PRE-DETERMINE: Advancing Sudden Arrhythmic Death Prediction in Coronary Artery Disease in the Absence of Severe Systolic Dysfunction

猝死和/或猝死（SAD），通常由致死性室性心律失常（室性心律失常）引起。 在冠心病（CHD）的情况下，心动过速和心室颤动（VT/VF）， 据估计，美国每年有31万人。SAD的减少继续落后于那些 尽管复苏治疗取得了进展，但仍观察到其他冠心病（CHD）结局， 植入式心律转复器（ICD）的使用。目前预防SAD的方法仍然是 集中于在左心室射血分数（LVEF）<30-35%的患者中放置ICD-尽管 大多数SAD发生在LVEF >30- 35%的情况下。实际上， 对高危人群的研究不足，因此治疗不足。尽管这一需求未得到满足， 很少（如果有的话）有前瞻性研究检查CHD和LVEF >30-35%的个体中SAD风险预测， ICD治疗可能具有成本效益的足够长的时间范围。正因为如此，前- DETERMINE队列研究旨在解决这一科学差距， 研究LVEF >30- 35%的CHD患者SAD风险预测的临床相关方法。在这 申请，我们建议利用最初由NHLBI资助的基础队列资源继续裁定 除了竞争性死亡原因外，累积SAD和VT/VF事件，以达到10年以上的终点 裁定，以便能够开发和验证多标记SAD风险预测模型， 在这种独特的方法中生成的多维临床、ECG、成像、生物标志物和遗传数据的组合， 5761例CHD患者的多中心队列研究。我们还将利用基础队列来询问新的脂肪酸 衍生的类二十烷酸和假定的心律失常调节蛋白质组学分析物与SAD风险的关系， 冠心病患者死亡的竞争性原因。竞争风险分析的新方法将用于 将绝对和比例SAD风险整合到SAD风险预测模型中， SAD与非SAD死亡原因之间的关系。机器学习方法将应用于 从多模态数据中发现传统模型不易检测到的相互关系和潜在特征。 我们工作的首要目标是准确识别更广泛人群中的个体子集， 有足够高的SAD绝对和比例风险，值得纳入随机试验， 一级预防ICD治疗。目前提案的目的还提供了新的机会， 致死性室性心律失常发生的潜在机制途径， 冠心病患者SAD预防的新靶点--超越ICD置入--甚至可能 在一般人群中，CHD是大多数SAD事件的基础。继续和扩大 PRE-DETERMINE研究将为科学领域的研究人员提供独一无二的资源， 受训人员为减轻SAD负担的共同目标而合作。

Sudden and/or arrhythmic death (SAD), which typically results from lethal ventricular arrhythmias (ventricular tachycardia and ventricular fibrillation, VT/VF) in the setting of coronary heart disease (CHD), afflicts an estimated 310,000 persons annually in the United States. Reductions in SAD have continued to lag those observed for other coronary heart disease (CHD) outcomes despite advances in resuscitation therapies and the use of implantable cardioverter-defibrillators (ICDs). Current approaches to SAD prevention remain centered on placing ICDs in patients with left ventricular ejection fraction (LVEF) <30-35% – even though the majority of SAD occurs in the setting of LVEF >30-35%. In effect, the proportionately larger segment of the at-risk population has been understudied and thus undertreated. Despite this unmet need, there remain very few, if any, prospective studies examining SAD risk prediction in individuals with CHD and LVEF >30-35% over a long enough time horizon where ICD therapy might be cost-effective. For this very reason, the PRE- DETERMINE Cohort Study was intentionally designed to address this scientific gap and prospectively study clinically relevant approaches to SAD risk prediction in CHD patients with LVEF >30-35%. In this application, we propose to leverage the originally NHLBI-funded base cohort resource to continue adjudication of accruing SAD and VT/VF events, in addition to competing causes of death, to attain 10+ years of endpoint adjudication to enable the development and validation of multi-marker SAD risk prediction models based on combinations of multi-dimensional clinical, ECG, imaging, biomarker, and genetic data generated in this unique multicenter cohort of 5761 CHD patients. We will also leverage the base cohort to interrogate novel fatty acid derived eicosanoids and putative arrhythmia modulating proteomic analytes in relation to risk for SAD and competing causes of mortality in patients with CHD. Novel methods of competing risk analyses will be used to integrate absolute and proportional SAD risk into SAD risk prediction models and to elucidate separate associations between SAD vs. non-SAD causes of death. Machine learning approaches will be applied to uncover inter-relations and latent features from multi-modality data not easily detected by conventional models. An overarching goal of our work is to accurately identify those individual subsets of the broader population who have sufficiently high absolute and proportional risk for SAD that they warrant inclusion in randomized trials of primary prevention ICD therapy. The aims of the current proposal also offer new opportunities to identify potential mechanistic pathways underlying the genesis of lethal ventricular arrhythmias that could serve as novel targets for SAD prevention – extending beyond ICD placement – in patients with CHD and possibly even in the general population wherein CHD underlies most SAD events. The continuation and expansion of the PRE-DETERMINE study will provide the scientific field with a one-of-a kind resource for investigators and trainees collaborating toward the common goal of reducing the burden of SAD.