Aging Fitness & Failure: Mechanisms of Diastolic Dysfunction

描述（由申请人提供）：心力衰竭是老年人的灾难，约占350亿美元，并导致大量的发病率和死亡率;约50%的CHF老年患者患有射血分数保留的心力衰竭（HFpEF），这是一种与舒张功能异常相关的多因素疾病。受该研究项目先前工作的刺激，未来5年的全球目标是测试预防和逆转与久坐老化和HFpEF相关的舒张功能受损的新策略。其中包括：A）在CV可塑性仍然存在的情况下，在生命早期实施新的运动训练策略;和B）旨在改善老年人和HFpEF患者的放松并恢复功能能力的潜在病理生理学的药理学探针。该计划的目的是：具体目标1：检验以下假设：久坐的中年男性和女性（4-5 - 64岁）每周进行4-5次运动训练，持续2年，将改善心脏和血管顺应性，达到与终身锻炼者（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计划前后对心血管结构和功能进行有创和无创评估。具体目的2：检验HFpEF患者僵硬、缓慢舒张的心脏 在运动期间引起肺毛细血管压力显著升高，这导致在达到最大HR之前过早疲劳，从而引起明显的“变时性功能不全”。我们进一步假设，久坐的老年人和HFpEF患者由于SERCA 2a活性的下调而减缓了松弛，这是年龄相关的Lustropic功能受损的假定细胞机制。我们计划为此目的进行两组实验：1）测量HR对两种单独干预的反应：a）中枢心血管通路的最大激活（“中枢指令”）从40%最大随意收缩的静态握力到疲劳; B）面对神经节阻滞时递增剂量的异丙肾上腺素以隔离无反射补偿的肾上腺素能反应;和2）与年龄匹配的年轻对照组相比，对HFpEF患者在静息和运动期间的心脏功能进行侵入性和非侵入性评估：a）在输注istaroxime（一种实验药物，由于其上调SERCA 2 a活性的能力而具有显著的抗心律失常特性）后;和B）在Na+/K+ ATP酶抑制对照（地高辛）后。在这些目标实现后，我们将建立一个新的，实用的运动训练策略，旨在防止心血管硬化与老化，并最终防止HFpEF。这种确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患者明显变时性功能不全和运动能力受损的机制，这有可能为这种具有挑战性的综合征开辟新的治疗选择。

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.