In the U.S. more than one million patients sustain left ventricular (LV) injury after myocardial infarction (Ml). Many adapt to the loss of contractile function and the myocardial scar by infarct expansion, global LV dilatation and reduced contractility. This post Ml process is termed remodeling. The broad goal of this proposal is to better understand how early regional biomechanical changes in regional strain after Ml relate to graded remodeling. Increased strain that may be defined as dimensional changes or stretch results from alteration of LV geometry. It is the product of infarct size and ventricular load. We will test the hypothesis that remodeling at 10weeks after Ml in an ovine model can be predicted by increases in regional strain detected at seven days following infarction. We believe we will be able to detect a threshold of area! strain that will be associated with a 40% increase in free wall diastolic dimension. We want to know how strain affects excitation contraction coupling (ECC) and Ca2+ signaling in ventricular myocytes. Because the myocyte stretch response includes mechanotransduction of various intracellular signaling programs that affect Ca2+ handling and ECC, we will study coordinate changes in select proteins, including the phosphoinositide 3'kinase (P13K) family. We uniquely will reduce post Ml strain below threshold for remodeling post Ml strain by catheter based micro ventricular assist blood pump. Reduction of strain will permit us to observe its effect on post Ml remodeling and the molecular processes we determined in the unregulated strain condition. This proposal brings together the unique combination of expertise required to complete the aims. Regional strain will be measured by embedded crystal array, ECC will be evaluated by Ca2+ handling derived from regional single cell isolates, and molecular analysiswill be completed on regional tissue and single cells. The strain history of the regional cell and tissue samples will be known. New knowledge from this work will permit us to have a greater appreciation of the strain-stretch response on remodeling. The experiments and methods are designed to be translated to patients. We need to know when hearts will remodel after Ml and need to gain insight into critical molecular processes for possible future medical therapies. Accordingly, we will learn the impact of controlled strain after large infarction with an interventionally applied micro VAD.
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