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Cardiac angiogenic imbalance leads to peripartum cardiomyopathy.

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-1?, 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?. 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.

SUBMITTER: Patten IS

PROVIDER: S-EPMC3356917 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Cardiac angiogenic imbalance leads to peripartum cardiomyopathy.

Patten Ian S IS Rana Sarosh S Shahul Sajid S Rowe Glenn C GC Jang Cholsoon C Liu Laura L Hacker Michele R MR Rhee Julie S JS Mitchell John J Mahmood Feroze F Hess Philip P Farrell Caitlin C Koulisis Nicole N Khankin Eliyahu V EV Burke Suzanne D SD Tudorache Igor I Bauersachs Johann J del Monte Federica F Hilfiker-Kleiner Denise D Karumanchi S Ananth SA Arany Zoltan Z

Nature 20120509 7398

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 ...[more]

PMID: 22596155

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Project description:AimsPeripartum cardiomyopathy (PPCM) may result in a number of detrimental adverse cardiovascular events, notably persistent left ventricular ejection fraction (LVEF) reduction or even mortality. Imaging parameters on cardiac magnetic resonance (CMR) and their prognostic implications have rarely been perused in PPCM. We aimed to describe CMR's prognostic value in predicting poor left ventricular (LV) function recovery using late gadolinium enhancement (LGE) and T2-weighted or T2 mapping.Methods and resultsPubMed, Europe PMC, and ScienceDirect were screened for studies on late gadolinium enhancement (LGE) and myocardial oedema using CMR and PPCM. The outcome of interest was poor LV function recovery, with a follow-up period of at least 6 months. Comparisons between groups with the presence of LGE, myocardial oedema, and recovered against non-recovered patients were pooled. A random-effects model was employed to calculate the effect size. All pooled results were expressed as risk ratios (RRs) and 95% confidence intervals (CI). The area under the curve (AUC) was generated to test overall prognostic accuracy. Six cohort studies with 162 patients were included. The mean age of participants in this study was 30.6 years, and the majority of patients were diagnosed with PPCM after delivery. LGE was associated with a higher risk of poor LV function recovery, particularly when conducted at a later stage of disease (≥2.8 months) [RR = 2.83 (95% CI = 1.25-6.40); P = 0.001]. On the contrary, CMR conducted early (<2.8 months) exhibited a greater predictive value for myocardial oedema perceived by T2 mapping [RR = 3.44 (95% CI = 1.04-11.34); P = 0.043]. Diagnostic-test accuracy meta-analysis revealed that LGE had a sensitivity of 73% (95% CI, 56-85%), specificity of 79% (95% CI, 45-95%), and AUC of 0.78 (95% CI, 0.75-0.82) in predicting poor LV recovery when performed in the later phase, whereas significant myocardial oedema in those with non-recovered LV function had a sensitivity of 12% (95% CI, 2-52%), specificity of 68% (95% CI, 39-88%), and AUC of 0.40 (95% CI, 0.36-0.44) while undertaken in the latter phase. Our findings support the notion that inflammation plays a significant role in PPCM and that alterations to tissue composition occur in a time-dependent manner.ConclusionsContrast-enhanced CMR can be utilized as an adjunct examination in post-partum PPCM patients to stratify the risk of poor LV function recovery while conducted at a suitable point in time.

Project description:BackgroundPregnancy imposes significant cardiovascular adaptations, including progressive increases in plasma volume and cardiac output. For most women, this physiological adaptation resolves at the end of pregnancy, but some women develop pathological dilatation and ultimately heart failure late in pregnancy or in the postpartum period, manifesting as peripartum cardiomyopathy (PPCM). Despite the mortality risk of this form of heart failure, the molecular mechanisms underlying PPCM have not been extensively examined in human hearts.MethodsProtein and metabolite profiles from left ventricular tissue of end-stage PPCM patients (N=6-7) were compared with dilated cardiomyopathy (DCM; N=5-6) and nonfailing donors (N=7-18) using unbiased quantitative mass spectrometry. All samples were derived from the Sydney Heart Bank. Data are available via ProteomeXchange with identifier PXD055986. Differential protein expression and metabolite abundance and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed.ResultsProteomic analysis identified 2 proteins, SBSPON (somatomedin B and thrombospondin type 1 domain-containing protein precursor) and TNS3 (tensin 3), that were uniquely downregulated in PPCM. SBSPON, an extracellular matrix protein, and TNS3, involved in actin remodeling and cell signaling, may contribute to impaired tissue remodeling and fibrosis in PPCM. Metabolomic analysis revealed elevated levels of homogentisate and deoxycholate and reduced levels of lactate and alanine in PPCM, indicating disrupted metabolic pathways and glucose utilization. Both PPCM and DCM shared pathways related to inflammation, immune responses, and signal transduction. However, thyroid hormone signaling was notably reduced in PPCM, affecting contractility and calcium handling through altered expression of PLN (phospholamban) and Sarcoendoplasmic Reticulum Calcium ATPase (SERCA). Enhanced endoplasmic reticulum stress and altered endocytosis pathways in PPCM suggested additional mechanisms of energy metabolism disruption.ConclusionsThe present study reveals unique posttranslational molecular features of the PPCM myocardium, which mediates cellular and metabolic remodeling, and holds promise as potential targets for therapeutic intervention.

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Cardiac angiogenic imbalance leads to peripartum cardiomyopathy.

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Cardiac angiogenic imbalance leads to peripartum cardiomyopathy.

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