ALTERATIONS IN AUTONOMIC INNERVATION AND ELECTROPHYSIOLOGY

我们的长期目标是研究自主神经的作用， 神经系统在诱发和维持心律失常中的作用 导致冠状动脉狭窄的心脏猝死 疾病和心室肥大。虽然重要的是， 自主神经系统在这方面是无可争议的，许多 其运作机制尚不清楚。我们知道 缺血/梗死改变了自主神经支配模式， 心室但这些变化如何导致心脏性猝死， 还是个谜对于伴有心室肥大的心脏， 胚胎发生过程中自主神经系统 未经调查然而，我们实验室的初步数据表明， α-肾上腺素能刺激的重要作用。但有一点很清楚， 心室的结构变化发生在两个冠状动脉 动脉疾病和肥大，这些结构变化必须改变 细胞与细胞之间的通讯， 变得容易变得电不稳定。在这个项目中，我们 将研究正常狗和人类心脏的自主神经支配模式 与冠状动脉的变化进行比较 疾病和肥大。我们将研究神经支配模式， 测量体内功能反应（即，有效变化 不应期、诱发性心律失常和传入诱发反射） 和体外（即，光学映射）。我们将使用正电子发射 断层扫描（PET）成像检查交感神经和副交感神经 神经支配和心肌血流和代谢。功能 然后将在体内和体外获得的反应与 PET图像和通过组织学/病理学确定的神经支配模式 免疫组织化学技术。一旦我们确定了 心脏，我们将进行一系列相同的调查，在体内， 在体外，在患有冠状动脉疾病和肥大的心脏中。后 初步的结构/功能研究，然后我们将尝试 纠正潜在的解剖和功能紊乱， 使用心肌细胞移植的心肌梗塞或心肌肥大 技术.经过基因工程改造的细胞 并释放神经生长因子、转化生长因子β 1或 将成纤维细胞生长因子植入心肌或注射 进入心包腔这些蛋白质对于 神经系统的维持和发育或组织修复 和伤口愈合。我们假设这些肽可以“正常化”一些 与冠状动脉相关的解剖和功能异常 动脉疾病和肥大，从而减少 心律失常的发展。

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.