MECHANISMS OF EXERCISE INTOLERANCE IN HEART FAILURE

描述：心力衰竭（CHF）的运动耐量不佳 与左心室（LV）收缩性能相关，相反， 随着左心房（LA）压力（P）的水平变化更密切。 在申请人的实验室和患者中的观察表明， CHF有一个逆转的正常运动引起的增强， LV舒张和舒张早期LV P下降，导致增加 因此，CHF中静息时存在的舒张功能障碍是 在劳累时加重，是运动的重要原因 不耐受CHF。产生这种异常运动的机制 CHF后的反应尚未确定。因素可能 包括CHF患者左心室舒张对 收缩负荷、血管紧张素（ANG）II、心率和肾上腺素能增加 运动时产生刺激。虽然心肌ANG II 在CHF演习期间尚未确定水平，申请人的 初步观察表明，循环ANG II水平 在CHF运动期间增加到非常高的水平。因此， LV舒张可能减慢，舒张期充盈动力学 在CHF运动期间通过增加对ANG II的敏感性和 高ANG II水平。本申请的目的是调查 左室舒张功能异常的综合反应机制， CHF后运动时舒张早期LV P和LA P增加 来自：1）LV舒张和舒张充盈的敏感性增加 ANG II的动力学，其在心肌中增加到高水平 CHF运动期间; 2）对收缩负荷增加的敏感性增加 在运动过程中; 3）减少放松产生的增加 通过运动时心率的增加和肾上腺素能刺激; （4）血管内缺血。他们的研究将量化 异常反应的这些可能机制中的每一个的重要性 左室充盈动力学与运动的关系， 分别在诱导CHF前后测定左室压（LV P）、左室容积（V）和左室压（LA P）， 快速心室起搏他们还将确定系统和 CHF运动过程中心肌的肾素-ANG活化。他们将 单独、前后评价各潜在因素的影响 CHF，以及阻断心脏收缩负荷增加的作用， 速率、肾上腺素能刺激和ANG II（均使用ACE抑制剂 和/或ANG II受体阻断剂）对运动前的反应的影响 在CHF之后。这一新的信息机制的异常 舒张期充盈动力学的反应，在CHF运动，将有助于 靶向治疗提高CHF患者运动耐量。

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.