Human genetic variation and ventricular fibrillation resuscitation outcomes

描述（由申请人提供）：尽管在美国每年有成千上万的心脏骤停患者尝试复苏，但在大多数社区，心室颤动骤停后的存活率低于20%。骤停后的死亡主要是由于心脏或大脑的压倒性/不可逆转的损伤。虽然心脑复苏的预测因素已经确定，但它们总共占与预后相关的方差的比例不到25%，这表明其他因素在很大程度上影响了复苏的成功。重要的是，遗传变异存在于许多可能潜在影响临床结果的相互关联的生物学途径中。然而，基因变异对心室纤颤停搏后心脏和大脑预后的影响尚未得到评估。更好地了解心脏和大脑复苏的遗传决定因素将促进对心室颤动病理生理学的了解，这反过来可能对复苏护理具有临床意义。该申请的具体目的是研究心室颤动的心脏和大脑复苏结果与复苏三个阶段（电、血流动力学和代谢阶段）相关通路中候选基因的常见遗传变异之间的关系。

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.