Heart-related defects are the most common fatal birth defect in the US, with nearly 10,000 infants per year born with a heart defect resulting in death or requiring major surgery for survival. In the long-term, children with surgically corrected structural heart defects must endure a greatly increased chance of developing arrhythmias which can result in sudden cardiac death. Recent studies have recognized a relationship between mechanical properties of the extracellular environment and the maturation, excitability, frequency of spontaneous beating and electrical coupling of cardiac muscle cells. To date, nobody has examined the altered mechanical properties in hearts with structural defects or the direct relation to electrophysiological effects. Additionally, knowledge about single ventricular function and mechanics has lagged behind that of the left or right ventricle. MR studies of cardiac wall motion have indicated that right ventricular (RV) contraction differs considerably from left ventricular (LV) contraction. Whereas LV blood ejection is accomplished by circumferential shortening, RV function is mainly achieved by shortening of its free wall in the longitudinal direction. The LV is considered a better pumping chamber, although the specific mechanical properties that lead to this difference have not been studied. In normal subjects, beneficial ventricular-ventricular interactions between the LV and the RV have been well demonstrated. In functional single ventricles, there is no second ventricle to augment the function of the systemic ventricle. There is evidence of a worse prognosis in patients with a single RV when compared to patients with a single LV, likely related to an intrinsic difference in systolic mechanics between a systemic RV and a systemic LV. An understanding of the electrochemical and mechanical properties of the myocardium in functional single ventricles will lead to the design of better surgical and medical treatment strategies. In order to test the hypothesis that structural alterations in the heart directly alter the electrical conduction properties of cardiac cells, leading to electrophysiological complications, strains in single ventricle hearts will be quantified using MRI-based techniques, and the electrophysiological effect of culturing cardiomyocytes on surfaces allowing those measured strain magnitudes will be evaluated. Measurement of individual ion currents and evaluation of ion channel protein expression will be used to elucidate the electrophysiological mechanisms behind changes in excitability. Finally, effect of gradients in strain magnitude on the electrophysiology of cardiac cells will be quantified. The results of these studies will provide insight into normal cardiac development, electrophysiological complications in hearts with structural congenital defects, and provide constraints for novel therapies aimed at correcting structural defects or regenerating heart tissue.
Though surgical repair options exist for children born with severe heart defects resulting in one ventricle, instead of the normal two ventricles, these children remain at a highly elevated risk of sudden cardiac death, estimated at 25 to 100 times that of the healthy young population. This research study aims to understand the reasons behind the increased risk by focusing on changes in electrical function of the heart that occurs along with single ventricle defects and repairs. The results of this study will more thoroughly explain mechanical and electrical effects in this population of children, and could lead to improved therapies or patient monitoring, that can ultimately reduce sudden cardiac death in children with heart defect.
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