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).

项目摘要/摘要 年龄是心血管疾病发展的最强预测因子。外周动脉疾病(PAD) 是一种常见的使人衰弱的心血管疾病，其特征是动脉粥样硬化病变。 和腿部中等大小的动脉。2015年的数据显示，全球有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%。超过44亿美元被花费在 在美国每年都会有PAD。PAD与行走过程中的疼痛(即“间歇性跛行”)有关， 功能独立性降低，冠心病和心脏性死亡的风险极高。 换句话说，患有I期或II期PAD(也称为“跛行”)的患者去看医生是因为 他们腿部疼痛，但冠状动脉疾病最有可能导致他们死亡。因此，有效的战略是 需要改善PAD患者的步行能力和冠脉血管健康。在此R21应用程序中，我们 提出机械驱动的干预研究，以改善一种在老年人中高度流行的疾病 人口。我们将使用T1转换方法。具体地说，我们正在应用基本和临床研究结果 探讨改善冠心病患者步行能力和冠脉功能的新策略 诊断为PAD。在目标1中，我们将评估急性心脏选择性β-1阻断(与艾司洛尔联合)对血管紧张素转换酶的影响。 PAD运动过程中冠脉血流量、小腿肌肉氧合和全身血压。在目标2中，我们将评估 日粮添加硝酸盐(甜菜根汁)4~6天对小腿肌肉冠脉血流量的影响 PAD运动时的氧合作用和全身血压。有很强的科学前提来进行 建议进行的研究。尽管PAD的患病率和相关的不良冠状动脉结果，只有我们最近 已发表的研究(Ross等人2017年)测量了PAD患者在运动期间的冠脉血流量。此外， 这项单一研究评估了饮食中补充硝酸盐对步行能力和 PAD患者的外周血管反应乏力，没有使用真正的安慰剂。在此T1翻译版本中 项目，我们将通过进行严格设计的、机制驱动的干预来填补这些知识空白 有症状性PAD的老年人(55-85岁)的研究。如果这些探索性研究发现β1-封锁和/或 膳食硝酸盐对PAD安全有效，我们的调查团队将处于有利地位，进行 多中心研究(最终需要改变这些患者的护理标准)。