Sudden cardiac arrest and circulating hydrogen sulfide

心脏骤停和循环硫化氢

• 批准号: 10170417
• 负责人: Nona Sotoodehnia
• 金额: $ 71.44万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170417
• 关键词: Accounting; Address; Adult; Anabolism; Animal Model; Animals; Apoptosis; Arrhythmia; Atherosclerosis; Biochemical; Biocompatible Materials; Biological; Cardiac; Cardiac Electrophysiologic Techniques; Cardiac Myocytes; Case-Control Studies; Cell Survival; Cell physiology; Cellular biology; Cessation of life; Clinical; Clinical assessments; Cohort Studies; Complex; Coronary Arteriosclerosis; Data; Dietary Factors; Disease; Drug Targeting; Electrophysiology (science); Environmental Pollutants; Enzymes; Erythrocyte Membrane; Etiology; Evaluation; Functional disorder; General Population; Genes; Genetic; Genetic Variation; Genomics; Health; Heart Arrest; Heart Hypertrophy; Heart Injuries; Heart failure; Homeostasis; Human; Hydrogen Sulfide; Hypoxia; Injury; Ischemia; Link; Measurement; Measures; Mediating; Mediation; Membrane; Mendelian randomization; Metabolism; Methodology; Molecular; Muscle Cells; Myocardial Infarction; Myocardial Ischemia; Outcome; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Physical activity; Physiological; Plasma; Population; Population Study; Prevention; Property; Public Health; Reactive Oxygen Species; Regulation; Reperfusion Injury; Reperfusion Therapy; Research Project Grants; Risk; Risk Factors; Role; Sampling; Signal Transduction; Signaling Molecule; Smoking; Stress; Tachyarrhythmias; Testing; Time; Tissues; Toxic effect; Transcriptional Regulation; Vasodilator Agents; Ventricular; Ventricular Fibrillation; cardioprotection; carotid intima-media thickness; case control; clinical material; combat; coronary artery occlusion; genomic data; heart function; improved; in vivo; innovation; ischemic injury; knock-down; modifiable risk; mortality; multidisciplinary; myocardial infarct sizing; new therapeutic target; novel; phenotypic data; population based; preservation; prevent; prospective; response; risk stratification; small hairpin RNA; study population; transcriptome; transcriptome sequencing

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.

项目概要 心脏骤停 (SCA) 仍然是一个主要的公共卫生问题，导致高达 仅在美国每年就有 40 万人死亡。在西方人群中，心室颤动是最常见的 SCA 的电生理机制，而冠状动脉疾病 (CAD) 是最常见的潜在原因 疾病。尽管最近在 CAD 的治疗和预防方面取得了进展，但 SCA 仍然是治疗和预防 CAD 的方法之一。 死亡的主要原因。对于一般人来说，预防 SCA 的有效方法很少 人口。识别高风险人群并发现心律失常的新治疗靶点 预防和治疗对于公共卫生具有重要意义。 硫化氢 (H2S) 是一种有毒环境污染物，近年来已成为重要的环境污染物。 生理信号分子。 H2S 是已确定的三种气体递质之一（另外两个是 NO 和 CO） 在各种组织中具有重要的生物学作用，以维持正常功能。 H2S被认为是 保护心肌细胞功能并防止毒性的心脏保护基质。与此最相关的 应用中，H2S 在调节 L 型 Ca2+、Na+ 和 ATP 依赖性方面具有电生理学意义 K+ (KATP) 通道可维持正常 QT 期并缩短术后 QT 期延长 各种动物模型的缺血再灌注损伤。 H2S 还可以预防室性快速心律失常 在心脏肥大和缺血/再灌注损伤期间。抑制主要酶 心脏组织中的 H2S 生物合成导致心脏组织和循环中的 H2S 水平降低 血浆，并导致心脏损伤。该研究项目将检验以下假设：较高的循环 H2S 浓度与较低的 SCA 风险相关。目标 1 将检查与 SCA 相关的风险 两项基于人群的大型 SCA 研究中对血浆和红细胞膜中循环 H2S 的研究。目标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以及 首次确定与 H2S 心脏稳态相关的基因组途径，以识别新的 参与缺氧应激下 H2S 合成尤其是代谢的途径。两个目标 共同将有助于制定新的临床策略来对抗 SCA、改善风险分层并识别 新颖的 H2S 相关药物靶点，以实现更好的治疗和预防。