Inhibiting C-Reactive Protein Synthesis by Cardiac Glycosides in Humans

Abstract

The role of C-reactive protein (CRP) in cardiovascular disease has been controversially discussed for almost two decades. Specific CRP inhibition, followed by use of CRP inhibitors in controlled clinical trials may be the only way to prove or disprove a causative role for CRP in cardiovascular disease. Endogenous and plant-derived inhibitors of the Na(+)/K(+)-ATPase, i.e. the cardiac glycosides ouabain, digoxin and digitoxin, potently inhibit CRP synthesis in human hepatoma cells and primary human hepatocytes in vitro. In the herein described single-center C-reactive protein- Digoxin Observational Study (C-DOS), 60 patients with decompensated heart failure, NYHA III-IV and severely reduced Left Ventricular Ejection Fraction (LVEF<40%), and elevated CRP plasma levels will be treated by either digoxin+conventional heart failure therapy (30 patients) or by conventional heart failure therapy alone (30 patients). Plasma CRP levels in both groups will be assessed for 21 days. Plasma CRP levels (day21-day0) will be compared by regression analysis in order to find out whether digoxin significantly lowers CRP plasma levels in humans. The trial will not answer the question whether CRP is causative in cardiovascular disease but, by following a step by step approach, investigates for the first time whether cardiac glycosides lower CRP plasma levels in humans. The study hereby serves as a pilot study for subsequent phase III trials. Importantly, it is the first trial ever that systematically uses a direct CRP synthesis inhibitor in