Cardioprotective Adaptation to Intermittent Hypoxia

描述（由申请人提供）：越来越多的证据表明，间歇性缺氧可增强心脏对缺血应激的抵抗力。最近，我们通过20天的5-10分钟常压缺氧程序，加上4分钟的常氧期，每天总计25-70分钟的缺氧，证明了对犬心肌的显著保护。在17只非缺氧犬中，在1小时冠状动脉闭塞/5小时再灌注方案期间，39 - 4%的缺血心肌梗死，82%的犬发生室性心动过速和/或室颤。在9只缺氧条件犬中，仅1.1 ~ 0.3%的缺血心肌发生梗死，无室性心动过速或室颤发生。两组缺血心肌侧支循环血流量、动脉血细胞比容和O2含量相似。这些显着的结果表明，适应间歇性常压缺氧可以提供一个安全，强大和实用的治疗补充传统的药物和手术干预，以保护心肌缺血即将发生。然而，这种现象，特别是在大型哺乳动物中，严格的临床前研究是必不可少的实施缺氧调节作为一种新的方式，以防止在临床环境中的心脏损伤。本研究的总体目标是解决有关间歇性低氧适应的实际应用和机制的三个重要问题：1）在适应程序中断后，心脏保护持续多长时间？2)缺氧预处理在预防持续性冠状动脉闭塞超过1小时造成的心肌损伤方面的有效性如何？3)循环性缺氧-复氧引起的心肌氧化应激是否引起心脏保护性适应？为了解决这些问题，缺氧条件和非缺氧对照犬将经受左前降支冠状动脉的闭塞和再灌注，同时监测室性心律失常。将测量心肌梗死面积、缺血性心肌风险和侧支血流量，以量化缺血性损伤。从这项调查中产生的缺氧诱发的心脏保护的信息将提供重要的基础，为未来的临床开发这一强大的现象。在美国，心肌缺血及其后遗症是导致死亡和残疾的主要原因，但很少有非侵入性干预措施可用于预防心肌缺血性损伤。申请人已经证明，短暂的、间歇性的、常压缺氧程序对缺血诱导的心肌梗塞和致命性心律失常产生显著的保护作用。从这项调查中产生的缺氧诱发的心脏保护的信息将建立一个实证基础，以支持这种强大的心脏保护现象的最终临床应用。

DESCRIPTION (provided by applicant): There is increasing evidence that intermittent hypoxia enhances cardiac resistance to ischemic stress. Recently, we demonstrated remarkable protection of canine myocardium by a 20 day program of 5-10 min normobaric hypoxia, with intervening 4 min periods of normoxia, totaling 25-70 min of hypoxia per day. In 17 non-hypoxic dogs, 39 ¿ 4% of ischemic myocardium infarcted during a 1 hour coronary occlusion/5 hour reperfusion protocol, and 82% of the dogs developed ventricular tachycardia and/or fibrillation. In 9 hypoxia conditioned dogs, only 1.1 ¿ 0.3% of ischemic myocardium infarcted, and no ventricular tachycardia or fibrillation occurred. Collateral blood flow to ischemic myocardium and arterial hematocrit and O2 content were similar in both groups. These remarkable results suggest that adaptation to intermittent normobaric hypoxia could provide a safe, powerful and practical treatment complementary to conventional pharmaceutical and surgical interventions to protect myocardium from impending ischemia. However, rigorous preclinical studies of this phenomenon, particularly in large mammals, are essential to implement hypoxia conditioning as a novel modality to prevent cardiac injury in clinical settings. The global objective of the proposed investigation is to address three important questions regarding the practical application and mechanism of intermittent hypoxia conditioning: 1) How long does the cardioprotection persist after the conditioning program is interrupted? 2) How effective is hypoxia conditioning at preventing myocardial injury inflicted by protracted coronary occlusions exceeding 1 hour? 3) Does oxidative stress, produced in myocardium by cyclic hypoxia-reoxygenation, evoke cardioprotective adaptations? To address these questions, hypoxia-conditioned and non-hypoxic control dogs will be subjected to occlusion and reperfusion of the left anterior descending coronary artery, while ventricular arrhythmias are monitored. Myocardial infarct size, ischemic myocardium at risk, and collateral blood flow will be measured to quantify ischemic injury. Information on hypoxia-evoked cardioprotection resulting from this investigation will provide the crucial foundation for future clinical exploitation of this powerful phenomenon. Myocardial ischemia and its sequelae are the leading causes of death and disability in the United States, yet few noninvasive interventions are available to prevent ischemic damage to the myocardium. The applicants have demonstrated that a program of brief, intermittent, normobaric hypoxia produces remarkable protection against ischemia- induced myocardial infarction and lethal arrhythmias. Information on hypoxia-evoked cardioprotection resulting from this investigation will establish an empirical foundation to support eventual clinical application of this powerful cardioprotective phenomenon.