Electrical Heterogeneity and Cardiac Arrhythmias

描述（由申请人提供）：在前11年的资助中，我们的实验室发现并表征了犬心室心肌固有的电异质性。心外膜、心内膜和一种称为M细胞的独特细胞群在电生理功能和对药物的反应性方面有所不同。这些差异随后被证明是心电图各种波形的基础，当被放大时，就会形成危及生命的室性心律失常的发展基础，包括与先天性长QT、短QT、Brugada综合征以及儿茶酚胺能性室性心动过速（VT）相关的多态性室性心律失常。最近，我们和其他人将长QT期、短QT期和Brugada综合征与儿童和婴儿猝死联系起来，并提供证据表明这些机制可能在一定程度上导致婴儿猝死综合征（SIDS）。在拨款的最后阶段，我们定义了犬心脏中出现这些电和药理学异质性的发育阶段，以便更好地了解离子通道功能障碍如何在生命的早期阶段促进这些遗传综合征的表现。在拨款的下一个时期，我们建议1)检查长QT间期、短QT间期和Brugada综合征的实验模型的特征，这些模型先前在成年犬心室楔形制剂中开发，在新生儿心脏楔形制剂中开发；2)将我们的发现扩展到跨壁异质性的力学方面，定义三种细胞类型在细胞缩短和钙瞬态方面的差异及其随发育的变化；3)检查在心室发现的电和药理学异质性在多大程度上适用于每个发育阶段的心房。我们的竞争性更新的主要目标是探讨在心脏发育的每个阶段，心室内的机械异质性在多大程度上补充了跨壁电异质性，以及这些跨壁差异的加剧如何促进危及生命的室性和心房心律失常的发展。我们的长期目标是产生对我们理解婴幼儿心律失常死亡有意义的信息。

DESCRIPTION (provided by applicant): In the previous 11 years of the grant, our laboratory uncovered and characterized the electrical heterogeneity intrinsic to canine ventricular myocardium. Epicardium, endocardium and a unique population of cells termed M cells were shown to differ with respect to electrophysiological function and responsiveness to drugs. These distinctions were then shown to underlie the various waveforms of the ECG and when amplified to create the substrate for the development of life-threatening ventricular arrhythmias, including the polymorphic ventricular arrhythmias associated with the congenital long QT, short QT, and Brugada syndromes as well as catecholaminergic ventricular tachycardia (VT). Recently, we and others have linked the long QT, short QT and Brugada syndromes to sudden death in children and infants and provided evidence that these mechanisms may contribute in small part to sudden infant death syndrome (SIDS). In the last period of the grant, we defined the developmental stages at which these electrical and pharmacologic heterogeneities arise in the canine heart so as to better understand how ion channel dysfunction may contribute to manifestation of these hereditary syndromes in early stages of life. In the next period of the grant we propose to 1) examine the characteristics of the experimental models of long QT, short QT and Brugada syndromes previously developed in adult canine ventricular wedge preparations, in wedge preparations from neonatal hearts; 2) extend our findings to mechanical aspects of transmural heterogeneity, defining distinctions in cell shortening and calcium transients among the three cell types and their change with development; and 3) examine to what extent electrical and pharmacologic heterogeneity uncovered in the ventricle apply to the atria at each stage of development. The principal goals of our competitive renewal are to probe the extent to which mechanical heterogeneity complements transmural electrical heterogeneity within the ventricles of the heart at each stage of development and how accentuation of these transmural distinctions contributes to the development of life-threatening ventricular and atrial arrhythmias. Our long-range goal is to generate information that will contribute meaningfully to our understanding of arrhythmic death in infants and young children.