Our long term objective is to investigate the role of the autonomic nervous system in precipitating and maintaining cardiac arrhythmias responsible for sudden cardiac death in hearts with coronary artery disease and ventricular hypertrophy. While the importance of the autonomic nervous system in this regard is indisputable, many of the mechanisms by which it operates are unknown. We do-know that ischemia/infarction alters the autonomic innervation patterns to the ventricles. But how these changes contribute to sudden cardiac death is still a puzzle. For the heart with ventricular hypertrophy, the role of the autonomic nervous system in arrhythmogenesis is virtually uninvestigated. Yet preliminary data from our laboratory suggest an important role for alpha-adrenergic stimulation. What is clear, however, is that structural changes in the ventricles occur in both coronary artery disease and hypertrophy and these structural changes must alter cell-to-cell communication in such a way that the myocardial substrate becomes vulnerable to becoming electrically unstable. In this project we will study autonomic innervation patterns in normal dog and human hearts to be able to compare them with the changes found in coronary artery disease and hypertrophy. We will examine innervation patterns by measuring functional responses in vivo (i.e., changes in effective refractory period, arrhythmia inducibility, and afferent-evoked reflexes) and in vitro (i.e., optical mapping). We will use positron emission tomography (PET) imaging to examine sympathetic and parasympathetic innervation, and myocardial blood flow and metabolism. The functional responses obtained in vivo and in vitro will then be correlated with the PET images and with innervation patterns determined by histological/ immunohistochemical techniques. Once we have characterized the normal hearts we will perform an identical series of investigations, in vivo and in vitro, in hearts with coronary artery disease and hypertrophy. After the initial structural/functional studies, we will then attempt to correct the underlying anatomical and functional derangements caused by myocardial infarction or hypertrophy using cardiomyocyte grafting techniques. Cells that have been genetically engineered to overexpress and release nerve growth factor, transforming growth factor beta1, or fibroblast growth factor will be implanted in the myocardium or injected into the pericardial space. These proteins are important for the maintenance and development of the nervous system or for tissue repair and wound healing. We postulate that these peptides may """"""""normalize"""""""" some of the anatomical and functional abnormalities associated with coronary artery disease and hypertrophy and thereby reduce the propensity for arrhythmia development.
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