Altered Creatine Kinase Energy Metabolism in Human Heart Failure

人类心力衰竭中肌酸激酶能量代谢的改变

• 批准号: 7729864
• 负责人: ROBERT G WEISS
• 金额: $ 56.1万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-19 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7729864
• 关键词: ATP Hydrolysis; ATP Synthesis Pathway; Address; Adrenergic beta-Antagonists; Affect; Arts; Attention; Be++ element; Beryllium; Bioenergetics; Buffers; Carbon; Cardiac; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Chemicals; Clinical; Clinical Data; Clinical Research; Clinical Treatment; Creatine Kinase; Creatine Kinase MB Isoenzyme; Data; Dilated Cardiomyopathy; Disease; EFRAC; Elements; Energy Metabolism; Energy Transfer; Enzymes; Event; Exhibits; Free Energy; Functional disorder; Funding; Future; Grant; Heart; Heart Rate; Heart Transplantation; Heart failure; Heterogeneity; Hospitalization; Human; Intervention; Kinetics; Laboratories; Left Ventricular Hypertrophy; Magnetic Resonance; Malignant - descriptor; Measures; Metabolic; Metabolism; Modeling; Morbidity - disease rate; Mus; Muscle Cells; Myocardial; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphocreatine; Process; Pump; Qualifying; Reaction; Relative (related person); Research; Role; Severities; Stress; Techniques; Technology; Testing; Time; Translations; Tyrosine; United States National Institutes of Health; Work; base; chemotherapy; clinical practice; clinically relevant; design; experience; gene therapy; improved; inhibitor/antagonist; inorganic phosphate; insight; interest; mortality; new technology; novel; patient population; prognostic; public health relevance; translational study

DESCRIPTION (provided by applicant): Heart failure (HF) is the final common pathway for most cardiovascular diseases and is associated with high mortality and morbidity. Because ATP is required for normal myocardial contractile function, it has been hypothesized that impaired ATP synthesis and/or delivery contribute to contractile dysfunction in HF patients. Our focus is on the creatine kinase (CK) reaction which generates ATP at the contractile elements, is the major cardiac energy reserve responsible for buffering ATP, and which is particularly critical because of the temporally varying energy demands of the beating heart and the spatial heterogeneity of the ATP generating and utilizing reactions within myocytes. We developed the first non-invasive means to measure the rate of ATP synthesis through myocardial CK in the human heart and observed significant reductions in human HF of sufficient magnitude to theoretically limit ATP delivery during the cardiac cycle. In other patients, the kinetics of ATP turnover through CK distinguished failing and non-failing hearts. This body of clinical evidence demonstrates a critical role for reduced CK capacity in human HF and is now supported by causal evidence that reduced CK contributes to dysfunction and remodeling in a murine model of HF. These recent, novel clinical and basic results from our laboratory provide the justification and rationale for studies to address important mechanistic and clinically-relevant issues concerning the prognostic and causal roles of reduced CK capacity in human HF as outlined in these specific aims. The first three aims examine the hypothesis that reduced CK capacity is a causal factor in progressive contractile dysfunction. They do so by testing whether it is an independent predictor of important clinical HF outcomes, including mortality, cardiac transplantation and HF hospitalization (first aim), that HF medications known to improve survival and clinical outcomes improve cardiac CK flux and energetics (second aim) and that reduced CK flux occurs when contractile dysfunction is first recognized in patients with malignant disease receiving cardiotoxic but also lifesaving chemotherapy (third aim). We will also examine two more mechanistic questions that can only now be tested in HF patients due, in part, to new higher field 3T MR scanners. These are whether spatial heterogeneity in CK flux and energetics across the myocardial wall contributes to dysfunction in HF patients and whether the temporal heterogeneity in ATP demand during the cardiac cycle is an important factor related to reduced CK buffering capacity on impaired function (fourth aim). The latter would have direct clinical relevance in terms of the importance of heart rate interventions in this patient population. We believe these proposed, truly translational studies address critical and timely questions of mechanistic and clinically-relevant importance. Our group is uniquely qualified and the timing is ideal to exploit recent observations and new technology to advance our understanding of the role of impaired ATP delivery through CK in human HF. PUBLIC HEALTH RELEVANCE: The pumping action of the heart, like an engine, requires chemical fuel and the failing heart has been hypothesized to be low on fuel. The chemical fuel used by the heart is ATP and we recently developed the first means to measure the rate of ATP turnover in the human heart and find it is significantly reduced in heart failure. The proposed studies are important because they will determine whether that reduction in ATP rate predicts heart failure progression in death, and what the underlying mechanisms are that could be targeted for future heart failure therapy.

描述(由申请人提供)：心力衰竭(HF)是大多数心血管疾病的最终常见途径，与高死亡率和发病率有关。由于正常的心肌收缩功能需要三磷酸腺苷，已有假说认为三磷酸腺苷合成和/或递送受损导致心力衰竭患者的收缩功能障碍。我们的重点是肌酸激酶(CK)反应，它在收缩元件上产生ATP，是负责缓冲ATP的主要心脏能量储备，由于心脏跳动的能量需求的时间变化和心肌细胞内ATP产生和利用反应的空间异质性，这一反应尤其关键。我们开发了第一种非侵入性的方法来测量人类心脏中通过心肌CK合成ATP的速率，并观察到人心衰显著减少，其幅度足以在理论上限制心动周期中的ATP输送。在其他患者中，通过CK的ATP周转动力学区分衰竭和非衰竭心脏。这一组临床证据表明，CK能力降低在人类心力衰竭中起着关键作用，现在有因果证据支持，CK降低有助于心力衰竭小鼠模型的功能障碍和重塑。我们实验室最近的这些新的临床和基本结果为研究提供了理由和理论基础，以解决重要的机制和临床相关问题，这些问题涉及到这些特定目标中概述的人心力衰竭中CK能力降低的预后和因果作用。前三个目的是检验CK能力降低是进行性收缩功能障碍的一个原因的假设。他们通过测试它是否是包括死亡率、心脏移植和心力衰竭住院在内的重要临床心力衰竭结果的独立预测因子(第一目的)，已知可改善存活率和临床结果的心力衰竭药物改善心脏CK流量和能量(第二目的)，以及当接受心脏毒性但也挽救生命的化疗的恶性肿瘤患者首次发现收缩功能障碍时，CK流量减少发生(第三目的)。我们还将研究另外两个机械性问题，这两个问题现在只能在心力衰竭患者身上测试，部分原因是新的高场3T磁共振扫描仪。这些是CK流量和跨心肌壁能量的空间异质性是否导致心力衰竭患者的功能障碍，以及心动周期内ATP需求的时间异质性是否是降低CK对功能受损的缓冲能力的重要因素(第四个目标)。就心率干预在这一患者群体中的重要性而言，后者将具有直接的临床相关性。我们相信，这些建议的、真正的转译研究解决了关键和及时的机械性和临床相关的重要问题。我们的团队是唯一合格的，时机理想，利用最近的观察和新技术来促进我们对通过CK传递受损的ATP在人类心力衰竭中的作用的理解。与公共健康相关：心脏的泵送活动，就像发动机一样，需要化学燃料，而衰竭的心脏被假设为燃料不足。心脏使用的化学燃料是三磷酸腺苷，我们最近开发了第一种测量人类心脏中三磷酸腺苷周转率的方法，发现在心力衰竭时，三磷酸腺苷的周转率显著降低。拟议的研究很重要，因为它们将确定ATP率的降低是否可以预测死亡中的心力衰竭进展，以及未来心力衰竭治疗可能针对的潜在机制是什么。