Blood Pressure Control During Exercise in Heart Failure

描述(由申请人提供)：超过500万美国人患有心力衰竭，每年有超过50万的新诊断病例。每年的治疗费用接近400亿美元，仅住院费用就超过200亿美元。心力衰竭的发生率随着年龄的增长而增加，在少数族裔人群中明显更高。因此，心力衰竭在美国和全世界都是一个主要的健康问题。运动不耐受是心力衰竭的典型症状。即使是适度的运动也可能使病人筋疲力尽，上气不接下气。在这种情况下，交感神经系统经常发生极度激活，导致严重的外周血管收缩。甚至冠状动脉血管也可能收缩，导致局部缺血，室性心律失常和心脏性猝死的发生率增加。在心力衰竭受试者的运动中，交感神经系统被夸大激活的机制尚不清楚。以前的研究表明，肌肉代谢反射和动脉压力反射的异常激活参与了这些反应。这项相互竞争的更新建议侧重于扩大我们对心力衰竭运动期间心血管功能神经控制变化的研究。我们将利用我们的创新和高度复杂的意识，慢性仪器化的犬类模型。我们的长期目标是进一步阐明心力衰竭患者运动时交感神经系统高度激活的机制，以及这些反应在心血管功能综合控制中的功能后果。本研究的重点在于心力衰竭患者运动时对冠状动脉血流的神经元控制的改变和对心功能的影响，以及在这种情况下活跃的骨骼肌的血管收缩在介导过度的交感神经激活中的作用。这项建议的一个主要优点是我们独特的能力，可以在心力衰竭诱导前后，在同一动物的休息和运动过程中实时同时测量一些关键的中枢和外周血液动力学参数。我们认为，这些纵向设计的实验将为心力衰竭患者在运动过程中心血管控制机制的改变提供令人信服的新信息。 与公共健康相关：在美国，心力衰竭是影响500多万美国人的主要死亡原因之一，每年新诊断的病例超过55万例。心力衰竭的一个显著特征是运动耐力下降。即使在正常受试者中，动态运动也是心血管控制的最大挑战之一，这种挑战在心力衰竭时明显加剧，导致交感神经活动显著增加，这可以引起冠脉循环的血管收缩 活跃的骨骼肌。这项建议的重点是确定肌肉代谢性反射和动脉压力感受性反射在心血管综合功能的改变控制中的作用。 在运动期间心力衰竭和交感神经张力升高对心功能和骨骼肌血流量的功能后果。

DESCRIPTION (provided by applicant): Over 5 million Americans suffer from heart failure with over a half a million newly diagnosed cases each year. The annual cost of treatment is approaching 40 billion dollars with over 20 billion dollars in hospital expenses alone. The incidence of heart failure increases with age and is markedly higher amongst minority populations. Therefore, heart failure presents a major health problem in the United States as well as worldwide. Exercise intolerance is a classic symptom of heart failure. Even moderate exercise may leave the patient exhausted and out of breath. In this setting often extreme activation of the sympathetic nervous system occurs causing profound peripheral vasoconstriction. Even the coronary vasculature may be vasoconstricted causing local ischemia and increased incidence of ventricular arrhythmias and sudden cardiac death. The mechanisms mediating this exaggerated activation of the sympathetic nervous system during exercise in subjects with heart failure are poorly understood. Previous studies have implicated abnormal activation of the muscle metaboreflex and arterial baroreflex in mediating these responses. This competing renewal proposal is focused on expanding our investigations of altered neural control of cardiovascular function during exercise in heart failure. We will utilize our innovative and highly complex conscious, chronically instrumented canine model. Our long term goal is to further elucidate the mechanisms responsible for the heightened activation of the sympathetic nervous system during exercise in heart failure and the functional consequences of these responses in the integrative control of cardiovascular function. This proposal is focused on the altered neuronal control of coronary blood flow and the impact on ventricular function during exercise in heart failure as well as the role of vasoconstriction in active skeletal muscle in mediating the exaggerated sympathetic activation in this setting. A major strength of the proposal is our unique capability of simultaneous measurement of a number of critical central and peripheral hemodynamic parameters in real time at rest and during exercise in the same animals before and after induction of heart failure. These longitudinally designed experiments we feel will provide compelling new information on the altered mechanisms of cardiovascular control during exercise in heart failure. PUBLIC HEALTH RELEVANCE: Heart failure is one of the leading causes of death in the U.S. affecting over 5 million Americans with over 550,000 new cases diagnosed each year. A hallmark feature of heart failure is decreased exercise tolerance. Even in normal subjects, dynamic exercise presents one of the greatest challenges to cardiovascular control and this challenge is markedly exacerbated in heart failure resulting in often profound increases in sympathetic nerve activity which can elicit vasoconstriction of the coronary circulation as well as the active skeletal muscle. The focus of this proposal is to determine the roles of the muscle metaboreflex and arterial baroreflex in this altered control of integrative cardiovascular function during exercise in heart failure and the functional consequences of the heighted sympathetic tone on ventricular function and skeletal muscle blood flow.