Aging, Fitness & Failure: Diastolic Dysfunction

衰老与左心室(LV)松弛和顺应性的改变有关，即使在没有明显的共病情况下，如冠状动脉疾病或高血压。这种“舒张期功能障碍”可能导致左心室充盈压升高，并导致充血性心力衰竭(CHF)的体征和症状，尽管存在收缩功能的保留。这个问题对于老年CHF患者来说是至关重要的，在这些患者中，近一半的人可能以舒张期功能障碍为主，这是他们心力衰竭的原因。这项建议的广泛目标是确定与人类正常、健康的衰老相关的舒张期功能的准确变化，并将这些变化与由于舒张期功能障碍而导致的CHF相关的变化进行比较。需要测试的假说包括：1)与健康的年轻人相比，正常衰老与左心室的松弛和室壁顺应性的改变有关，从而导致心室充盈受损。此外，与久坐不动的健康老年人相比，这种异常在Fit中将大幅减少；2)CHF患者和左心室收缩功能正常的患者有更明显的左心腔顺应性和舒张性异常，这有助于CHF的发展；3)无论是健康老年人，还是CHF合并舒张期功能障碍的患者，运动训练都将改善舒张期功能异常，将是一种有效的治疗方法。为了验证这些假设，我们建议完成以下具体目标：a)通过构建正常、久坐和健康的老年人的心功能(Starling)和LV压力/容量曲线，直接测量舒张期的静态成分。将使用最先进的成像技术评估舒张期的动态成分，包括：组织多普勒成像、彩色多普勒M型回波和带有心肌标记的磁共振成像。B)选择一组收缩功能正常的CHF患者，并用相同的方法量化左心室的松弛和顺应性；c)对久坐不动的老年人和CHF合并舒张期功能障碍的患者进行延长(一年)的耐力运动训练后，重复特定的舒张期功能测量。这些研究将有助于全面了解正常衰老和物理条件对左室舒张功能的影响，并将确定在没有收缩功能障碍的情况下导致充血性心力衰竭的特定舒张期异常。将确定恢复正常舒张期功能所需的准确运动剂量，并将为这些人群提供具体的运动处方。

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.