Novel Therapies to Improve Cardiac and Skeletal Muscle O2 Supply-Demand Mismatch in Older Adults with Peripheral Arterial Disease

改善患有外周动脉疾病的老年人心脏和骨骼肌 O2 供需失配的新疗法

• 批准号: 9789793
• 负责人: DAVID N PROCTOR
• 金额: $ 19.51万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789793
• 关键词: Acute; Adrenergic Agents; Adrenergic Antagonists; Adult; Affect; Age; Aging; American; Arterial Fatty Streak; Arteries; Atherosclerosis; Blood Vessels; Blood flow; Cardiac Death; Cardiovascular Diseases; Clinical; Coronary; Coronary Arteriosclerosis; Coronary heart disease; Data; Development; Diagnosis; Disease; Drug Kinetics; Elderly; Exercise; Exertion; Funding; Goals; Health; Heart; Hypoxia; Impairment; Intermittent Claudication; Intervention; Intervention Studies; Ischemia; Isometric Exercise; Juice; Kinetics; Knowledge; Leg; Measures; Medical; Methods; Multicenter Studies; Muscle; Myocardial; Myocardial Ischemia; Myocardium; Near-Infrared Spectroscopy; Nitrates; Nitric Oxide; Organ; Outcome; Oxygen; Pain; Pain in lower limb; Pathway interactions; Patient Care; Patients; Performance; Peripheral; Peripheral arterial disease; Personal Satisfaction; Pharmaceutical Preparations; Physiological; Placebos; Population; Positioning Attribute; Prevalence; Property; Protocols documentation; Publishing; Research Personnel; Risk; Skeletal Muscle; Supplementation; Symptoms; Systemic blood pressure; Systolic heart failure; Testing; Therapeutic; Time; Tissues; Translating; Ultrasonography; United States; Vasodilation; Visit; Walking; arm; cardiovascular disorder risk; claudication; clinically relevant; coronary event; design; dietary nitrate; esmolol; exercise intolerance; functional independence; hemodynamics; high risk; human subject; improved; novel; novel therapeutics; pressure; response; standard of care; temporal measurement; translational approach; treadmill

Project Summary / Abstract Aging is the strongest predictor for the development of cardiovascular disease. Peripheral arterial disease (PAD) is a common and debilitating form of cardiovascular disease characterized by atherosclerotic lesions in the large and medium sized arteries of the legs. Data from 2015 suggest that > 200 million people worldwide have PAD; PAD is prevalent in 7% of people age 55-59 and in 20% of people age 80-84. More than $4.4 billion is spent on PAD each year in the United States. PAD is associated with pain during walking (i.e., “intermittent claudication”), decreased functional independence, and an extremely high risk of coronary heart disease and cardiac death. Stated another way, patients with stage I or stage II PAD (also called “claudication”) visit their doctor because they have leg pain, but coronary disease is what will most likely kill them. Therefore, effective strategies that improve walking ability and coronary vascular health in PAD patients are needed. In this R21 application we propose mechanistic-driven intervention studies to improve a disease that is highly prevalent in the geriatric population. We will use a T1 translational approach. Specifically, we are applying basic and clinical findings toward new strategies to improve walking ability and coronary vascular function in human subjects with diagnosed PAD. In Aim 1, we will evaluate the effect of acute cardioselective β1 blockade (with esmolol) on coronary blood flow, calf muscle oxygenation, and systemic BP during exercise in PAD. In Aim 2, we will evaluate the effect of four to six days of dietary nitrate supplementation (beetroot juice) on coronary blood flow, calf muscle oxygenation, and systemic BP during exercise in PAD. There is a strong scientific premise to conduct the proposed studies. Despite the prevalence of PAD and the associated poor coronary outcomes, only our recently published study (Ross et al 2017) has measured coronary blood flow during exercise in PAD patients. Moreover, the single study that evaluated the effects of dietary nitrate supplementation on walking performance and peripheral vascular responses in PAD was underpowered and did not use a true placebo. In this T1 translational project, we will fill these gaps in knowledge by conducting rigorously designed, mechanism-driven intervention studies in older adults (55-85 yr) with symptomatic PAD. If these exploratory studies identify β1-blockade and/or dietary nitrate as safe and efficacious for PAD, our team of investigators will be well positioned to conduct a multi-center study (which would be needed to ultimately change the standard of care in these patients).

项目概要/摘要 衰老是外周动脉疾病（PAD）发生的最强预测因素。 是一种常见且令人衰弱的心血管疾病，其特征是大面积动脉粥样硬化病变 2015 年的数据表明，全球有超过 2 亿人患有 PAD； PAD 在 55-59 岁的人群中占 7%，在 80-84 岁的人群中占 20%，为此花费了超过 44 亿美元。 在美国，PAD 每年都与行走时的疼痛（即“间歇性跛行”）相关。 功能独立，冠心病和心源性死亡的风险极高。 换句话说，患有 I 期或 II 期 PAD（也称为“跛行”）的患者去看医生，因为 他们有腿痛，但冠状动脉疾病最有可能杀死他们，因此，有效的策略是 在此 R21 应用中，我们需要改善 PAD 患者的步行能力和冠状血管健康。 机制驱动的干预研究提出了一种在老年人中高度流行的疾病 具体来说，我们将应用基础和临床发现。 寻找改善人类受试者步行能力和冠状血管功能的新策略 在目标 1 中，我们将评估急性心脏选择性 β1 阻断（使用艾司洛尔）对诊断的 PAD 的影响。 在目标 2 中，我们将评估 PAD 运动期间的冠状动脉血流量、小腿肌肉氧合和全身血压。 四到六天膳食硝酸盐补充剂（甜菜根汁）对冠状动脉血流量、小腿肌肉的影响 PAD 运动期间的氧合和全身血压 进行该研究有强有力的科学前提。 尽管 PAD 普遍存在且冠心病结局不佳，但我们最近才进行了研究。 已发表的研究（Ross et al 2017）测量了 PAD 患者运动期间的冠状动脉血流量。 评估膳食硝酸盐补充剂对步行表现和 PAD 中的外周血管反应动力不足，并且在此 T1 转化中未使用真正的安慰剂。 项目中，我们将通过严格设计、机制驱动的干预来填补这些知识空白 针对患有 PAD 症状的老年人（55-85 岁）的研究如果这些探索性研究确定了 β1 阻断和/或。 膳食硝酸盐对 PAD 安全有效，我们的研究团队将有能力开展一项研究 多中心研究（需要最终改变这些患者的护理标准）。