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: 8115199
• 负责人: ROBERT G WEISS
• 金额: $ 56.95万
• 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/8115199
• 关键词: ATP Hydrolysis; ATP Synthesis Pathway; Address; Adrenergic beta-Antagonists; Affect; Attention; 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; Health; 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; 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相关。由于正常的心肌收缩功能需要ATP，因此有假设认为ATP合成和/或递送受损会导致心衰患者的收缩功能障碍。我们的重点是肌酸激酶（CK）反应，它在收缩元件处产生ATP，是主要的心脏能量储备，负责缓冲ATP，由于心脏跳动的能量需求的时间变化以及肌细胞内ATP产生和利用反应的空间异质性，这一点尤为重要。我们开发了第一种通过心肌CK测量人体心脏ATP合成速率的非侵入性方法，并观察到人体HF的显著降低，其幅度足以在理论上限制心脏周期中ATP的传递。在其他患者中，通过CK的ATP转换动力学可区分衰竭和非衰竭心脏。这些临床证据证明了人类HF中CK容量降低的关键作用，现在有因果证据支持CK减少有助于小鼠HF模型的功能障碍和重塑。这些来自我们实验室的最新的、新颖的临床和基础结果为研究解决重要的机制和临床相关问题提供了理由和基础，这些问题涉及到人类心衰中CK容量降低的预后和因果作用，如这些具体目标所述。前三个目的检验的假设，降低CK容量是一个因果因素的进行性收缩功能障碍。他们通过测试它是否是一个重要的心衰临床结果的独立预测因子，包括死亡率、心脏移植和心衰住院（第一个目标），已知的心衰药物改善生存和临床结果改善心脏CK通量和能量（第二个目标），当在接受心脏毒性但挽救生命的化疗的恶性疾病患者中首次发现收缩功能障碍时，CK通量会减少（第三个目标）。我们还将研究另外两个机制问题，这些问题目前只能在HF患者中进行测试，部分原因是新的高场3T MR扫描仪。这些问题包括心肌壁上CK通量和能量的空间异质性是否导致心衰患者功能障碍，以及心周期中ATP需求的时间异质性是否是与功能受损的CK缓冲能力降低相关的重要因素（第四个目标）。后者将有直接的临床相关性，就心率干预的重要性在这一患者群体。我们相信这些建议，真正的转化研究解决关键和及时的问题，机制和临床相关的重要性。我们的团队是唯一有资格的，时机是理想的，可以利用最近的观察和新技术来推进我们对通过CK的ATP递送受损在人类心衰中的作用的理解。公共卫生相关性：心脏的泵送作用，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ATP，我们最近开发了第一种方法来测量人类心脏中ATP的周转率，并发现它在心力衰竭中显着减少。拟议的研究很重要，因为它们将确定ATP率的降低是否预测心力衰竭在死亡中的进展，以及未来心力衰竭治疗的潜在机制是什么。