? In infants and children with congenital heart defects, myocardial hypertrophy in response to chronic pressure or volume overload remains one of the most common causes of heart failure. Despite surgical advances, a chronic high workload state is a common problem seen in management of congenital heart defects and often results in contractile dysfunction and poor tolerance to ischemia imposed by cardiac surgery. To further investigate mechanisms responsible for progression of compensated hypertrophy to decompensated with ventricular dilatation and failure, we have developed a model of pressure-overload hypertrophy from aortic banding of rabbits at 10 days of age, where ventricular hypertrophy progresses from compensated to severe hypertrophy, followed by ventricular dilatation and failure over a 7-8 week period. Concomitant with these changes there is a decline in microvascular density in severe hypertrophy, with impaired substrate delivery and mitochondrial oxidative capacity. We hypothesize that in pressure-overload hypertrophy, the stimulus for myocyte hypertrophy does not result in a concomitant trigger for capillary growth leading to an imbalance of substrate demand to supply. Furthermore, we postulate that activity of hypoxia inducible factor (HIF), the main regulator of adaptive changes to hypoxia in tissues, decreases as hypertrophy progresses to failure. We also postulate that interventions that activate/upregulate HIF will promote capillary growth in pressure-overload hypertrophy and will maintain the normal balance between substrate supply and demand. To test this hypothesis we will pursue two interrelated aims:
aim i. determine the activity/expression of hif-1 o_in hypertrophied heart and effects of therapeutic hif activation/upregulation on microvascular density.
aim ii - determine the role of mitochondrial dysfunction in regulation of hif- 1a signaling in the hypertrophied myocardium. these studies will provide an improved understanding of the mechanism responsible for the development of heart failure in pressure-overload hypertrophy and will evaluate therapeutic strategies to prevent the onset of failure and improve tolerance to ischemia in hypertrophied myocardium. ? ?
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