Cardiac angiogenic imbalance leads to peripartum cardiomyopathy

Abstract

Peri-partum cardiomyopathy (PPCM) is a frequently fatal disease that affects women near delivery, and occurs more frequently in women with pre-eclampsia and/or multiple gestation. The etiology of PPCM, or why it associates with pre-eclampsia, remains unknown. We show here 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 sub-clinical cardiac dysfunction, the extent of which correlates with circulating levels of sFlt1. Exogenous sFlt1 alone caused diastolic dysfunction in wildtype 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 strongly suggest that PPCM is in large part a vascular disease, caused by excess anti-angiogenic signaling in the peri-partum 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.

Hypoxic Induction of Vascular Endothelial Growth Factor (VEGF) and Angiogenesis in Muscle by Truncated Peroxisome Proliferator-activated Receptor γ Coactivator (PGC)-1α

“…We recently showed that PGC-1␣ also dramatically induces angiogenesis, thereby coordinating oxygen/fuel delivery (via vessels) with their consumption (in mitochondria) (5,6). PGC-1␣ expression is induced by hypoxia in muscle cells and is required for full hypoxic induction of angiogenic genes such as VEGF.…”

Pregnancy and heart disease: what Internists should know

“…In case of preeclampsia sFLt1 is higher and correlates with cardiac dysfunction. 84 Another study that supports angiogenic imbalance is the one of Hilfiker-Kleiner et al These authors demonstrated that mice with a knockout in the cardiac tissue-specific signal transduction and activator of transcription 3 (STAT3) develop PC. 87 Lack of STAT3 produces an increased cleavage of prolactin into an antiangiogenic and proapoptotic 16kDa isoform by cathepsin D. This prolactin fragment is also responsible for endothelial damage and myocardial dysfunction.…”

“…83 This hypothesis has been already introduced in the past, but experimental demonstration supporting it, has been offered only recently. In particular a systemic angiogenic imbalance 84 has been demonstrated on mice lacking cardiac PGC-1 alfa, a regulator of pro-angiogenic factors such as vascular endothelial growth factor (VEGF). These mice developed PC, which was responsive to dual proangiogenic therapy 79,85,86 (VEGF plus bromocriptine).…”

New Developments in the Pathogenesis of Preeclampsia

“…Small studies have shown that levels of sFlt-1 remained higher in women with a history of preeclampsia in the postpartum period 76,77 Whether a persistent anti-angiogenic milieu in the post-partum period may contribute to lasting endothelial dysfunction and an elevated risk of CVD in women remains unknown. Recent studies also suggest that preeclampsia is a major risk factor for peripartum cardiomyopathy and that imbalances in angiogenic factors may be critical for both disorders 78 . Babies born to preeclampsia are also at risk for pulmonary hypertension in the long term 79 .…”