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Cardiac angiogenic imbalance leads to peripartum cardiomyopathy

Nature volume 485, pages 333–338 (2012)Cite this article

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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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Figure 1: Mice lacking cardiac PGC-1α develop peri-partum cardiomyopathy.
Figure 2: PGC-1α regulates an angiogenic program in cardiomyocytes.
Figure 3: Mice lacking cardiac PGC-1α have reduced microvascular density that is worsened by pregnancy.
Figure 4: Combined treatment with VEGF and bromocriptine rescues PPCM in PGC-1α HKO mice.
Figure 5: Women with pre-eclampsia have depressed cardiac function that correlates with circulating sFLT1 levels, and sFLT1 causes cardiac dysfunction in mice.
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.

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Acknowledgements

S.R. is supported by a Harvard Faculty Development and Diversity Award. S.S is supported by a John Hedley White grant. G.C.R. is supported by a Merck Fellowship. M.R.H. is supported by Harvard Catalyst, the Clinical and Translational Science Center, and Harvard University and affiliated academic health care centers. S.A.K. is an investigator of the Howard Hughes Medical Institute. Z.A. is supported by the NHLBI, the Smith Family Foundation, the Ellison Medical Foundation, the March of Dimes Foundation, and the Harvard Stem Cell Institute.

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  1. Ian S. Patten and Sarosh Rana: These authors contributed equally to this work.

Authors and Affiliations

  1. Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA ,

    Ian S. Patten, Glenn C. Rowe, Cholsoon Jang, Laura Liu, Caitlin Farrell, Nicole Koulisis, Federica del Monte & Zoltan Arany

  2. Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA ,

    Ian S. Patten

  3. Division of Maternal Fetal Medicine/Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA,

    Sarosh Rana, Michele R. Hacker & Julie S. Rhee

  4. Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA,

    Sajid Shahul, John Mitchell, Feroze Mahmood & Philip Hess

  5. Division of Nephrology/Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA,

    Eliyahu V. Khankin, Suzanne D. Burke & S. Ananth Karumanchi

  6. Department of Cardiothoracic, Transplantation and Vascular Surgery, Medizinische Hochschule Hannover, Carl-Neuberg Strasse, D-30625 Hannover, Germany,

    Igor Tudorache

  7. Department of Cardiology and Angiology, MedizinischeHochschule Hannover, Carl-Neuberg Strasse, D-30625 Hannover, Germany,

    Johann Bauersachs & Denise Hilfiker-Kleiner

  8. Howard Hughes Medical Institute, 330 Brookline Avenue, Boston, 02115, Massachusetts, USA

    Suzanne D. Burke & S. Ananth Karumanchi

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Contributions

I.S.P. performed the majority of the mouse experimental work, with the assistance of G.C.R, L.L., N.K. and C.F. The clinical MPI study was preformed by S.R., S.S., J.S.R., M.R.H., J.M., F. M. and P.H. sFLT1 measurements were performed by S.R. MPI studies were performed by E.V.K. and S.D.B. The endothelial migration studies were performed by L.L. and C.J. Samples from women with PPCM were provided by J.B., F.d.M., I.T. and D.H.-K. These authors also provided input on the manuscript. The study was conceived and supervised by S.A.K. and Z.A. The experimental procedures were designed by Z.A., who also wrote the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Denise Hilfiker-Kleiner or Zoltan Arany.

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Competing interests

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

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Patten, I., Rana, S., Shahul, S. et al. Cardiac angiogenic imbalance leads to peripartum cardiomyopathy. Nature 485, 333–338 (2012). https://doi.org/10.1038/nature11040

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