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: 8628165
• 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 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8628165
• 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领域的职业发展的为期 5 年的综合培训计划。我已在哥伦比亚大学医学中心完成了心力衰竭 (HF) 和移植方面的高级培训。我现在计划开展一项指导性研究计划，以获得独立学术生涯所需的额外科学培训，重点关注充血性心力衰竭的转化研究。因此，在整个获奖期间，我将接受医学研究设计和实施方面的正式培训，并在慢性心力衰竭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·金斯堡（Henry Ginsberg）将指导我的科学职业发展。 Ulrich Jorde 博士在 NIH 领域拥有丰富的经验，重点研究充血性心力衰竭患者的心血管药理学和生理学。他的特殊专长是进行以运动生理学和神经激素激活为中心的机制研究，他的实验室最近的重点是心力衰竭的燃料代谢。 Jorde 博士也是左心室辅助装置治疗医学方面的著名专家。共同导师Henry Ginsberg博士是国际公认的脂蛋白代谢专家。 Ginsberg 博士对与胰岛素抵抗和糖尿病相关的血脂异常的病理生理学特别感兴趣。此外，还有一个由心血管和内分泌医学领域的基础和临床科学家（Ira Goldberg 博士、Jeanine Albu、Domenico Accili、Dympna Gallagher 和 Yoshifumi Naka）、统计学家（Rajasekhar Radakrishnan 博士）和管理人员（Jaime Rubin 博士）组成的咨询委员会将提供科学和职业建议，以补充全面的教学计划。该提议的主要假设是，肾上腺素能激活的增加导致脂肪组织中基础 FFA 的释放增加，并且这种基础 FFA 分泌的增加导致（通过类似于 HF 中 NE 所见的储存消耗）导致 FFA 对运动的反应不足，从而运动不耐受。我们建议通过对伴或不伴 IR 的心力衰竭患者进行巢式病例对照研究来检验这一假设（目标 1）。此外，我们将使用长期机械循环支持和 LVAD 来正式测试逆转 HF 是否逆转 IR 并使循环 FFA 可用性正常化（目标 2）。目标 1：研究 IR 心衰患者运动引起的 FFA 可用性降低的机制。在目标 1a 中，我们假设我们在 HF-IR 运动期间观察到的 FFA 可用性降低是由于运动引起的脂肪组织 FFA 释放减少，而不是循环中 FFA 清除增加。我们将确定 15 名患有 IR 的 HF 受试者（HF-IR）、15 名匹配的 HF 但无 IR（HF-No-IR）的受试者以及一组健康对照。将测量 HF 受试者的全身脂肪、器官特异性脂肪和肌肉质量，以控制身体成分。然后，我们将使用心肺运动测试 (CPET) 和稳定同位素技术来评估运动引起的循环 FFA 变化，以测量 FFA 外观和血浆清除率（FFA 周转率）。在目标 1b 中，我们假设 FFA 释放减少的机制是减弱儿茶酚胺诱导的脂肪细胞脂肪分解。将在所有受试者活检获得的脂肪组织中测量基础和儿茶酚胺诱导的 FFA 释放率，以测试长期承受血浆 NE 水平升高（同时测量）的脂肪细胞是否在急性儿茶酚胺挑战期间无法增加 FFA 的释放。我们还将测量肝素后血浆脂蛋白脂肪酶 (LPL) 活性，以评估每组受试者中循环脂蛋白衍生 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。在目标 2 中，我们假设 LVAD 疗法可逆转心力衰竭中的 IR，并恢复运动诱导的 FFA 可用性。我们将研究 20 名接受 LVAD 植入的心力衰竭患者。我们将全面评估身体成分、IR、脂肪细胞 FFA 释放、LPL 活性、肾上腺素能激活和运动引起的 FFA 可用性以及目标 1 中所述的 FFA 周转。将使用 CPET 和血流动力学研究连续评估心力衰竭的严重程度。测试将在 LVAD 之前以及之后 1、3 和 6 个月进行。意义：心力衰竭是一种地方性疾病，心力衰竭中发生IR预示着功能能力下降和预后恶化。我们将确定 HF-IR 的机制基础，特别强调改变的 FFA 代谢及其可逆性，并为未来的研究提供方向：如果我们的通量研究表明 FFA 释放受损是可用性受损的基础，他们将确定脂肪组织和脂质分解是潜在的治疗目标。例如，使用高亲脂性药物针对脂肪组织进行肾上腺素能阻断可以使基础FFA分泌正常化，从而恢复FFA对心力衰竭运动的反应。相反，如果增加的 FFA 去除分数是 HF-IR 中应激诱导的 FFA 水平较低的基础，则应研究心脏和/或骨骼肌 FFA 代谢。我们使用 LVAD 疗法作为非药物手段来逆转和研究晚期 HF-IR 的方法是全新的，如果成功，将为治疗和可能预防 HF 早期阶段的 HF-IR 奠定基础。