Cardioprotective Adaptation to Intermittent Hypoxia

对间歇性缺氧的心脏保护适应

• 批准号: 7390757
• 负责人: ROBERT T MALLET
• 金额: $ 17.64万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7390757
• 关键词: Accounting; Acetylcysteine; Address; Anterior Descending Coronary Artery; Antioxidants; Area; Arrhythmia; Blood flow; Canis familiaris; Cardiac; Cause of Death; Clinical; Clinical Research; Complement; Condition; Coronary; Coronary Occlusions; Coronary artery; Daily; Developed Countries; Developing Countries; Development; Event; Fostering; Foundations; Future; Hematocrit procedure; Hour; Hypoxia; Individual; Infarction; Injury; Intervention; Investigation; Ischemia; Left; Mammals; Measures; Membrane; Modality; Modeling; Monitor; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Obstruction; Operative Surgical Procedures; Oxidative Stress; Pharmacologic Substance; Physiological reperfusion; Prophylactic treatment; Protocols documentation; Reactive Oxygen Species; Reperfusion Therapy; Resistance; Risk; Role; Score; Stress; Tachyarrhythmias; Testing; Therapeutic; United States; Ventricular; Ventricular Arrhythmia; Ventricular Tachycardia; artery occlusion; clinical application; conditioning; day; disability; myocardial infarct sizing; novel; practical application; pre-clinical; preclinical study; prevent; programs

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.

描述（由适用提供）：越来越多的证据表明间歇性缺氧增强了对缺血性压力的心脏抵抗力。最近，我们通过5-10分钟正常的缺氧的20天计划表明了犬心肌的明显保护，其中4分钟的正常氧气介入，每天总计25-70分钟的缺氧。在17只非催眠犬中，在1小时的冠状动脉闭塞/5小时再灌注方案中，有39％的缺血性心肌梗塞，其中82％的狗发生了心室心动过速和/或纤维化。在9条缺氧的狗中，只有1.1»梗塞缺血性心肌的0.3％，并且没有发生心室心动过速或颤动。两组的副血液流向缺血性心肌和动脉血细胞比容，O2含量相似。这些显着的结果表明，适应间歇性正常的缺氧可以为传统的药物和手术干预措施提供安全，强大和实用的治疗完件，以保护心肌免受即将发生的缺血。然而，这种现象的严格临床前研究，尤其是在大型哺乳动物中，对于实施低氧条件作为一种新型方式至关重要，以防止在临床环境中进行心脏损伤。拟议的调查的全球目标是解决有关间歇性低氧条件的实际应用和机制的三个重要问题：1）在调节计划中断后，心脏保护持续了多长时间？ 2）缺氧条件有效预防超过1小时的冠状动脉闭塞造成的心肌损伤？ 3）在心肌中通过环状缺氧 - 抗氧化产生的氧化应激会引起心脏保护适应吗？为了解决这些问题，缺氧条件和非催眠对照犬将受到左室前降冠状动脉的阻塞和再灌注，同时监测心室心律不齐。心肌梗死大小，处于危险的缺血性心肌和附带血流将测量以量化缺血性损伤。这项投资引起的缺氧诱发心脏保护的信息将为将来对这种强大现象的临床开发提供至关重要的基础。心肌缺血及其后遗症是美国死亡和残疾的主要原因，但很少有非侵入性干预措施可以防止对心肌的缺血性损害。申请人表明，一项简短，间歇性，正常的缺氧的计划可为缺血诱导的心肌梗死和致命性心律不齐提供明显的保护。这项投资产生的缺氧诱发心脏保护的信息将建立一个经验基础，以支持这种强大的心脏保护现象的最终临床应用。

项目成果

Intermittent hypoxia: Cause of or therapy for systemic hypertension?

• DOI: 10.3181/0710-mr-267
• 发表时间: 2008-06-01
• 期刊: EXPERIMENTAL BIOLOGY AND MEDICINE
• 影响因子: 3.2
• 作者: Serebrovskaya, Tatiana V.;Manukhina, Eugenia B.;Mallet, Robert T.
• 通讯作者: Mallet, Robert T.

δ-Opioid receptors: Pivotal role in intermittent hypoxia-augmentation of cardiac parasympathetic control and plasticity.

• DOI: 10.1016/j.autneu.2016.07.007
• 发表时间: 2016-07
• 期刊: AUTONOMIC NEUROSCIENCE-BASIC & CLINICAL
• 影响因子: 2.7
• 作者: Estrada, Juan A.;Barlow, Mathew A.;Yoshishige, Darice;Williams, Arthur G., Jr.;Downey, H. Fred;Mallet, Robert T.;Caffrey, James L.
• 通讯作者: Caffrey, James L.