In the previous 11 years of the grant, our laboratory uncovered and characterized the electrical heterogeneity intrinsic to canine ventricular myocardium. Epicardium, endocardium and a unique population of cells termed M cells were shown to differ with respect to electrophysiological function and responsiveness to drugs. These distinctions were then shown to underlie the various waveforms of the ECG and when amplified to create the substrate for the development of life-threatening ventricular arrhythmias, including the polymorphic ventricular arrhythmias associated with the congenital long QT, short QT, and Brugada syndromes as well as catecholaminergic ventricular tachycardia (VT). Recently, we and others have linked the long QT, short QT and Brugada syndromes to sudden death in children and infants and provided evidence that these mechanisms may contribute in small part to sudden infant death syndrome (SIDS). In the last period of the grant, we defined the developmental stages at which these electrical and pharmacologic heterogeneities arise in the canine heart so as to better understand how ion channel dysfunction may contribute to manifestation of these hereditary syndromes in early stages of life. In the next period of the grant we propose to 1) examine the characteristics of the experimental models of long QT, short QT and Brugada syndromes previously developed in adult canine ventricular wedge preparations, in wedge preparations from neonatal hearts; 2) extend our findings to mechanical aspects of transmural heterogeneity, defining distinctions in cell shortening and calcium transients among the three cell types and their change with development; and 3) examine to what extent electrical and pharmacologic heterogeneity uncovered in the ventricle apply to the atria at each stage of development. The principal goals of our competitive renewal are to probe the extent to which mechanical heterogeneity complements transmural electrical heterogeneity within the ventricles of the heart at each stage of development and how accentuation of these transmural distinctions contributes to the development of life-threatening ventricular and atrial arrhythmias. Our long-range goal is to generate information that will contribute meaningfully to our understanding of arrhythmic death in infants and young children. ? ? ? ? ?
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