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

描述(由申请者提供)：这份建议书详细说明了我在学术心血管内科的职业发展的5年综合培训计划。我在哥伦比亚大学医学中心完成了心力衰竭(HF)和移植方面的高级培训。我现在计划开始一项有指导的研究计划，以获得额外的科学培训，以便从事专注于充血性心力衰竭的翻译研究的独立学术生涯。因此，在整个获奖期间，我将接受设计和进行医学研究的正式培训，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。乌尔里希·乔德博士和亨利·金斯伯格博士将指导我的科学事业发展。Ulrich Jorde博士在美国国立卫生研究院有着良好的记录，重点研究充血性心力衰竭患者的心血管药理学和生理学。他的专长是进行以运动生理学和神经激素激活为中心的机械学研究，他的实验室最新的重点是HF中的燃料代谢。乔德博士也是左心辅助装置疗法医学方面的知名专家。共同导师亨利·金斯伯格博士是国际公认的脂蛋白新陈代谢专家。金斯伯格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，由心血管和内分泌医学领域的知名基础和临床科学家(Ira Goldberg博士、Jeanine Albu博士、Domeico Accili博士、Dympna Gallagher博士和Yoshiumi Naka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。这一建议的主要假设是，肾上腺素能激活增加导致脂肪组织基础FFA释放增加，这种增加的基础FFA分泌(通过类似于HF中NE的存储消耗)导致FFA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胰岛素抵抗的心衰患者进行嵌套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左冠状动脉前降支来正式测试逆转心衰是否逆转IR并使循环中FFA的利用度正常化(目标2)。目的1：探讨运动诱导的游离脂肪酸在IR心力衰竭患者中有效性降低的机制。在目标1a中，我们假设我们在HF-IR运动期间观察到的FFA利用率下降是由于运动导致脂肪组织FFA释放的减少，而不是FFA从循环中清除的增加。我们将确定15名有IR的HF受试者(HF-IR)，15名匹配的HF无IR的受试者(HF-No-IR)，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的外观和从血浆中清除的分数(FFA周转率)。在目标1b中，我们假设FFA释放减少的机制是钝化儿茶酚胺诱导的脂肪细胞脂肪分解。所有受试者的活检获得的脂肪组织中基础的和儿茶酚胺诱导的FFA释放率将被测量，以测试长期承受血浆NE水平升高的脂肪细胞(同时测量)在急性儿茶酚胺激发时是否未能增加FFA的释放量。我们还将测量肝素后血浆脂蛋白脂酶(LPL)的活性，以评估循环脂蛋白衍生的FFA在每组受试者中的可用性。目的2：确定LVAD治疗是否以及如何逆转IR和运动性FFA升高的缺陷。在目标2中，我们假设LVAD治疗逆转了心力衰竭的IR，并恢复了运动诱导的FFA的可用性。我们将研究20例接受LVAD植入术的心衰患者。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利用率以及FFA周转情况。心衰的严重程度将使用CPET和血流动力学研究进行系列评估。检查将在左冠状动脉腔内成形术前以及术后1、3、6个月进行。意义：心力衰竭是一种地方性疾病，心力衰竭时IR的发展预示着功能能力的下降和预后的恶化。我们将确定HF-IR的机制基础，特别是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肪分解为潜在的治疗靶点。例如，针对脂肪组织使用高亲脂性药物的肾上腺素能阻滞剂可以使基础FFA分泌正常化，从而恢复FFA对运动的反应。相反，如果FFA清除分数的增加是低应激诱导的FFA水平在HF-IR中的基础，那么应该研究心肌和/或骨骼肌的FFA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是一种全新的方法，如果成功，将为在HF的早期阶段治疗和可能预防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.