Sudden cardiac arrest and circulating hydrogen sulfide

项目摘要 心脏骤停（SCA）仍然是一个主要的公共卫生问题， 仅在美国每年就有40万人死亡。在西方人群中，室颤是最常见的 冠状动脉疾病（CAD）是SCA最常见的潜在电生理机制， 疾病尽管最近在CAD的治疗和预防方面取得了进展，但SCA仍然是最常见的疾病之一。 死亡的主要原因。对于一般情况， 人口识别风险增加的患者，并发现心律失常的新治疗靶点 预防和治疗对公众健康极为重要。 硫化氢，H2S，是一种有毒的环境污染物，最近已经成为一种重要的环境污染物。 生理信号分子H2S是已确定的三种气体传递物之一（沿着还有NO和CO） 在各种组织中具有重要的生物学作用以维持适当的功能。H2S被认为是 保护心肌细胞功能并防止毒性的心脏保护底物。与此最相关的 H_2S在调节L型Ca ~（2+）、Na ~+和ATP依赖性中具有电生理意义 K+（KATP）通道，维持正常的QT周期，并减少延长的QT周期， 缺血再灌注损伤的各种动物模型。H2S还可防止室性快速性心律失常 在心肌肥大和缺血/再灌注损伤期间。抑制主要的酶， 心脏组织中的H2S生物合成导致心脏组织以及循环中的H2S水平降低 血浆，并导致心脏损伤。这项研究项目将测试假设， H2S浓度与SCA风险较低相关。目标1将检查与SCA相关的风险 和循环H2S在血浆和红细胞膜在两个大的人群为基础的研究SCA。目的2 将测试H2S调节在缺氧应激期间成人心肌细胞功能障碍中的作用， 第一次，确定与H2S心脏稳态相关的基因组途径，以确定新的 参与低氧胁迫下H2S合成尤其是代谢的途径。两个目标 共同将有助于开发新的临床策略，以对抗SCA，改善风险分层， 用于更好的治疗和预防的新型H2S相关药物靶标。

Project Summary Sudden cardiac arrest (SCA) continues to be a major public health concern, accounting for up to 400,000 annual deaths in the US alone. In Western populations, ventricular fibrillation is the most common electrophysiologic mechanism for SCA while coronary artery disease (CAD) is the most common underlying disease. Despite recent advances in treatment and prevention of CAD, SCA continues to be one of the leading causes of mortality. There are few effective approaches to SCA prevention for the general population. Identifying those at increased risk, and discovering novel therapeutic targets for arrhythmia prevention and treatment is of great public health importance. Hydrogen sulfide, H2S, is a toxic environmental pollutant that has recently emerged as an important physiological signaling molecule. H2S is one of three identified gasotransmitters (along with NO and CO) with significant biological roles in various tissues to maintain proper function. H2S is recognized as a cardioprotective substrate that preserves cardiomyocyte function and prevents toxicity. Most relevant to this application, H2S has electrophysiological significance in regulating L-type Ca2+, Na+ and ATP dependent K+ (KATP) channels that maintain a normal QT-period and reduce the prolonged QT period following ischemia reperfusion injury in various animal models. H2S also protects against ventricular tachyarrhythmia during cardiac hypertrophy and ischemia/reperfusion injury. Inhibition of the major enzyme responsible for H2S biosynthesis in cardiac tissue leads to reduced H2S levels in both cardiac tissue as well as circulating plasma, and results in cardiac injury. This research project will test the hypothesis that higher circulating H2S concentrations are associated with lower risk of SCA. Aim 1 will examine the risk associated with SCA and circulating H2S in plasma and RBC membranes in two large population-based studies of SCA. Aim 2 will test the role of H2S regulation in adult human cardiomyocyte dysfunction during hypoxic stress and for the first time, determine the genomic pathways associated with cardiac homeostasis of H2S to identify new pathways involved in the synthesis and especially metabolism of H2S under hypoxic stress. The two aims together will aid in developing new clinical strategies to combat SCA, improve risk stratification and identify novel H2S related drug targets for better treatment and prevention.