ADMA and prognosis in patients with heart failure and preserved ejection fraction

Abstract

Background: Elevated plasma levels of the endogenous nitric oxid synthase inhibitor asymmetric dimethylarginine (ADMA) contribute to endothelial dysfunction (ED) and seem to be a predictor for cardiovascular mortality. ED plays an important role in heart failure, but few studies have investigated the relation between ADMA, peripheral ED and prognosis in patients with heart failure and preserved ejection fraction (HFpEF). Purpose: This study was performed to determine whether ADMA and ED measured by flow mediated dilation (FMD) can predict prognosis of patients with HFpEF. Methods: We conducted a prospective study on 72 patients with HFpEF. We determined: left ventricular ejection fraction (LVEF), the ratio of early transmitral flow velocity to tissue Doppler early diastolic mitral annular velocity (E/e'), FMD, ADMA and NT-proBNP levels. All patients were in NYHA class II or III, had LVEF > 50%, and E/e' >15. Patients were prospectively followed-up for heart failure-related events, including heart failure-related death and hospitalization due to worsening of heart failure for 30 months. Results: Median values for ADMA were 0,54±0,13 μmol/l. During follow-up 26 of patients had an event: 20 patients were hospitalized due to worsening of heart failure, six patients died for cardiac reasons. There was a strong correlation between ADMA and NTproBNP (p=0, 0006, r=0, 51) and an inverse correlation between ADMA and FMD (p<0.0001, r= -0, 8) and between FMD and NT-proBNP (p<0, 0001, r= -0, 63). Heart failure related death correlated with ADMA (p=0,001, r=0,49), NT-proBNP (p=0,04, r=0,31)and inversely FMD (p=0,01, r= -0,38). In multiple regression analysis independent predictor for death remained only ADMA (p=0,03, r=0,49). Worsening of heart failure correlated with ADMA (p<0, 0001, r=0, 79), NT-proBNP (p<0, 0001, r=0, 69) and inversely with FMD (p<0, 0001, r= -0, 8). In multiple regression analysis the strongest predictor for worsening of heart failure was ADMA (p=0,003, r=0,9) followed by FMD (p=0,03, r= -0,8) and NT-proBNP (p=0,04, r=0,69). Conclusions: Endothelial dysfunction is a predictor of poor prognosis in patients with heart failure and preserved ejection fraction. ADMA provides the strongest independent prediction of disease progression and adverse long-term outcomes.