MECHANISMS OF EXERCISE INTOLERANCE IN HEART FAILURE

心力衰竭运动不耐受的机制

• 批准号: 2460097
• 负责人: William C. Little
• 金额: $ 24.76万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2460097
• 关键词: ACE inhibitors; adrenergic receptor; angiotensin II; dogs; dyspneas; endocardium; exercise; heart failure; heart pharmacology; heart rate; intracardiac pressure; muscle relaxation; myocardial ischemia /hypoxia; myocardium

DESCRIPTION: Exercise tolerance in heart failure (CHF) is not well correlated with left ventricular (LV) systolic performance, instead, it varies more closely with the level of left atrial (LA) pressure (P). Observations in applicant's laboratory and in patients indicate that in CHF there is a reversal of the normal exercise induced augmentation of LV relaxation and fall in early diastolic LV P with a resulting increase in LA P. Thus, the diastolic dysfunction present at rest in CHF is exacerbated during exertion and is an important cause of exercise intolerance in CHF. The mechanisms that produce this abnormal exercise response after CHF have not been determined. Factors that might contribute include altered responses of LV relaxation in CHF to the increased systolic load, angiotensin (ANG) II, heart rate and adrenergic stimulation that occur during exercise. Although myocardial ANG II levels have not been determined during CHF exercise, applicant's preliminary observations indicate that circulating ANG II levels increase to very high levels during CHF exercise. Thus, it appears possible that LV relaxation may be slowed and diastolic filling dynamics altered during CHF exercise by both increased sensitivity to ANG II and high ANG II levels. The purpose of this application is to investigate the mechanisms of the abnormal integrated response of LV relaxation and increased early diastolic LV P and LA P during exercise after CHF result from: 1) increased sensitivity of LV relaxation and diastolic filling dynamics to ANG II, which increases to high levels in the myocardium during CHF exercise; 2) increased sensitivity to increased systolic load during exercise; 3) reduction in the augmentation of relaxation produced by the increase in heart rate and adrenergic stimulation during exercise; and 4) endocardial ischemia. Their studies will quantify the relative importance of each of these possible mechanisms of the abnormal response of LV filling dynamics to exercise in dogs chronically instrumented to measure LV P and volume (V) and LA P before and after inducing CHF by rapid ventricular pacing. They will also determine systemic and myocardial activation of the renin-ANG during CHF exercise. They will evaluate the effect of each potential factors alone, before and after CHF, and the effect of blocking the increase in systolic load, heart rate, adrenergic stimulation and ANG II (both with an ACE inhibitor and/or an ANG II receptor blocker) on the response to exercise before and after CHF. This new information on the mechanism of the abnormal response of diastolic filling dynamics during CHF exercise, will help target therapy to improve exercise tolerance in patients with CHF.

描述：心力衰竭运动耐受性（CHF）不好 与左心室（LV）收缩性能相关，相反 随着左心（LA）压力（p）的水平更加紧密变化。 申请人实验室和患者的观察表明 CHF有正常运动引起的逆转 LV放松并在早期舒张期LV P中掉落，导致增加 因此，在LaP中，CHF中静止的舒张功能障碍为 在劳累期间加剧，是锻炼的重要原因 瑞士法郎的不宽容。产生这种异常运动的机制 CHF后的反应尚未确定。可能的因素 贡献包括CHF中LV松弛的反应改变对 收缩压增加，血管紧张素（ANG）II，心率和肾上腺素能 运动过程中发生的刺激。虽然心肌ANG II 尚未确定CHF练习期间的水平，申请人的 初步观察表明循环ANG II水平 瑞士法郎运动期间增加到很高的水平。因此，它出现了 LV松弛可能会放慢并舒张填充动力学 通过增加对Ang II和Ang II的敏感性和 高ANG II水平。此申请的目的是调查 LV松弛和 CHF结果后运动期间增加了早期舒张期LV P和LA P 从：1）提高LV松弛和舒张期填充的灵敏度 ANG II的动力学，在心肌中增加到高水平 在CHF运动中； 2）提高对收缩负荷增加的敏感性 在锻炼期间； 3）减少产生的放松的增强 通过运动过程中心率和肾上腺素能刺激的增加； 4）心内膜缺血。他们的研究将量化亲戚 异常反应的每种可能机制的重要性 lv填充动力学以在长期仪器中锻炼到 测量LV P和体积（V）和LA P，在诱导CHF之前和之后 快速心室起搏。他们还将确定系统性和 CHF运动过程中肾素角的心肌激活。他们会的 单独评估每个潜在因素的效果，之前和之后 CHF以及阻止收缩期增加的效果，心脏 速率，肾上腺素能刺激和ANG II（均具有ACE抑制剂 和/或ANG II受体阻滞剂）在锻炼之前的反应 和瑞士法郎之后。有关异常机制的新信息 CHF运动期间舒张期充满动力的反应将有助于 靶向治疗以提高CHF患者的运动耐受性。