During the past grant period, the investigators performed a variety of studies asking clinically pertinent questions about more effective uses of diuretics. In the current proposal, they propose two large new studies that logically extend their previous work.
The aim of the first study is to delineate the mechanism of the pharmacodynamic resistance to loop diuretics that occurs in patients with congestive heart failure (CHF). This resistance could occur by increased proximal tubular reabsorption of sodium, increased distal reabsorption of sodium and/or a change in the dynamics of the interaction of the loop diuretic with the Na-K-2Chl transporter of the loop of Henle. The answers to these questions should illuminate the mechanisms of sodium retention in CHF and thus allow more rational and effective use of diuretic combinations. This study will entail using diuretics with sites of action at different portions of the nephron as probes of this pathophysiology. They will employ methods familiar to them in clinical studies designed to systematically examine the role of different nephron sites in causing diuretic resistance. They will also perform a clinic-based study in which they will attempt to define causes for clinical deterioration in patients with CHF. This study will utilize a unique electronic medical record at the University of Indiana, the Regenstreif Medical Record System (RMRS). This system captures a wealth of clinical data that will be extracted and linked with compliance data, plasma renin and aldosterone activity and quality of life assessments obtained during this study to answer a series of focused questions. Each patient studied will be followed for at least one year. The investigators will perform multivariate analyses to determine causes of clinical deterioration. These data will provide insights into the causes and pathophysiology of decompensation in patients with CHF, thus enhancing our understanding of this increasingly prevalent disease and leading to better therapeutic strategies.
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