking cardiac PGC-1α have reduced microvascular density that is worsened by pregnancy
a–b, Relative mRNA expression of the indicated genes (a) and VEGF protein levels (b) in HKO versus control hearts. c–d, Vascular density in hearts from CT and HKO mice nulliparous or post-partum (PP). Representative images stained for CD31 (PECAM) are shown in c, and quantified in d. e–f, Reduced cardiac MIBI uptake in PP HKO versus PP CT animals. Representative SPECT/CT images are shown in f, and quantified in e. n≥5 for all groups. Error bars are +/− SE. *p<0.05 versus control.
Figure 4
Figure 4. Combined treatment with VEGF and Bromocriptine rescues PPCM in PGC-1α HKO mice
a, Schema of proposed role of cardiac PGC-1α in the regulation of cardiac angiogenesis, and defending against pregnancy-induced anti-angiogenic factors. b, Experimental outline. c, Sample echocardiograms from PP HKO, PP CRE, and PP HKO mice receiving both bromocriptine and VEGF treatments (PP HKO + Br/VEGF). d–h, Indicated echocardiographic measures (d–f), heart weight (g), and heart weight/tibial length ratio (h), in post-partum mice of the indicated genotypes. n≥5 for all groups. Error bars are +/− SE. *p<0.05 versus PP CRE control. †p<0.05 versus PP HKO.
Figure 5
Figure 5. Women with pre-eclampsia have depressed cardiac function that correlates with circulating sFlt1 levels, and sFlt1 causes cardiac dysfunction in mice
a, Sample tracing of tissue Doppler imaging. MPI: myocardial performance index. IVCT: isovolemic contraction time. IVRT: isovolemic relaxation time. b–c, Elevated MPI (b) and E/E′ (c) in women with pre-eclampsia (PE) versus normal (NL) pregnancies. p=0.01 and p=0.02, respectively. d, Elevated MPI correlates with sFlt1 levels. R=.59. p=0.003. e, Elevated MPI in pregnant mice infected with adenovirus expressing sFlt1. p=0.01 n≥5 for all groups. *p<0.05 versus control.
Figure 6
Figure 6. sFlt1 is sufficient to induce cardiomyopathy in HKO mice, women with PPCM have elevated sFlt1 levels, and pre-eclampsia as a risk factor for PPCM
a–c, Heart weight/tibial length ratios (a), echocardiographic fractional shortening (b), and LV end-systolic dimensions (c) in HKO mice injected with adenovirus expressing sFlt1, versus controls. d, Elevated sFlt1 levels in post-partum women with PPCM. p=0.002. e–f, Prevalence of pre-eclampsia among all deliveries (e) and among women with PPCM (f) at Harvard teaching hospitals in the previous 9 years.
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