? Both autologous skeletal myoblasts and bone marrow mononuclear cells have been used in Phase 1 clinical trials to treat CHF - sometimes with negative outcomes. We propose that these undesired results arise from a lack of understanding of the appropriate cell type and delivery conditions for a given cardiac injury. We hypothesize that different cell types, doses, locations for cell delivery and/or routes of administration are necessary to maximize function with minimal toxicity (e.g. electrical abnormalities) - depending on whether the injury is acute (MI) or chronic (HF). Our ultimate goal is to define cell delivery scenarios that increase function with a minimum of risk. We will test our hypothesis via three specific aims: 1) In both acute and chronic models of cardiac injury, we will alter cell type (myoblasts vs. bone marrow mononuclear cells) and delivery profiles (dose, location, route of delivery) and compare the ability to maximize regional and global contractility or to positively impact remodeling. 2) We will investigate the mechanism of functional improvement by quantifying cell retention, survival and biodistribution; by histologically analyzing the location, potential electromechanical connectivity, and phenotype of injected cells; and by determining the impact of cell type and delivery parameters on cardiac, skeletal muscle and peripheral blood indicators of cardiac injury and heart failure. 3) We will examine the impact of cell type and delivery on safety by: electrical (Holter) monitoring of animals for 1 week to 3 months after delivery of cells; comparing the inducibility and termination of sustained ventricular tachyarhythmias in animals receiving cells under various delivery conditions; correlating electrical findings with functional and histologic outcomes including biodistribution; and retrieving cells from center or periphery of infarcted myocardium for patch clamp analysis of threshold potential, current-voltage relationships and action potential properties. ? ? Accomplishing these aims should allow a comparison of how cell type and delivery affect the safety and efficacy of cardiac myogenesis or CCM in acute and chronic cardiac injury and allow us to better predict what cell profile may be useful in a given clinical scenario. Given the incidence of adverse electrical events observed clinically, determining the safety profile of specific modalities of cardiac cell therapy is critical to establishing cell based CCM as a legitimate therapeutic intervention for ischemic heart disease or congestive heart failure (CHF). ? ?
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