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

描述（由申请人提供）：这份提案详细介绍了我在学术心血管医学方面的职业发展的一个全面的5年培训计划。我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。我现在计划开始一个有指导的研究项目，以获得额外的科学训练，为一个独立的学术生涯专注于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，并在慢性心衰患者的运动生理学和燃料代谢方面获得深入的经验。Drs。Ulrich Jorde和Henry Ginsberg将指导我的科学事业发展。Ulrich Jorde博士在充血性心力衰竭患者的心血管药理学和生理学方面有很强的NIH跟踪记录。他的专长是开展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知名专家。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，一个由心血管和内分泌医学领域的基础和临床科学家组成的咨询委员会(dr。Ira Goldberg, 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）将提供科学和职业建议，以补充全面的教学计划。该建议的主要假设是，肾上腺素能激活的增加导致脂肪组织中基础游离脂肪酸释放的增加，而这种基础游离脂肪酸分泌的增加（通过与心力衰竭中NE类似的储存消耗）导致游离脂肪酸对运动的反应不足，从而导致运动不耐受。我们建议通过对合并和不合并IR的HF患者进行巢式病例对照研究来验证这一假设（目的1）。此外，我们将使用带有LVAD的长期机械循环支持来正式测试逆转HF是否能逆转IR并使循环FFA可用性正常化（目的2）。目的1：研究伴有IR的HF患者运动诱导的FFA可用性降低的机制。在aim 1a中，我们假设我们在运动中观察到的FFA有效性降低是由于运动诱导的脂肪组织中FFA释放减少，而不是循环中FFA清除率增加。我们将确定15例伴有IR的HF受试者（HF-IR）， 15例伴有匹配的无IR的HF受试者（HF- no -IR）和一组健康对照。将测量HF受试者的总体脂、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试验（CPET）和稳定同位素技术来评估运动引起的循环FFA的变化，以测量FFA的外观和血浆的部分清除率（FFA周转率）。在aim 1b中，我们假设减少FFA释放的机制是钝化儿茶酚胺诱导的脂肪细胞脂解。通过对所有受试者进行活组织检查，在脂肪组织中测量基础和儿茶酚胺诱导的游离脂肪酸释放率，以测试脂肪细胞长期受到血浆NE水平升高（同时测量）是否不能在急性儿茶酚胺攻击期间增加游离脂肪酸释放。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来源的FFA的可用性。目的2：确定LVAD治疗是否以及如何逆转IR和运动诱导的FFA增加的缺陷。在aim 2中，我们假设LVAD治疗可以逆转HF患者的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成分、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FFA周转，如目标1所述。心衰的严重程度将通过CPET和血流动力学研究进行连续评估。测试将在LVAD之前以及1、3和6个月后进行。意义：心衰是一种地方性疾病，心衰患者发生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FFA代谢的改变及其可逆性，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作为潜在的治疗靶点。例如，使用高亲脂性药物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，从而恢复心力衰竭患者对运动的FFA反应。相反，如果增加的游离脂肪酸去除是HF-IR中低应激诱导的游离脂肪酸水平的基础，则应该研究心脏和/或骨骼肌游离脂肪酸代谢。我们使用LVAD治疗作为一种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早期HF- ir奠定基础。

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.