Publication Date:
2012-05-19
Description:
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-1alpha, 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-1alpha. 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356917/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356917/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Patten, Ian S -- Rana, Sarosh -- Shahul, Sajid -- Rowe, Glenn C -- Jang, Cholsoon -- Liu, Laura -- Hacker, Michele R -- Rhee, Julie S -- Mitchell, John -- Mahmood, Feroze -- Hess, Philip -- Farrell, Caitlin -- Koulisis, Nicole -- Khankin, Eliyahu V -- Burke, Suzanne D -- Tudorache, Igor -- Bauersachs, Johann -- del Monte, Federica -- Hilfiker-Kleiner, Denise -- Karumanchi, S Ananth -- Arany, Zoltan -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 May 9;485(7398):333-8. doi: 10.1038/nature11040.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22596155" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Bromocriptine/pharmacology/therapeutic use
;
Cardiomyopathies/blood/drug therapy/*etiology/*physiopathology
;
Disease Models, Animal
;
Female
;
Heart/drug effects/physiopathology
;
Humans
;
Kaplan-Meier Estimate
;
Male
;
Mice
;
Mice, Knockout
;
Myocytes, Cardiac/drug effects/metabolism
;
Neovascularization, Pathologic/*complications/drug therapy/*physiopathology
;
Neovascularization, Physiologic/drug effects/physiology
;
Pre-Eclampsia/physiopathology
;
Pregnancy
;
Pregnancy Complications, Cardiovascular/blood/drug
;
therapy/*etiology/*physiopathology
;
Trans-Activators/deficiency/genetics/metabolism
;
Transcription Factors
;
Vascular Endothelial Growth Factor A/pharmacology/therapeutic use
;
Vascular Endothelial Growth Factor
;
Receptor-1/blood/genetics/metabolism/pharmacology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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