Insulin Resistance in Chronic Heart Failure: pathophysiology and potential for re

慢性心力衰竭中的胰岛素抵抗：病理生理学和治疗潜力

• 批准号: 8438447
• 负责人: Nir Uriel
• 金额: $ 13.92万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-05 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8438447
• 关键词: Academic Medical Centers; Activities of Daily Living; Acute; Adipocytes; Adipose tissue; Administrator; Adrenergic Agents; Advisory Committees; Affect; Appearance; Award; Biopsy; Blood Circulation; Body Composition; Body fat; Cardiac; Cardiopulmonary; Cardiovascular Physiology; Cardiovascular system; Catecholamines; Chronic; Clinical; Complement; Congestive Heart Failure; Data; Defect; Development; Diabetes Mellitus; Disease; Dyslipidemias; Endemic Diseases; Endocrine; Excision; Exercise; Exercise Physiology; Exercise stress test; Fatty acid glycerol esters; Foundations; Functional disorder; Future; Glycosylated Hemoglobin; Glycosylated hemoglobin A; Heart failure; Heparin; Insulin; Insulin Resistance; Laboratories; Left; Link; Lipids; Lipolysis; Lipoproteins; Measures; Mechanics; Mediating; Medical; Medical Research; Medicine; Mentors; Metabolism; Nested Case-Control Study; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Norepinephrine; Organ; Patients; Phase; Plasma; Prevention; Process; Research; Rest; Risk; Risk Factors; Scientist; Serum; Severities; Skeletal Muscle; Staging; Stress; Techniques; Testing; Tissues; Training; Training Programs; Translational Research; Transplantation; Triglycerides; United States; United States National Institutes of Health; Woman; adrenergic; cardiovascular pharmacology; career; career development; design; diabetic; experience; fatty acid metabolism; hemodynamics; implantation; interest; lipophilicity; lipoprotein lipase; men; muscle form; novel; outcome forecast; programs; response; stable isotope; therapeutic target; ventricular assist device

DESCRIPTION (provided by applicant): This proposal details a comprehensive 5-year training program for my career development in academic Cardiovascular Medicine. I have completed advanced training in Heart Failure (HF) and Transplant at Columbia University Medical Center. I now plan to embark on a mentored research program to obtain additional scientific training necessary for an independent academic career focused on translational research in congestive HF. Accordingly, throughout the period of this award, I will receive formal training in the design and conduct of medical research and gain in-depth experience in exercise physiology and fuel metabolism in patient with chronic HF. Drs. Ulrich Jorde and Henry Ginsberg will mentor my scientific career development. Dr. Ulrich Jorde has a strong NIH track-record with emphasis on cardiovascular pharmacology and physiology in patients with congestive HF. His particular expertise is in conducting mechanistic studies centered on exercise physiology and neurohormonal activation, and his laboratory's most recent focus is fuel metabolism in HF. Dr. Jorde is also a renowned expert in the medical aspects of left ventricular assist device therapy. Dr. Henry Ginsberg, the co-mentor, is an internationally recognized expert in lipoprotein metabolism. Dr. Ginsberg has a particular interest in the pathophysiology of dyslipidemia associated with insulin resistance and diabetes mellitus. In addition, an advisory committee of established basic and clinical scientists in cardiovascular and endocrine medicine (Drs. Ira Goldberg, Jeanine Albu, Domenico Accili, Dympna Gallagher, and Yoshifumi Naka) statistician (Dr. Rajasekhar Radakrishnan) and administrators (Dr Jaime Rubin) will provide scientific and career advice to complement a comprehensive didactic program. The main hypothesis of this proposal is that increased adrenergic activation causes increased basal FFA release from adipose tissue and that this increased basal FFA secretion contributes (via storage depletion akin to what is seen with NE in HF) to an inadequate FFA response to exercise and thus exercise intolerance. We propose to test this hypothesis by performing a nested case control study of HF patients with and without IR (Aim 1). Additionally, we will use long term mechanical circulatory support with a LVAD to formally test whether reversing HF reverses IR and normalizes circulating FFA availability (Aim 2). Aim 1: To investigate mechanisms underlying reduced exercise-induced FFA availability in HF patients with IR. In aim 1a, we hypothesize that the decreased FFA availability we observed during exercise in HF-IR is due to decreased exercise-induced FFA release from adipose tissue rather than increased clearance of FFA from the circulation. We will identify 15 HF subjects with IR (HF-IR), 15 subjects with matched HF without IR (HF-No-IR), and a group of healthy controls. Total body fat, organ specific fat, and muscle mass will be measured in HF subjects to control for body composition. We will then evaluate exercise-induced changes in circulating FFA using cardiopulmonary exercise testing (CPET) and stable isotope techniques to measure FFA appearance and fractional clearance from plasma (FFA turnover). In aim 1b, we hypothesize that the mechanism for decreased FFA release is blunted catecholamine-induced adipocyte lipolysis. Basal and catecholamine-induced rates of FFA release will be measured in fat tissue obtained by biopsies of all subjects to test whether adipocytes chronically subjected to elevated plasma NE levels (measured simultaneously) fail to increase release of FFA during an acute catecholamine challenge. We will also measure post heparin plasma lipoprotein lipase (LPL) activity to assess the availability of circulating lipoprotein-derived FFA in each group of subjects. Aim 2: To determine whether and how LVAD therapy reverses IR and the defect in exercise-induced increase in FFA. In aim 2, we hypothesize that LVAD therapy reverses IR in HF and also restores exercise induced FFA availability. We will study 20 HF patients undergoing LVAD implantation. We will comprehensively assess body composition, IR, adipocyte FFA release, LPL activity, adrenergic activation and exercise-induced FFA availability as well as FFA turnover as described in aim 1. The severity of HF will be serially assessed using CPET and hemodynamic studies. Tests will be done before as well as 1, 3 and 6 months after LVAD. Significance: HF is a disease of endemic proportions, and the development of IR in HF heralds a decline in functional capacity and worsening prognosis. We will determine the mechanistic underpinnings of HF-IR with particular emphasis on altered FFA metabolism and its reversibility and provide direction for future studies: If our flux studies demonstrate that impaired FFA release underlies impaired availability, they will identify fat tissue and lipid breakdown as potential therapeutic targets. For example, adrenergic blockade using high lipophilicity agents directed at the adipose tissue may normalize basal FFA secretion and thus restore FFA response to exercise in HF. In contrast, if increased fractional FFA removal underlies the low stress-induced FFA levels in HF-IR, cardiac and/or skeletal muscle FFA metabolism should be studied. Our approach using LVAD therapy as a non-pharmacological means to reverse and study late stage HF-IR is entirely novel and, if successful, will lay the foundation for treatment and possibly prevention of HF-IR in earlier phases of HF.

描述（由申请人提供）：该提案详细介绍了我在学术心血管医学职业发展的5年培训计划。我已经在哥伦比亚大学医学中心完成了心力衰竭（HF）和移植的高级培训。我现在计划着手进行一项指导的研究计划，以获得针对充满交通HF转化研究的独立学术职业所需的其他科学培训。因此，在整个奖项期间，我将获得有关医学研究的设计和进行正式培训，并在慢性HF患者的运动生理学和燃料代谢方面获得深入的经验。博士。乌尔里希·乔德（Ulrich Jorde）和亨利·金斯伯格（Henry Ginsberg）将指导我的科学职业发展。乌尔里希·乔德（Ulrich Jorde）博士拥有强大的NIH田径记录，重点是充血HF患者的心血管药理学和生理学。他的特殊专业知识是进行以运动生理和神经激活为中心的机械研究，而他的实验室最近重点是HF中的燃料代谢。乔德博士还是左心室辅助设备治疗的医学方面的著名专家。院长亨利·金斯伯格（Henry Ginsberg）博士是脂蛋白代谢的国际认可的专家。金斯伯格博士对与胰岛素抵抗和糖尿病有关的血脂异常的病理生理特别感兴趣。 In addition, an advisory committee of established basic and clinical scientists in cardiovascular and endocrine medicine (Drs. Ira Goldberg, Jeanine Albu, Domenico Accili, Dympna Gallagher, and Yoshifumi Naka) statistician (Dr. Rajasekhar Radakrishnan) and administrators (Dr Jaime Rubin) will provide scientific and career advice to complement a comprehensive didactic program.该提案的主要假设是，肾上腺素能激活的增加导致脂肪组织的基础FFA释放增加，而这种增加的基础FFA分泌增加（通过与NE在HF中看到的相似的储存耗尽相似）对FFA对运动的反应不足，从而对运动的反应不足。我们建议通过对有或没有IR的HF患者进行嵌套病例对照研究来检验这一假设（AIM 1）。此外，我们将使用LVAD的长期机械循环支持正式测试逆转HF是否逆转IR并归一化循环FFA的可用性（AIM 2）。目的1：研究HF患者的HF患者的运动诱导的FFA供应减少的机制。在AIM 1A中，我们假设我们在HF-IR中观察到的FFA可用性降低是由于运动诱导的脂肪组织释放的FFA释放而不是增加循环中FFA的清除率。我们将确定15名具有IR（HF-IR）的HF受试者，15位具有IR（HF-NO-IR）的HF匹配的受试者以及一组健康对照。总体脂肪，器官特异性脂肪和肌肉质量将在HF受试者中测量以控制身体成分。然后，我们将使用心肺运动测试（CPET）和稳定的同位素技术评估运动引起的循环FFA的变化，以测量血浆（FFA营业额）的FFA外观和分数清除率。在AIM 1B中，我们假设FFA释放降低的机制是钝化的儿茶酚胺诱导的脂肪细胞脂解。基础和儿茶酚胺诱导的FFA释放速率将在通过所有受试者的活检获得的脂肪组织中测量，以测试在急性稳定胺挑战期间，脂肪细胞长期持续长期受到血浆NE水平升高（同时测量）未能增加FFA的释放。我们还将测量肝素血浆脂蛋白脂肪酶（LPL）活性，以评估每组受试者中循环脂蛋白衍生的FFA的可用性。目标2：确定LVAD治疗是否以及如何逆转IR以及运动引起的FFA增加的缺陷。在AIM 2中，我们假设LVAD疗法会逆转HF中的IR，并恢复运动诱导的FFA可用性。我们将研究20例接受LVAD植入的HF患者。我们将全面评估身体组成，IR，脂肪细胞FFA释放，LPL活性，肾上腺素能激活和运动诱导的FFA可用性以及AIM 1中所述的FFA更新。HF的严重程度将通过CPET和血液动力学研究串行评估。测试将在LVAD之前以及1、3和6个月之前进行。意义：HF是一种流行比例的疾病，HF中IR的发展预示功能能力下降和预后恶化。我们将确定HF-IR的机械基础，特别着重于FFA代谢及其可逆性的改变，并为将来的研究提供了方向：如果我们的磁通研究表明，FFA释放受损的可用性受损，他们将识别出脂肪组织和脂质分解为潜在的治疗靶标。例如，使用针对脂肪组织的高亲脂性剂的肾上腺素能阻断可能使基础FFA分泌归一化，从而恢复了FFA对HF运动的反应。相比之下，如果分数增加的去除量增加，则应研究HF-IR，心脏和/或骨骼肌FFA代谢的低应力诱导的FFA水平。我们使用LVAD疗法作为逆转和研究晚期HF-IR的非药物手段的方法是完全新颖的，如果成功的话，将为治疗奠定基础，并可能在HF的早期阶段预防HF-IR。