Aging Fitness & Failure: Mechanisms of Diastolic Dysfunction

描述（由申请人提供）：心力衰竭是老年人的祸害，占近350亿美元，并造成大量发病率和死亡率；~50%的老年CHF患者有心力衰竭并保留射血分数（HFpEF），这是一种与舒张功能异常相关的多因素疾病。受该研究项目前期工作的启发，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相关的舒张功能受损。这包括：A)在生命早期实施新颖的运动训练策略，而CV可塑性仍然存在；B)以改善老年人和HFpEF患者的放松状态，恢复功能能力为目标的基础病理生理药理探测。具体目标1：验证这样一个假设，即在45-64岁的久坐中年男性和女性中，每周进行4-5次运动训练，持续2年，将使心脏和血管的依从性提高到与终身锻锻者（和久坐的年轻人）相当的程度。我们将在高强度有氧间歇、低强度耐力和力量训练或瑜伽控制的运动项目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：验证假设HFpEF患者僵硬，缓慢放松的心脏

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.