ALTERATIONS IN AUTONOMIC INNERVATION AND ELECTROPHYSIOLOGY

我们的长期目标是研究自主神经的作用 诱发和维持心律失常的神经系统 冠状动脉疾病患者心源性猝死的原因 疾病和心室肥厚。虽然这一点很重要 自主神经系统在这方面是无可争辩的，许多 它的运作机制尚不清楚。我们确实知道这一点 缺血/梗死改变自主神经支配模式 脑室。但这些变化如何导致心源性猝死 仍然是个谜。对于有心肌肥厚的心脏来说，其作用 自主神经系统在心律失常发生中的作用 未经调查。然而，我们实验室的初步数据表明， 对α-肾上腺素能刺激的重要作用。然而，有一点是明确的， 心脏的结构变化在两个冠状动脉中都会发生 动脉疾病和肥厚以及这些结构性变化必须改变 细胞间的通讯方式使心肌底物 变得容易变得不稳定。在这个项目中，我们 将研究正常狗和人心脏的自主神经支配模式 能够将它们与冠状动脉中发现的变化进行比较 疾病和肥大。我们将通过以下方式检查神经支配模式 测量体内的功能反应(即有效反应的变化 不应期、心律失常诱发性和传入诱发反射) 和体外(即光学标测)。我们将使用正电子发射 体层摄影术(PET)检查交感神经和副交感神经 神经支配、心肌血流和新陈代谢。功能界别 在体内和体外获得的反应将与 PET图像和由组织学确定的神经支配模式 免疫组织化学技术。一旦我们描述了正常的 心脏，我们将进行一系列相同的研究，在体内和 在体外，在冠状动脉疾病和肥厚的心脏中。之后 最初的结构/功能研究，然后我们将尝试 纠正由以下原因引起的潜在解剖和功能紊乱 心肌细胞移植治疗心肌梗死或肥厚 技巧。通过基因工程获得过高表达的细胞 并释放神经生长因子，转化生长因子β1，或 将成纤维细胞生长因子植入心肌或注射 进入心包间隙。这些蛋白质是重要的 神经系统的维持和发育或用于组织修复 和伤口愈合。我们推测，这些多肽可能会使一些 与冠状动脉相关的解剖和功能异常 动脉疾病和肥厚，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.