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LV功能障碍患者方面能力有限。 超过一半的SCD患者在EP测试中是不可诱导的，这强调了需要新的方法来识别导致猝死的底物。 存活的慢性功能障碍或冬眠心肌，不适合血运重建，似乎是随后心源性死亡的主要危险因素，并且存在于高达60%的缺血性心肌病患者中。 血运重建可提高生存率，但由于手术风险过高或技术限制，大多数冬眠心肌患者均采用药物治疗。 特定原因的死亡率数据有限，但似乎是由心肌梗死引起的，而不是由致死性MI或进行性CHF引起的。 为了支持这一点，冬眠心肌的猪在没有MI或CHF的情况下从VT/VF发展SCD。 致命性心律失常的潜在触发因素包括SR钙摄取和释放蛋白的区域性减少、肌细胞肥大和交感神经支配改变。 这项建议的中心假设是，冬眠心肌的存在，而不是疤痕识别缺血性心肌病患者的一个大的子集，在SCD的高风险。 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，将招募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），将量化不适合冠状动脉血运重建的患者中心肌梗死的患病率和数量。 目的1将确定对存活率（保存的（18）F-2-脱氧葡萄糖）和减少的静息流量（13）N-氨之间的不匹配进行成像是否可以预测冬眠心肌中SCD（或ICD放电VT/VF作为替代终点）的风险增加。 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活力测试更好地预测SCD风险。 目标3将通过评价ICD患者的功能、活力和交感神经支配的时间变化，确定在SCD事件中止后，PET识别的底物是否稳定。 我们的长期目标是开发更好的方法来识别最有可能从植入ICD的SCD一级预防中获益的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.