Hibernating Myocardium and Sudden Cardiac Death

描述(由申请人提供)：目前可用的电生理学方法在识别大多数死于心脏性猝死(SCD)的冠心病和左心室功能障碍患者的能力方面存在局限性。超过一半的SCD患者在EP测试中是不能诱发的，这强调了需要新的方法来识别导致心律失常死亡的底物。存活的慢性功能障碍或冬眠心肌不能再血管化，似乎是随后心脏死亡的主要危险因素，并存在于高达60%的缺血性心肌病患者中。血运重建可提高存活率，但由于程序风险或技术限制，大多数冬眠心肌患者可通过医学手段进行治疗。病因特异性死亡率数据有限，但似乎是心律失常，而不是致命性心肌梗死或进展性心力衰竭。为了支持这一点，在没有MI或CHF的情况下，冬眠心肌的猪从VT/VF发展为SCD。致死性心律失常的潜在诱因包括局部SR钙摄取和释放蛋白减少、心肌细胞肥大和交感神经支配改变。这一建议的中心假设是冬眠心肌的存在而不是疤痕的存在识别了一大部分缺血性心肌病患者，这些患者是SCD的高危人群。我们进一步假设，这种风险与慢性反复缺血引起的交感神经分布的不均质性有关。我们提出了一项前瞻性观察性研究，将纳入360名冠心病患者，心力衰竭I-III级，EF&lt；=35%。使用正电子发射断层扫描(PET)，将量化不适合冠状动脉血运重建术的患者的心肌收缩的发生率和数量。目的1将确定存活心肌(保存的F-2-脱氧葡萄糖)和静息流量减少(13)N-氨之间的不匹配成像是否可以预测冬眠心肌SCD(或以VT/VF为替代终点的ICD放电)的风险增加。目的2将使用(11)C-羟基麻黄碱进行去甲肾上腺素摄取成像，以确定心肌交感神经支配的不均一性是否比生存试验更好地预测SCD的风险。目的3将通过评估ICD患者的功能、生存能力和交感神经支配的时间变化，确定在流产的SCD事件后，PET确定的底物是否稳定。我们的长期目标是开发更好的方法来识别最有可能从放置ICD的SCD一级预防中受益的CAD患者。

DESCRIPTION (provided by applicant): Currently available electrophysiological approaches are limited in their ability to identify the majority of patients with CAD and LV dysfunction that succumb to sudden cardiac death (SCD). Over half of the patients developing SCD are not inducible at EP testing underscoring the need for new ways to identify substrates leading to arrhythmic death. Viable chronically dysfunctional or hibernating myocardium, not amenable to revascularization, appears to be a major risk factor for subsequent cardiac death and is present in up to 60 percent of patients with ischemic cardiomyopathy. Revascularization improves survival but most patients with hibernating myocardium are managed medically due to prohibitive procedural risks or technical limitations. Cause specific mortality data is limited but appears to be arrhythmic rather than from fatal MI or progressive CHF. In support of this, swine with hibernating myocardium develop SCD from VT/VF in the absence of MI or CHF. Potential triggers of lethal arrhythmias include regional reductions in SR calcium uptake and release proteins, myocyte hypertrophy and altered sympathetic innervation. The central hypothesis of this proposal is that the presence of hibernating myocardium as opposed to scar identifies a large subset of patients with ischemic cardiomyopathy that are at high risk for SCD. We further hypothesize that this risk is related to inhomogeneity in sympathetic innervation arising from chronic repetitive ischemia. We propose a prospective observational study that will enroll 360 patients with CAD, Class I-III CHF and an EF <= 35 percent. Using positron emission tomography (PET), the prevalence and amount ofhibemating myocardium will be quantified in patients that are not candidates for coronary revascularization. Aim 1 will determine whether imaging the mismatch between viability (preserved ( 18)F-2-deoxyglucose) and reduced resting flow (13)N-ammonia can predict an increased risk of SCD (or ICD discharge for VT/VF as a surrogate end-point) in hibernating myocardium. Aim 2 will image norepinephrine uptake using ( 11)C-hydroxyephedrine to determine whether inhomogeneity in myocardial sympathetic innervation predicts SCD risk better than viability testing. Aim 3 will identify whether the substrate identified by PET is stable after an aborted SCD event by evaluating temporal changes in function, viability and sympathetic innervation in patients with an ICD. Our long-term objective is to develop better approaches to identify patients with CAD who are most likely to benefit from primary prevention of SCD with placement of an ICD.