Hibernating Myocardium and Sudden Cardiac Death

描述（由申请人提供）：目前可用的电生理方法在识别大多数死于心源性猝死（SCD）的CAD和左室功能障碍患者方面的能力有限。超过一半的SCD患者在EP测试中不能被诱导，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，不适应血运重建，似乎是随后心源性死亡的主要危险因素，存在于高达60%的缺血性心肌病患者中。血运重建术可提高生存率，但由于程序性风险或技术限制，大多数冬眠心肌患者需接受医学治疗。具体原因死亡率数据有限，但似乎是心律失常，而不是致命的心肌梗死或进行性心力衰竭。在没有心肌梗塞或心力衰竭的情况下，具有冬眠心肌的猪可由VT/VF发展为SCD。致死性心律失常的潜在触发因素包括SR钙摄取和释放蛋白的局部减少、肌细胞肥大和交感神经支配的改变。该建议的中心假设是，冬眠心肌的存在而不是瘢痕的存在确定了缺血性心肌病患者中有很大一部分是SCD的高风险人群。我们进一步假设这种风险与慢性重复性缺血引起的交感神经支配的不均匀性有关。我们提出了一项前瞻性观察性研究，将纳入360例CAD， I-III级CHF和EF <= 35%的患者。使用正电子发射断层扫描（PET），在不适合冠状动脉血管重建术的患者中，可以量化心肌缺血的发生率和数量。目的1将确定在冬眠心肌中，生存能力（保存的（18）f -2-脱氧葡萄糖）和静息流量（13）n -氨之间的不匹配成像是否可以预测SCD风险的增加（或将ICD放电作为VT/VF的替代终点）。目的2将使用（11）c -羟麻黄碱成像去甲肾上腺素摄取，以确定心肌交感神经支配的不均匀性是否比生存能力测试更能预测SCD风险。目的3将通过评估ICD患者的功能、活力和交感神经支配的时间变化，确定PET鉴定的底物在SCD流产事件后是否稳定。我们的长期目标是开发更好的方法来识别CAD患者，这些患者最有可能从放置ICD的SCD一级预防中获益。

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.