Thursday, April 18, 2024
4/18/2024
ABSTRACT Heart failure is a global pandemic affecting over 26 million patients worldwide including over 5 million Americans with over 550,000 newly diagnosed cases each year in the USA. The annual cost of treatment in our country is approaching 40 billion dollars. The incidence of heart failure increases with age and is markedly higher among 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. Often extreme activation of the sympathetic nervous system occurs during exercise causing profound peripheral vasoconstriction. High sympathetic activity is predictive of poor prognosis. Our recent studies have shown that the kidney, skeletal muscle and even the heart become targets for vasoconstriction with this veritable “sympathetic storm”. The mechanisms mediating this exaggerated activation of the sympathetic nervous system during exercise in subjects with heart failure are poorly understood. This competing renewal proposal is focused on expanding our investigations of altered neural control of cardiovascular function during exercise in heart failure. We propose that sympathetic over-activation during exercise stems from activation of multiple regional afferent nerves which combine to induce positive-feedback amplification of sympathetic activity creating vicious cycles. The kidney, skeletal muscle and the heart become both the sources of afferent activation of sympathetic activity and the targets of the increased vasoconstrictor tone. Further, depressed arterial baroreflex buffering of these positive feedback scenarios contributes to the excessive sympatho- activation. We will explore techniques aimed at lessening the activation of these regional afferents which would thereby decrease the massive sympathetic activation. We will utilize our innovative and highly complex conscious, chronically instrumented canine model. Our long term goal is to elucidate further 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 integrative control of cardiovascular function. A major strength of the proposal is our unique capability of simultaneous measurement 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 will provide compelling new information on the altered mechanisms of cardiovascular control during exercise in heart failure and may provide a basis for ameliorating the excessive activation of the sympathetic nervous system during exercise in these patients.
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