NEURONAL AND DEVELOPMENTAL REGULATION OF PACEMAKER CHANNELS

The general hypotheses of Project 1 center on remodeling of cardiac repolarization and rate as follows: (1) postnatal electrophysiologic modeling of ventricular myocardium results in evolution of transmural gradients for repolarization and its dispersion which, when excessive may be arrhythmogenic; (2) engineered pacemaker channels expressed in specific regions of the heart will develop regular, autonomic-responsive rhythms. Testing these hypotheses will satisfy the two major goals of Project 1: (1) to understand the evolution of ventricular repolarization in developing hearts, its clinical implications and its linkage to sympathetic innervation and angiotensin II, and (2) to learn whether specific pacemaker constructs expressed in vivo can determine cardiac rhythm. In studies of intact animals, isolated tissues and single myocytes in canine and rat models, our 5 aims are to test the following hypotheses: 1: Evolution of transmural dispersion of repolarization and of rate adaptation depends importantly on evolution of I-to, I-Kr and I-Ks; 2: The distribution of I-to, I-Kr and I-Ks in epi-, endo- and midmyocardium in young hearts predisposes to proarrhythmic actions of I-Kr blocking drugs; 3: In canine ventricle developmental evolution of a transmural gradient for KChlP2 around days 40-60 of age determines the transmural gradient for I-to; 4A: Endogenous angiotensin II modulates developmental evolution of repolarization; 4B: The postnatal changes in I-Ks are modulated by sympathetic innervation, such that denervation will slow the evolution of I-Ks and expression of the transmural gradient; 4C: The general hypotheses of Project 1 center on remodeling of cardiac repolarization and rate as follows: (1) postnatal changes in I-to are modulated by sympathetic innervation and the cardiac angiotensin II pathway; 5: Specific alpha and beta subunit constructs of the pacemaker channel can function as pacemakers in the heart in situ. This research will help us understand the mechanisms underlying postnatal evolution of repolarization and rate, and their modulation. The implications are far-reaching in light of the potential lethality of specific pathophysiologic events inducing arrhythmias in children and adults and the need for better understanding of etiology, prevention and treatment. Moreover, if the engineering of pacemaker current can provide reproducible, consistent impulse initiation for the heart this will suggest important new therapeutic directions for treatment of sinus node dysfunction and of heart block.