Regions of viable dysfunctional or hibernating myocardium are present in up to 60% of patients with ischemic cardiomyopathy and have a profound negative impact on survival. The increase in mortality appears to be related to a high rate of sudden death (SD) and is supported by similar observations in chronically instrumented pigs with hibernating myocardium where SD is due to spontaneous VT/VF without evidence of infarction, acute ischemia or heart failure. The triggers and substrate factors responsible for SD have not yet been identified but, like humans, there is evidence of sympathetic activation immediately preceding the event. In addition, we have found regional inhomogeneity in sympathetic nerve function assessed with positron emission tomography and 11C-hydroxyephedrine, postsynaptic down-regulation of regional beta-adrenergic-adenylyl cyclase coupling, and reduced functional responses to sympathetic stimulation. Collectively, these observations support the hypothesis that inhomogeneity in sympathetic nerve function is a major determinant of the risk for SD in the setting of hibernating myocardium. This proposal uses an established animal model of chronic hibernating myocardium and patients with ischemic heart disease in conjunction with positron emission tomography, histopathology and protein analyses to address four specific aims.
Aim #1 will test the hypothesis that dysinnervation in viable myocardium is functional and reversible after revascularization, in contrast to denervation associated with infarction.
In Aim #2, animals with SD will be resuscitated with implantable defibrillators in order to determine whether temporal dynamics in neural remodeling, including the severity and extent of sympathetic dysinnervation, nerve sprouting, and myocyte-nerve interactions play a key role in influencing the risk of SD.
Aim #3 will test the hypothesis that preventing inhomogeneity in sympathetic innervation and/or nerve sprouting with global ventricular denervation can prevent SD. Finally, Aim #4 will enroll patients scheduled for coronary artery bypass surgery to define the physiological, histological and molecular factors associated with sympathetic dysinnervation in viable dysfunctional myocardium, and the parameters that determine improvement after revascularization. Therefore, these studies will translate basic observations in animals to clinical pathophysiology in humans and identify novel substrate factors that contribute to the risk of SD in chronic ischemic heart disease.
