MECHANISMS OF EXERCISE INTOLERANCE IN HEART FAILURE

描述：心力衰竭(CHF)患者运动耐量不佳 与左心室(LV)收缩功能相关，相反，它 与左房(LA)压力(P)水平的变化更为密切。 在申请人的实验室和患者中的观察表明 CHF患者的正常运动诱发的心功能增强发生逆转 LV舒张期早期的LV松弛和下降并导致LV P升高 因此，在LA P中，CHF静息状态下的舒张期功能障碍是 在运动过程中加重，是运动的重要原因 慢性心力衰竭的不耐受。产生这种异常运动的机制 充血性心力衰竭后的反应尚未确定。可能存在的因素 贡献包括充血性心力衰竭左室舒张反应的改变 收缩负荷增加、血管紧张素II、心率和肾上腺素能 在运动过程中产生的刺激。虽然心肌血管紧张素II 在CHF锻炼期间尚未确定水平，申请者的 初步观察表明，循环血管紧张素II水平 在CHF运动期间增加到非常高的水平。因此，它看起来 可能的左室舒张减慢和舒张期充盈动力学 在CHF运动中对Ang II和Ang II的敏感性增加而改变 高Ang II水平。此应用程序的目的是调查 左心室舒张期和室上性心动过速综合反应异常的机制 充血性心力衰竭后运动时舒张期早期LV P和LA P升高 来自：1)左室舒张和舒张期充盈的敏感性增加 对Ang II的动力学作用，它在心肌中增加到高水平 在CHF运动期间；2)对收缩压负荷增加的敏感性增加 在运动过程中；3)减少放松产生的增强 运动时心率增加和肾上腺素能刺激； (4)心内膜缺血。他们的研究将量化相关的 异常反应的每一种可能机制的重要性 对长期使用仪器的狗进行运动的左心室充盈动力学 测定诱发充血性心力衰竭前后的LV-P、V和LA-P。 快速心脏起搏。他们还将决定系统性和 充血性心力衰竭运动中心肌肾素-血管紧张素转换酶的激活他们会 单独、前后评估每个潜在因素的影响 CHF，以及阻断心脏收缩负荷增加的作用 心率、肾上腺素能刺激和血管紧张素转换酶II(均使用ACE抑制剂 和/或血管紧张素Ⅱ受体阻滞剂)对运动反应的影响 充血性心力衰竭后。这一关于异常机制的新信息 心力衰竭运动中舒张期充盈动力学的反应将有所帮助 改善充血性心力衰竭患者运动耐量的靶向治疗。

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.