ISCHEMIA, NEUROHUMORS, ARRHYTHMIAS AND DIAGNOSIS

缺血性和非缺血性心律失常的治疗取决于 主要是基于经验主义。这在一定程度上是因为心电图 诊断既依赖于对现象学的理解，也依赖于 心律失常背后的实际机制。这反过来又反映了 事实是，我们对这些机制的理解存在重大差距 心肌细胞心律失常的诱导及其在正常心肌中的表达 心。拟议的研究针对与这些相关的两个领域 问题：正常和异常脉冲启动背后的机制， 以及自主神经调节在心律失常表达中的作用。我们 打算专注于心律失常的阿尔法肾上腺素能调制- 特别是在缺血的情况下；以及关于发展区分 心律失常的发生机制有利于临床诊断和治疗。二 主要假设将被检验：(1)阿尔法肾上腺素能受体-效应器 系统对过程中的异常脉冲启动有重要作用 缺血和再灌注；(2)通过使用起搏方案和 心脏活性药物我们可以确定心律失常的潜在机制， 了解他们在完整的心脏中的表现，并对他们进行治疗。 本文提出了15个具体的目标和假设。所有这些都与 自律性的正常与异常、及早与延迟的识别 后去极化和由此引发的活动。对于假设(1) 肾上腺素能刺激的作用(以及考虑 β和毒扁豆碱相互作用)。对于假设(2)， 使用起搏和心脏活性药物来区分机制有 考虑过了。这些实验结合了允许我们研究的技术 在细胞和通道水平上的机制，孤立的组织， 生化调节剂，以及完整动物的生化调节剂。此外，还有 心脏活性药物和起搏矩阵的应用已显示 在完整心脏水平上的诊断承诺。通过这件事 综合运用基础和临床电生理学技术， 连同生化和生物物理方法，我们相信我们将 提高我们对机械原理的理解和应用 对心律失常的诊断和防治的认识。

The treatment of ischemic and non-ischemic cardiac arrhythmias depends largely on empiricism. In part this is because electrocardiographic diagnosis relies as much on an understanding of phenomenology as on the actual mechanisms that underlie arrhythmias. This, in turn, reflects the fact that there are major gaps in our understanding of the mechanisms that induce arrhythmias in cardiac cells and their expression in the intact heart. The proposed research is directed at two areas that relate to these problems: the mechanisms underlying normal and abnormal impulse initiation, and the role of autonomic modulation in the expression of arrhythmias. We intend to concentrate on alpha adrenergic modulation of arrhythmias - especially in ischemia; and on developing means for discriminating among arrhythmogenic mechanisms to benefit clinical diagnosis and treatment. Two major hypotheses will be tested: (1) The alpha adrenergic receptor-effector system contributes importantly to abnormal impulse initiation during ischemia and reperfusion; (2) By using pacing protocols and a matrix of cardioactive drugs we can identify the mechanisms underlying arrhythmias, understand their manifestations in the intact heart, and treat them. Fifteen specific aims and subhypotheses are proposed. All relate to the identification of normal and abnormal automaticity and of early and delayed afterdepolarizations and resultant triggered activity. For hypothesis (1) the contributions of a adrenergic stimulation (and the consideration of beta and muscarinic interactions) are considered. For hypothesis (2) the use of pacing and cardioactive drugs to differentiate among mechanisms are considered. The experiments incorporate techniques that permit us to study mechanisms at the levels of the cell and channel, of isolated tissues, of biochemical modulators, and of intact animals. Moreover, there is application of a matrix of cardioactive drugs and pacing that has shown promise in diagnosis at the level of the intact heart. Through this combined approach, using basic and clinical electrophysiologic techniques, together with biochemical and biophysical methods, we believe we shall improve our understanding of mechanism and our application of this understanding to diagnosis, prevention and therapy of arrhythmias.