Aging Fitness & Failure: Mechanisms of Diastolic Dysfunction

描述(申请人提供)：心力衰竭是老年人的祸害，造成近350亿美元的损失，并导致相当大的发病率和死亡率；大约50%的老年CHF患者有心力衰竭并保留射血分数(HFpEF)，这是一种多因素疾病，与几种舒张性功能异常有关。受该研究项目以前工作的启发，未来5年的全球目标是测试新的策略，以预防和逆转与久坐衰老和HFpEF相关的舒张期功能受损。这些包括：A)在生命的早期实施新的运动训练策略，而心血管的可塑性仍然存在；以及B)针对潜在的病理生理学的药理探测，旨在改善老年人和HFpEF患者的放松，并恢复功能能力。该计划的目标是：具体目标1：检验这样一种假设：在久坐不动的中年男性和女性(45-64岁)中，每周进行4-5次运动训练2年，将改善心脏和血管顺应性，其程度相当于终身运动者(和久坐不动的年轻人)。我们将在一项包括高强度有氧间歇、低强度耐力和力量训练或瑜伽控制的运动计划前后对心血管结构和功能进行侵入性和非侵入性评估。具体目标2：检验HFpEF患者僵硬、缓慢松弛的心脏 在运动过程中导致肺毛细血管压力显著升高，导致在达到最大心率之前过早疲劳，从而导致明显的“变时性功能不全”。我们进一步假设，久坐的老年患者和HFpEF患者都由于SERCA2a活性的下调而减缓了松弛，SERCA2a活性是年龄相关的趋性功能受损的可能细胞机制。为此，我们计划进行两组实验：1)测量HR对两种不同干预措施的反应：a)从40%最大自主收缩的静态握力到疲劳的最大中枢心血管通路的最大激活；b)在神经节阻滞面前递增剂量的异丙肾上腺素，以隔离没有反射补偿的肾上腺素能反应；2)与年龄匹配的和年轻的对照组相比，对HFpEF患者在静息和运动时的心功能进行有创和非侵入性的评估：a)输注司他昔姆，一种由于能够上调SERCA2a活性而具有显著性欲的实验药物；和b)Na+/K+ATPase抑制对照(地高辛)。在这些目标实现后，我们将建立一种新的、实用的运动训练策略，旨在防止随着年龄的增长而导致的心血管僵硬，并最终防止HFpEF。这样的决定将具有巨大的公共卫生意义，因为这种情况一旦确定就很难治疗。此外，我们将使用新的生理学和药理学探针来确定HFpEF患者明显的变时性功能障碍和运动能力受损的机制，这可能为这一具有挑战性的综合征开辟新的治疗选择。 公共卫生相关性：这项研究试图预防和扭转健康老年人和舒张性心力衰竭患者的功能能力随年龄增长而恶化的情况。我们将制定优化的运动计划，以保持年轻的心脏结构，并将探索新的策略，以改善老年心脏的放松。

DESCRIPTION (provided by applicant): Heart failure is the scourge of the elderly accounting for nearly $35 billion dollars and causing substantial morbidity and mortality; ~50% of all aged patients with CHF have heart failure with a preserved ejection fraction (HFpEF), a multi-factorial condition associated with several abnormalities in diastolic function. Stimulated by previous work from this research program the global objective of the next 5 years is to test novel strategies to prevent and reverse the impaired diastolic function associated with sedentary aging and HFpEF. These include: A) novel exercise training strategies implemented early enough in life while CV plasticity still exists; and B) pharmacologic probes of underlying pathophysiology targeted to improve relaxation in the elderly and HFpEF patients, and restore functional capacity. The aims of the program are: Specific Aim 1: to test the hypothesis that exercise training implemented 4-5 times/week for 2 yrs in sedentary middle aged men and women (45-64yr) will improve cardiac and vascular compliance to a degree equivalent to life-long exercisers (and sedentary young). We will perform invasive and non-invasive assessment of cardiovascular structure and function before and after an exercise program involving high intensity aerobic intervals, lower intensity endurance and strength training or yoga control. Specific Aim 2: to test the hypothesis that the stiff, slowly relaxing heart of patients with HFpEF causes a marked elevation in pulmonary capillary pressure during exercise which leads to premature fatigue prior to achieving maximal HR, thus causing apparent "chronotropic incompetence". We further hypothesize that both sedentary aged and HFpEF patients have slowed relaxation due to down regulation of SERCA2a activity, the putative cellular mechanism underlying age related impaired lusitropic function. We plan to perform 2 sets of experiments for this aim: 1) to measure the HR response to two separate interventions: a) maximal activation of central cardiovascular pathways ("central command") from static handgrip at 40% maximal voluntary contraction to fatigue; b) incremental doses of isoproterenol in the face of ganglionic blockade to isolate ¿ adrenergic responsiveness without reflex compensation; and 2) to perform invasive and non-invasive assessment of cardiac function at rest and during exercise in patients with HFpEF compared to age matched and young controls: a) after infusion of istaroxime an experimental drug with prominent lusitropic properties due to its ability to upregulate SERCA2a activity; and b) after Na+/K+ ATPase inhibition control (digoxin). After these aims are accomplished, we will have established a novel, practical exercise training strategy designed to prevent the cardiovascular stiffening with aging, and ultimately to prevent HFpEF. Such a determination would have enormous public health significance since this condition is quite difficult to treat once established. In addition, we will use novel physiological and pharmacological probes to determine the mechanism of the apparent chronotropic incompetence and impaired exercise capacity in patients with HFpEF which has the potential to open up new therapeutic options for this challenging syndrome. PUBLIC HEALTH RELEVANCE: This research seeks to prevent and reverse the deterioration in functional capacity with advancing age, both in healthy seniors & patients with diastolic heart failure. We will develop an optimized exercise program to preserve youthful cardiac structure, & will explore new strategies to improve relaxation of the aged heart.