Human genetic variation and ventricular fibrillation resuscitation outcomes

描述（由申请人提供）：尽管美国每年有数十万心脏骤停患者尝试复苏，但在大多数社区，室颤骤停后的存活率低于20%。心脏骤停后的死亡主要是由于对心脏或大脑的压倒性/不可逆的损伤。虽然心脏和脑复苏的预测因素已经确定，但它们共同占与预后相关的方差的不到25%，表明其他因素对成功复苏有很大影响。重要的是，遗传变异存在于许多可能影响临床结果的相互关联的生物学途径中。然而，遗传变异对心室颤动停搏后心脏和大脑结果的影响尚未得到评估。更好地了解心脏和脑复苏的遗传决定因素将推进关于心室颤动的病理生理学的知识，这反过来可能对复苏护理具有临床意义。本申请的具体目的是检查室颤的心脏和脑复苏结局与复苏三个阶段（电、血液动力学和代谢阶段）相关通路中候选基因的常见遗传变异之间的关联。 为了进行调查，我们将组建一个约2500名受试者的生物储存库，这些受试者因心脏病而在院外室颤停搏，接受受过相当培训的护理人员的护理。生物储存库包括与临床和结果特征相关的生物信息（WBC和DNA）。我们建议完成非遗传协变量数据收集（第1年和第2年），评估选择候选途径中的常见遗传变异（第1年和第2年），并收集和分析数据（第3年和第4年）。基因分型将使用先进的高通量方法来有效地处理样本。分析将结合标准和新的遗传关联方法，以评估遗传变异是否以及如何影响复苏结果。

DESCRIPTION (provided by applicant): Although resuscitation is attempted in hundreds of thousands of cardiac arrest victims in the United States annually, survival following ventricular fibrillation arrest is less than 20% in most communities. Mortality following arrest is due largely to overwhelming/ irreversible injury to either the heart or brain. Although the predictors of heart and brain resuscitation have been identified, they collectively account for less than 25% of the variance related to prognosis, indicating that other factors substantially influence successful resuscitation. Importantly, genetic variation exists in many of the interrelated biological pathways that may potentially influence clinical outcomes. However, the influence of genetic variation on heart and brain outcomes following ventricular fibrillation arrest has not been evaluated. A better understanding of the genetic determinants of heart and brain resuscitation will advance knowledge regarding the pathophysiology of ventricular fibrillation, which in turn may have clinical implications for resuscitation care. The Specific Aims of the application are to examine the association of cardiac and brain resuscitation outcomes of ventricular fibrillation with common genetic variation in candidate genes in pathways related to the three phases of resuscitation -- electrical, hemodynamic, and metabolic phases. To undertake the investigation, we will assemble a biorepository of approximately 2500 subjects with out-of-hospital ventricular fibrillation arrest due to heart disease who receive care from comparably-trained paramedics. The biorepository includes biological information (WBC and DNA) that has been linked to clinical and outcome characteristics. We propose to complete nongenetic covariate data collection (years 1 and 2), assess common genetic variation in select candidate pathways (years 1 and 2), and assemble and analyze the data (years 3 and 4). Genotyping will use advanced, high-throughput methods to efficiently process samples. Analyses will incorporate standard and novel approaches of genetic association to assess if and how genetic variation influences resuscitation outcome.