Aging, Fitness & Failure: Diastolic Dysfunction

即使没有明显的合并症，如冠状动脉疾病或高血压，衰老也与左心室舒张和顺应性的改变有关。这种“舒张功能障碍”可能导致左室充盈压升高，并引起充血性心力衰竭（CHF）的体征和症状，尽管存在保留的收缩功能。这个问题对老年CHF患者至关重要，其中近1/2的患者可能主要以舒张功能障碍导致心力衰竭。该提案的主要目的是确定与人类正常健康衰老相关的舒张功能的精确变化，并将这些变化与舒张功能障碍引起的心力衰竭相关的变化进行比较。有待检验的假设包括：1)与健康年轻人相比，正常衰老与左室舒张和室腔顺应性的改变有关，导致心室充盈受损。此外，与久坐不动的健康老年人相比，这些异常将大大减少；2)伴有左室收缩功能保留的CHF患者左室顺应性和舒张异常更为明显，有助于CHF的发生；3)无论是健康老年人，还是合并舒张功能不全的CHF患者，运动训练都能改善舒张功能异常，是治疗该病的有效方法。为了验证这些假设，我们建议实现以下具体目标：a)通过构建良好、久坐和健康的老年人的心室功能（Starling）和左室压力/容积曲线，直接测量舒张的静态成分。舒张的动态成分将使用最先进的成像技术进行评估，包括：组织多普勒成像；彩色多普勒m模回波；还有心肌标记的磁共振成像。b)选择一组保留收缩功能的CHF患者，采用相同的方法量化左室舒张度和顺应性；c)在久坐老年人和伴有心衰和舒张功能不全的患者中，重复长时间（一年）耐力运动训练后的舒张功能的具体测量。这些研究将全面了解正常衰老和身体调节对左室舒张功能的影响，并将在没有收缩功能障碍的情况下确定导致CHF的特定舒张异常。将确定恢复正常舒张功能所需的精确运动剂量，并为这些人群制定具体的运动处方。

Aging is associated with alterations in left ventricular (LV) relaxation and compliance, even in the absence of manifest co-morbid conditions such as coronary artery disease or hypertension. This "diastolic dysfunction" may result in an elevation of LV filling pressure and cause signs and symptoms of congestive heart failure (CHF) despite the presence of preserved systolic function. This problem is critical for elderly CHF patients in whom nearly 1/2 may have predominantly diastolic dysfunction as the cause of their heart failure. The broad objective of this proposal is to determine the precise alterations of diastolic function associated with normal, healthy aging in humans, and compare these changes with those associated with CHF due to diastolic dysfunction. The hypotheses to be tested include: 1) Normal aging is associated with alterations in both relaxation and chamber compliance of the LV leading to impaired ventricular filling compared to healthy young adults. Moreover, such abnormalities will be substantially reduced in fit compared to sedentary healthy elderly subjects; 2) Patients with CHF and preserved LV systolic function have more pronounced abnormalities of LV chamber compliance and relaxation which contribute to the development of CHF; 3) Exercise training in both the healthy aged, as well as patients with CHF and diastolic dysfunction will improve abnormalities of diastolic function and will be an effective therapy for this disease. To test these hypotheses, we propose to accomplish the following specific aims: a) To measure the static component of diastole directly by constructing ventricular function (Starling) and LV pressure/volume curves in well, sedentary and fit elderly adults. The dynamic component of diastole will be assessed using state- of-the-art imaging techniques including: tissue Doppler imaging; color Doppler M-mode echo; and magnetic resonance imaging with myocardial tagging. b) To select a group of patients with CHF but preserved systolic function, and to quantify left ventricular relaxation and compliance using the same methods; c) To repeat the specific measures of diastolic function after a prolonged (one year) endurance exercise training program in both the sedentary elderly, and patients with CHF and diastolic dysfunction. These studies will result in a comprehensive understanding of the effect of normal aging and physical conditioning on LV diastolic function, and will identify the specific abnormalities of diastole which lead to CHF in the absence of contractile dysfunction. The precise dose of exercise necessary to restore normal diastolic function will be identified and will allow specific exercise prescription for these populations.