The objectives of this research proposal are to evaluate the physiology of endogenous ouabain in normal individuals, the pathophysiology of endogenous ouabain in patients with congestive heart failure, and the clinical implications of endogenous ouabain in heart failure patients. Ouabain has recently been identified as an endogenous human Na+,K+ATPase inhibitor with potential influence upon the function of the cardiovascular system (as well as other systems). Since ouabain concentrations are elevated in patients with congestive heart failure, these patients should be a particularly valuable source of information regarding the pathophysiology of endogenous ouabain in humans; resolution of the specific hemodynamic and metabolic abnormalities which lead to elevated plasma ouabain concentrations should help to elucidate its function and control. In addition, the clinical implications of endogenous ouabain might be particularly important in heart failure patients. Not only may the efficacy and toxicity of digoxin be related to the ouabain concentration, but ouabain's impact upon the physiology of congestive heart failure could be considerable. This grant application proposes nine related protocols to explore the factors which lead to, and the consequences of, increased ouabain concentrations in patients with heart failure. We will confirm the specificity of the assay in heart failure patients and assess the biological activity of the measured endogenous ouabain. Hemodynamic evaluation and assessment of plasma ouabain concentrations will be used to investigate the effects of vasodilation, cardiac performance, and volume upon endogenous ouabain concentrations. The clinical implications of endogenous ouabain will be evaluated by comparing the plasma ouabain concentration with the hemodynamic response to digoxin, the prevalence of ventricular arrhythmias, and mortality. Proposed studies will also explore the relationship of plasma and myocardial ouabain concentrations with its target, the sodium potassium pump, by measuring Na+,K+-ATPase binding sites, activity and mRNA.
| Silverman, M E; Pressel, M D; Brackett, J C et al. (1995) Prognostic value of the signal-averaged electrocardiogram and a prolonged QRS in ischemic and nonischemic cardiomyopathy. Am J Cardiol 75:460-4 |
