Mechanisms of VF maintenance in ischemia and infarction

本研究项目的主要目的是阐明室颤(VF)在正常炉膛以及在缺血和梗死心脏中维持的机制。了解这些机制对于设计预防心脏性猝死的改进疗法至关重要。我们将使用两种免费的准备：在分离的灌流的整个猪心中进行光学标测，在猪的左心室薄片中进行壁内电标测。具体目的1.探讨正常心脏室颤的发生机制。我们将使用一种新的成像技术从整个心外膜光学地形图VF。使用新的分析方法，我们将检测传播传导阻滞的发生，并检验两种替代假设：(1)传导阻滞区域与非均匀内在动作电位时程区域相关；(2)与速率相关的复极不稳定性导致心搏间期变化不断加剧，最终导致传导阻滞。我们还将从三个正交的感觉阵列(其中两个是室壁内的)在隔离的左心室平板上进行电子标测。我们将检验长寿壁内折返源在室颤期间持续存在的假设。具体目的2.探讨局部急性心肌缺血的室颤机制。我们将通过结扎冠状动脉来创建缺血区。我们将检验假设：(1)非缺血区的室颤与对照组相似。(2)缺血区和非缺血区的激活率不同，导致波阵面从缺血区向非缺血区移动。(3)新的波形形成在缺血边缘带比其他部位更常见。然而，在非缺血区，这些波的间歇对室颤没有贡献。具体目的3.探讨亚急性和慢性心肌梗死的室性心动过速机制。我们将在3天和30天大的穿壁性脑梗塞动物身上进行研究。我们将检验以下假设：(1)在梗塞3天的动物中，非梗死区的室颤动力学与对照组相似。(2)心肌梗死3d后，非梗死区的室性心动过速与对照组相似。(2)在梗死30天的动物中，重塑改变了室颤动力学，使其模式类似于肥厚的心脏(速度较慢，通常更有组织)。(3)新的波断形成在梗死灶边缘附近较多见。然而，在非梗死组织中，这些波的间歇不会对CF有贡献。

The broad objective of this research project is to elucidate the mechanism by which ventricular fibrillation (VF) is maintained in normal hearths and in hearts with ischemia and infarction. Understanding these mechanisms is essential for devising improved therapies for preventing sudden cardiac death. We will use two complimentary preparations; optical mapping in isolated perfused whole pig hearts and intramural electrical mapping in slabs of pig left ventricle. Specific Aim 1. Investigate VF mechanisms in normal hearts. We will map VF optically from the entire epicardium using a new imaging technique. Using novel analysis methodology, we will detect the occurrence of propagation block and test two alternative hypotheses: (1) regions of block correlate with areas of non-uniform intrinsic action potential duration (APD) and (2) rate-dependent repolarization instabilities cause escalating beat-to-beat APD variations that eventually culminate in block. We will also map electrically from three orthogonal sensory arrays (two of which are intramural) in isolated left ventricular slabs. We will test the hypothesis that long-lived intramural reentrant sources are continuously present during VF. Specific Aim 2. Investigate VF mechanisms in hearts with regional acute ischemia. We will create an ischemic region by ligating a coronary artery. We will test the hypothesis that: (1) VF in the non-ischemic region is similar to control. (2) Activation rates in the ischemic and non- ischemic regions differ, causing a functional for wavefronts moving from region to the other. (3) New wavebreak formation is more common in the ischemic border zone than elsewhere. However, these wavebreaks do not contribute to VF in the non-ischemic region. Specific Aim 3. Investigate VF mechanisms in hearts with subacute and chronic infarction. We will study in animals with transmural infarcts 3 and 30 days old. We will test the hypotheses that (1) In the animals with 3-days infarcts, VF dynamics in the non-infarcted region are similar to control. (2) In the animals with 3-day infarcts, VF dynamics in the non- infarcted region are similar to control. (2) In the animals with 30-day infarcts, remodeling changes VF dynamics so that the patterns resemble those in hypertrophied hearts (slower, generally more organized). (3) New wavebreak formation is more common near the border of the infarct than elsewhere. However, these wavebreaks do not contribute to CF in the non-infarcted tissue.