Transmural Variation in Cellular Level Contraction

Heart failure afflicts 6 million Americans and costs the United States $40 billion per year. Despite intensive efforts, treatment options for heart failure remain limited and the 5 year survival rate remains ~50%. New strategies are urgently required. Transmural variation in contractile function has rarely been studied by basic scientists but is potentially clinically significant. For example, imaging studies have shown that shortening of the middle transmural region is a better predictor of cardiovascular death than traditional functional measures, such as ejection fraction [1, 2]. Guidelines published by the American Society of Echocardiography also emphasize the importance of mid-myocardial contractility [3]. This revised project extends on the PI’s recent findings [4] that (a) non-failing human hearts exhibit transmural variation in contractile strength and (b) that heart failure disrupts the normal pattern. Specifically, in non-failing hearts, mid-myocardial tissue develops more force and more power than sub-endocardial and sub-endocardial regions. Heart failure depresses overall force and power and eliminates the transmural variation. Preliminary data suggest that these functional effects are driven primarily by changes in collagen content. Aim 1 will investigate this hypothesis by comparing functional measurements performed using multicellular preparations (which include extracellular matrix) and single cells (which do not). The hypothesis is that single cell function will not vary markedly with region and disease status while tissue level function increases with the proportion of tissue that is occupied by myocytes. Aim 2 will perform similar experiments using myocardial samples obtained from the same patients before and after they have been treated with a ventricular assist device. These experiments will determine whether mechanical support alters fibrosis and/or cell-level function. Finally, Aim 3 will use advanced finite element computer modeling to determine how the different transmural patterns impact global ventricular function. These calculations will link the cell and tissue-level results from the first two aims to organ-level behavior. All of experiments will be performed using human samples from the University of Kentucky cardiac biobank which currently contains ~2500 samples from 170 patients and organ donors. Aim 1: Determine how collagen impacts the force and power developed by myocardial samples from different transmural regions of non-failing and failing hearts. Hypothesis: Contractile function increases with the proportion of myocardium occupied by myocytes. Aim 2: Determine whether treatment with a ventricular assist device produces region-specific effects. Hypothesis: In vivo mechanical support with a ventricular assist device produces larger functional improvements in myocardial samples isolated from the mid-myocardium than in samples isolated from other regions. Aim 3: Determine how transmural patterns of myocardial function impact global ventricular function. Hypothesis: Increasing mid-myocardial contractile strength optimizes the efficiency of ventricular function.