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Shahul, Sajid

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Shahul

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Sajid

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Shahul, Sajid
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    Cardiac Angiogenic Imbalance Leads to Peripartum Cardiomyopathy
    (Nature Publishing Group, 2012) Patten, Ian S.; Farrell, Caitlin; Tudorache, Igor; Bauersachs, Johann; Hilfiker-Kleiner, Denise; Rana, Sarosh; Shahul, Sajid; Rowe, Glenn C; Jang, Cholsoon; Liu, Laura; Hacker, Michele; Rhee, Julie S.; Mitchell, John; Mahmood, Feroze-Ud-Den; Hess, Philip; Koulisis, Nicole; Khankin, Eliyahu; Burke, Suzanne; Del Monte, Federica; Karumanchi, Subbian; Arany, Zoltan Pierre
    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-\(1\alpha\), 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-\(1\alpha\). 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.