MYOCARDIAL ENERGY METABOLISM IN THE DYSFUNCTIONAL LV

左心室功能障碍时的心肌能量代谢

• 批准号: 6390096
• 负责人: Jianyi Zhang
• 金额: $ 12.89万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-05 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390096
• 关键词: Krebs' cycle; acetyl coA; adenosine triphosphate; adenosinetriphosphatase; bioenergetics; butyrates; catecholamines; congestive heart failure; cyclic AMP; disease /disorder model; fatty acid metabolism; glucose metabolism; heart circulation; heart function; heart metabolism; heart ventricle; hemodynamics; mitochondria; myocardial infarction; nicotinamide adenine dinucleotide; nuclear magnetic resonance spectroscopy; oxidative phosphorylation; oxygen consumption; pyruvates; swine

Following myocardial infarction a prolonged period of stable LV remodeling may be followed by myocardial exhaustion with the development of congestive heart failure (CHF). Hearts with stable remodeling or CHF have abnormal bioenergetic characteristics but whether limitations in the ATP synthetic or transport processes actually contribute to the transition from hemodynamic stability to CHF is unclear. The overall goals of the current proposal are: i. to determine whether functionally significant limitations of ATP synthetic capacity are present in compensated and CHF associated remodeled hearts and, ii. whether a metabolic therapeutic intervention can attenuate the remodeling process. This study will be carried out in a pig model of post-infarction left ventricular remodeling in which a significant portion of the infarcted animals develop CHF. The relationships between the severity of pump dysfunction and severity of alterations in myocyte oxygenation, myocardial bioenergetics (including ATP synthetic capacity), and regional myocardial blood flow will be determined. One major objective is to determine whether stable or failing remodeled hearts can be driven to workstates where oxygen or substrate availability limit function. Because CHF hearts have decreased responsiveness to catecholamine stimulation as a consequence of down regulation of the beta-adrenergic receptors, increases of cyclic AMP will be produced by direct stimulation of adenylyl cyclase with forskolin or by inhibition of phosphodiesterase with milrinone in addition to catecholamine infusion. In vivo mitochondrial respiration capacity will be examined with a mitochondrial uncoupling agent 2,4-dinitrophenol (DNP) which decreases the proton gradient in the mitochondrial membrane and drives MVO2 to levels above those dictated by the rates of ATP utilization. A third acute intervention will be the infusion of pyruvate and butyrate, substrates which bypass the rate limiting steps in generation of mitochondrial acetyl CoA. These interventions will allow determination of whether the maximum capacity for mitochondrial oxidative phosphorylation is limiting in the failing heart and, if so, whether the abnormality is in the ability of mitochondria of the CHF hearts to generate a proton gradient or whether ATP synthase or subsequent processes involved in ATP transport are at fault. The relationships and time-course of pump dysfunction and the alterations in myocardial energetics during the evolution of CHF will be examined by magnetic resonance imaging/spectroscopy. To examine whether limitations of long chain fatty acid metabolism alter myocardial CP/ATP or limit the maximal rate of ATP synthesis in the failing heart, animals will receive carnitine supplementation to compensate for the rate limiting step in long chain fatty acid metabolism and/or other abnormalities in intermediary metabolism. Taken together, the results of these studies will establish whether the ATP synthetic capacity: i. ultimately restricts myocardial maximal MVO2 in hearts with LV remodeling and failure, ii. contributes to the transition between stable remodeling and CHF and, iii. Whether a metabolic intervention can attenuate the remodeling response and the transition from stable remodeling to CHF.

在心肌梗塞后，随着充血性心力衰竭（CHF）的发展，可能会长时间稳定的LV重塑。具有稳定的重塑或CHF的心脏具有异常的生物能特征，但是ATP合成过程中的局限性或运输过程的局限性实际上导致了从血液动力学稳定性到CHF的过渡。当前建议的总体目标是：i。为了确定在功能上有显着的ATP合成能力的局限性，在补偿和CHF相关的重塑心脏和II中是否存在。代谢治疗干预措施是否可以减弱重塑过程。这项研究将在猪后左心室重塑的猪模型中进行，其中很大一部分梗塞动物会发展出CHF。泵功能障碍的严重程度与心肌氧化，心肌生物能学（包括ATP合成能力）与区域心肌血流的严重程度之间的关系。一个主要目的是确定是否可以将稳定或失败的重塑心脏驱动到氧气或底物可用性极限功能的工作状态。由于CHF心脏对β-肾上腺素能受体的减少调节的结果降低了对儿茶酚胺刺激的反应能力，因此环环AMP的增加将通过直接刺激使用福司蛋白或抑制磷酸二二酯酶和米尔德林酮抑制腺苷酮，从而产生。体内线粒体呼吸能力将使用线粒体解偶联剂2,4-二硝基苯酚（DNP）检查，该醇（DNP）降低了线粒体膜中的质子梯度，并将MVO2驱动MVO2降低MVO的水平，而不是由ATP利用率所决定的。第三次急性干预将是丙酮酸和丁酸酯的输注，这是绕过线粒体乙酰COA生成的速率限制步骤的底物。这些干预措施将允许确定在心脏失败的心脏氧化磷酸化的最大能力是否限制在心脏中，如果是的，则异常是在CHF心脏的线粒体能力上产生质子梯度还是产生质子梯度或ATP合酶是否涉及ATP转运的过程。 CHF演变过程中泵功能障碍的关系和时间课程以及心肌能量的改变将通过磁共振成像/光谱检查。 要检查长链脂肪酸代谢的局限性是否改变了心肌CP/ATP或限制心脏衰竭中ATP合成的最大速率，动物将接受肉碱补充以补偿长链脂肪酸代谢的速率限制步骤和中间代谢中的其他异常。综上所述，这些研究的结果将确定AT​​P合成能力是否：i。最终，在具有LV重塑和失败的心脏中限制心肌最大MVO2，ii。有助于稳定重塑与CHF和III之间的过渡。代谢干预是否可以减弱重塑反应以及从稳定重塑到CHF的过渡。