Recent studies by our group and others have demonstrated that ventricular myocardium is not homogeneous as previously thought, but is comprised of at least three electrophysiologically and functionally distinct cell types: epicardium, endocardium and a unique population of cells that we termed M cells, displaying characteristics intermediate between those of ventricular myocardial and Purkinje cells. The three cell types differ with respect to early and late repolarization characteristics. These distinctions have been shown to underlie the various waveforms of the ECG and when amplified create the substrate for the development of life-threatening ventricular arrhythmias, including the polymorphic ventricular arrhythmias associated with the long QT and Brugada syndromes. We and others have recently reported that both syndromes may also be responsible for sudden death in children and infants and may contribute at some level to sudden infant death syndrome (SIDS). Our basis for understanding the mechanisms involved are hampered by the near total absence of data regarding the developmental aspects of electrical heterogeneity in ventricular myocardium of larger mammals. An urgent need to close this gap in our knowledge is the motivating force and the principal aim of this competing renewal. Our objectives are to define the developmental stages at which these heterogeneities normally arise in the canine heart and to probe how ion channel defects known to contribute to the long QT and Brugada syndromes may intervene to disrupt the normal electrical function of the heart and set the stage for malignant arrhythmias in the early stages of life. Our principal goals are to probe the extent to which electrical heterogeneity exists within the heart at each stage of development, to identify the underlying mechanisms as well as the conditions and interventions that amplify or diminish the intrinsic differences in regional electrical behavior and to examine to what extent transmural electrical heterogeneity is responsible for developmental changes in the ECG. To achieve these goals, we propose to use a multilevel approach designed to provide and integrate voltage clamp and action potential data from isolated myocytes, tissues and arterially perfused canine ventricular wedge preparations. Our long-range goal is to generate information that will contribute to our understanding of the causes for arrhythmic death in infants and young children.
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