Rate Control and Cardiac Energitics in heart Failure

心力衰竭中的心率控制和心脏能量

• 批准号: 7750202
• 负责人: HANI N SABBAH
• 金额: $ 28.67万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-14 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7750202
• 关键词: Address; Adrenergic Agents; Adrenergic beta-Antagonists; Adverse event; Affect; Aliquot; Animals; Attention; Binding; Biochemical; Blood; Canis familiaris; Cardiac; Cardiac Myocytes; Cardiology; Chronic; Collaborations; Complex; Coronary; Data Analyses; Defect; Deterioration; Disease; Dopamine-beta-monooxygenase; EFRAC; Economic Burden; Energy Metabolism; Energy Transfer; Enzymes; Feedback; Freezing; Functional disorder; Future; Gene Proteins; Glucose-6-Phosphate; Glucosephosphate Dehydrogenase; Heart; Heart Rate; Heart failure; Histopathology; Hour; Inflammatory; Lead; Left Ventricular Remodeling; Left ventricular structure; Lipids; Malignant Neoplasms; Manuscripts; Mass Spectrum Analysis; Measurement; Measures; Medical; Messenger RNA; Metabolic; Metabolism; Mitochondria; Mitochondrial Proteins; Modeling; Morbidity - disease rate; Mus; Myocardial; Myocardial tissue; Myocardium; NADP; Nature; Organelles; Outcome; Oxidative Phosphorylation; Oxygen Consumption; Pacemakers; Patients; Pentosephosphate Pathway; Pentoxifylline; Pharmaceutical Preparations; Phenotype; Preparation; Prevention; Principal Investigator; Proteins; Quality of life; Reactive Oxygen Species; Recovery; Research Personnel; Respiration; Rest; Reverse Transcriptase Polymerase Chain Reaction; Role; Severities; Shapes; Source; Staging; Superoxides; System; Therapeutic; Time; Tissue Sample; Tissues; Tracer; Treatment Protocols; United States; Up-Regulation; Western Blotting; Work; adrenergic; animal care; base; beta-adrenergic receptor; cytokine; improved; in vivo; inhibitor/antagonist; ivabradine; molecular marker; mortality; nepicastat; novel; oxidative damage; prevent; programs; protein expression; social; therapy duration; vagus nerve stimulation

Heart failure (HF) is an enormous medical, social and economic burden. It is a leading cause of mortality and morbidity in the United States and rivals or exceeds that of many cancers. The search for better treatments for HF is one of the major challenges in cardiology. The high morbidity in HF is fueled by the progressive nature of the disease whereby the status of the affected patient worsens over time despite the absence of concurrent clinically adverse events. Therefore, any therapeutic approach that can retard this relentless progression or reverse it is bound to have a major impact on survival and on the quality of life of patients with HF. There are many reasons why a heart can fail. The concept that the failing heart is "energy starved" is a centerpiece of this project. A major reason why one should pay close attention to this topic is the underlying concept that any energy-sparing treatment for HF is likely to improve cardiac function and hence long-term outcome. Cardiac energy metabolism, while complex, can be reduced to essentially 3 components namely, 1) substrate utilization, 2) oxidative phosphorylation and 3) energy transfer and utilization. In HF, mitochondria, the source of ATP supply to cardiomyocytes is structurally and functionally abnormal leading to abnormal oxidative phosphorylation. In this project, modulation of energy utilization will be explored in the form of heart rate (HR) reduction and its impact on the progression of HF. Resting HR is increased in HF and is a determinant of poor long-term outcome. HR is a determinant of myocardial oxygen consumption and, hence, energy utilization. Our working hypothesis is that optimal HR reduction in the setting of HF prevents or reverses deterioration of mitochondrial function, maintains or restores normal cardiac substrate metabolism, and retards or reverses progressive LV dysfunction and remodeling. All studies will be conducted using the well established canine coronary microembolization model of chronic HF. Three distinctly differing approaches to chronic HR reduction will be implemented, namely, 1) chronic HR reduction with electrical Vagus nerve stimulation, 2) chronic HR reduction with pharmacological selective and specific inhibition of the pacemaker If current and 3) chronic HR reduction with traditional beta-adrenergic receptor blockers. All studies will be performed in dogs with moderate HF (LV ejection fraction ~35%) as well as in dogs with advanced HF (LV ejection fraction <20%).

心力衰竭（HF）是一种巨大的医疗，社会和经济负担。这是死亡的主要原因 美国和竞争对手的发病率超过了许多癌症。寻找更好的 HF治疗是心脏病学的主要挑战之一。 HF的高发病率是由 该疾病的进步性质，尽管有影响的患者的状况随着时间的流逝而恶化 没有并发的临床不良事件。因此，任何可以阻止此的治疗方法 不懈的进步或反向它一定会对生存和生活质量产生重大影响 HF患者。心脏会失败的原因有很多。失败的心脏是“能量的概念 饥饿是“是该项目的核心。 基本的概念，即HF的任何能源治疗都可能改善心脏功能和 因此，长期结果。心脏能量代谢虽然复杂，但可以简化为3 组件，即1）底物利用率，2）氧化磷酸化和3）能量转移和 利用率。在HF，线粒体中，对心肌细胞的ATP供应来源在结构和功能上是 异常导致异常氧化磷酸化。在这个项目中，能源利用的调节将 以心率（HR）降低及其对HF进展的影响进行探索。休息的人力资源是 HF的增加，是长期不良结果的决定因素。人力资源是心肌氧的决定因素 因此，消费量，因此，能源利用。我们的工作假设是最佳的人力资源降低 HF的设置可防止或逆转线粒体功能的恶化，保持或恢复正常 心脏底物代谢，并推迟或逆转进行性LV功能障碍和重塑。全部 研究将使用慢性HF的良好犬冠状动脉微栓塞模型进行。 将实施三种截然不同的慢性HR降低方法，即1）慢性HR 通过电迷走神经刺激的减少，2）用药理学选择性降低慢性HR和 如果电流和3）传统β-肾上腺素能降低慢性HR，则对起搏器的特定抑制作用 受体阻滞剂。所有研究将在中等HF（LV射血分数〜35％）的狗中进行 以及患有晚期HF的狗（LV射血分数<20％）。