Hypoxia Induces Dilated Cardiomyopathy in the Chick Embryo: Mechanism, Intervention, and Long-Term Consequences

Abstract

BackgroundIntrauterine growth restriction is associated with an increased future risk for developing cardiovascular diseases. Hypoxia in utero is a common clinical cause of fetal growth restriction. We have previously shown that chronic hypoxia alters cardiovascular development in chick embryos. The aim of this study was to further characterize cardiac disease in hypoxic chick embryos.MethodsChick embryos were exposed to hypoxia and cardiac structure was examined by histological methods one day prior to hatching (E20) and at adulthood. Cardiac function was assessed in vivo by echocardiography and ex vivo by contractility measurements in isolated heart muscle bundles and isolated cardiomyocytes. Chick embryos were exposed to vascular endothelial growth factor (VEGF) and its scavenger soluble VEGF receptor-1 (sFlt-1) to investigate the potential role of this hypoxia-regulated cytokine.Principal FindingsGrowth restricted hypoxic chick embryos showed cardiomyopathy as evidenced by left ventricular (LV) dilatation, reduced ventricular wall mass and increased apoptosis. Hypoxic hearts displayed pump dysfunction with decreased LV ejection fractions, accompanied by signs of diastolic dysfunction. Cardiomyopathy caused by hypoxia persisted into adulthood. Hypoxic embryonic hearts showed increases in VEGF expression. Systemic administration of rhVEGF165 to normoxic chick embryos resulted in LV dilatation and a dose-dependent loss of LV wall mass. Lowering VEGF levels in hypoxic embryonic chick hearts by systemic administration of sFlt-1 yielded an almost complete normalization of the phenotype.Conclusions/SignificanceOur data show that hypoxia causes a decreased cardiac performance and cardiomyopathy in chick embryos, involving a significant VEGF-mediated component. This cardiomyopathy persists into adulthood.

Impaired myocardial performance in a normotensive rat model of intrauterine growth restriction

“…In this context, it could be shown in vitro that mechanical stress to cardiomyocytes induces VEGF (34). Accordingly, Tintu et al (5) described the phenotype of a dilated cardiomyopathy and an increased expression of VEGF in chick embryos after hypoxia-induced IUGR. In contrast to our findings, Lim et al (7) did not detect any changes in myocardial capillarization in female IUGR rats.…”

“…Moreover, fetal hypoxia, a frequent cause of IUGR, resulted in early alterations of myocardial vasculature and changes in cardiac structure and function resembling dilated cardiomyopathy in chicks (5). The idea of early and primary cardiac changes after IUGR is supported by recent clinical studies.…”

Early onset fetal growth restriction

“…These observations were first made in 1989 by Barker and colleagues and confirmed in the last few decades [17,18]. It has been postulated that cardiovascular remodelling is due to hemodynamic redistribution and adaptation to hypoxia and insufficient nutrition [17][18][19][20][21][22].…”

The role of blood flow and microRNAs in blood vessel development

“…Hypoxia is known to stimulate the expression of arterial markers in endothelial (progenitor) cells in vitro. Surprisingly, exposing the developing embryo to global hypoxia, reduced arterial network formation in the yolk sac most likely due to a negative inotropic effect of hypoxia on cardiac activity (Tintu et al, 2009), resulting in reduced cardiac output and flow delivery to the vitelline circulation.…”