The Effects of Exercise Training on Coronary Vascular Function in Heart Failure

描述（由申请人提供）：本提案的总体目的是评估运动训练对心力衰竭患者冠状动脉血管功能障碍的影响，其长期目标是确定其作为一种可行治疗方法的疗效，并确定所涉及的分子机制。本提案的具体目的是：1)确定运动训练对心衰患者冠状动脉内暴露于腺苷、硝普钠、ET-1和sarafotoxin（一种ET-B受体激动剂）后体内平滑肌依赖性冠状血管功能的影响；2)确定运动训练对左室重构、毛细血管表面积、密度、直径、毛细血管间距离的影响；3)确定运动对体外平滑肌依赖性冠状动脉血管功能的影响，暴露于腺苷、ET-1、沙拉毒素和高钾去极化溶液的冠脉剥脱环；4)确定运动训练对K+和Ca2+电流以及BKCa、IKCal和l型Ca2+通道表达的影响。猪的心力衰竭压力过载模型将被利用，因为它们有一些与人类相似的生理特征，动物被放置在运动训练组或久坐组，与年龄匹配的久坐非带状组。动物将进行4个月的运动，并采用以下方法评估其效果：1)超声心动图对左心室重构和功能的影响；2)冠状动脉血管功能完好的体内插管；3)体外冠状动脉环肌造影评估独立于混杂神经或体液影响的功能；4)电生理学、RT-PCR、免疫印迹等方法阐明分子机制。这些技术的结合将允许从生物体水平到其分子成分的评估。公共卫生相关性：超过500万人被诊断患有心力衰竭（HF），其中估计每年有57,000人死亡。诊断后，预期寿命急剧下降，70-80%的患者在8年内死亡。虽然运动对其他疾病的有益作用已被证实，但其作为心衰治疗的可行疗法的作用不太明显，尽管最近的证据表明它可以提高生存率和生活质量。

DESCRIPTION (provided by applicant): The general purpose of this proposal is to assess the effects of exercise training on coronary vascular dysfunction in heart failure, with a long-term objective of determining its efficacy as a viable treatment and identifying the molecular mechanisms involved. The specific aims of this proposal are: 1.) Determine the effect of exercise training on in vivo smooth muscle dependent coronary vascular function after intracoronary exposure to adenosine, sodium nitroprusside, ET-1, and sarafotoxin (an ET-B receptor agonist) in HF; 2) Determine the effect of exercise training on LV remodeling, capillary surface area, density, diameter, and intercapillary distance; 3)Determine the effects of exercise on in vitro smooth muscle dependent coronary vascular function after exposure to adenosine, ET-1, sarafotoxin, and high potassium depolarizing solutions in denuded coronary rings; 4) Determine the effect of exercise training on K+ and Ca2+ currents, and BKCa, IKCal, and L-type Ca2+ channel expression. A swine pressure-overload model of HF will be utilized, as they have several physiological characteristics similar to humans, and animals placed in either exercise trained or sedentary groups, with age-matched sedentary non-banded counterparts. Animals will exercise for 4 mo. and the following methods will be used to assess its effects: 1) echocardiography for left ventricular remodeling and function; 2) in vivo catheterization for intact coronary vascular function; 3) in vitro coronary ring myography to assess function independent of confounding neural or humoral effects; 4) electrophysiology, RT-PCR, and immunoblot to illuminate molecular mechanisms. The combination of these techniques will allow assessment from the level of the organism to its molecular components. Public Health Relevance: Over 5 million people are diagnosed with heart failure (HF), of which an estimated 57,000 die annually. After diagnosis, life expectancy decreases dramatically and 70-80% of patients die within 8 years. Although the beneficial effects of exercise in other disease has been readily demonstrated, its role as a viable therapy in the treatment of HF is less apparent, although recent evidence suggests it improves survival and quality of life.