Dose-Dependent Prognostic Effect of Carvedilol in Patients With Chronic Heart Failure::Special Reference to Ranscardiac Gradient of Norepinephrine

he β-blockers improve cardiac function and prolong survival in patients with systolic chronic heart failure (CHF).1–4 In the Multicenter Oral Carvedilol Heart Failure Assessment (MOCHA) trial, carvedilol (6.25– 25 mg/day) was associated with dose-related improvements in left ventricular (LV) function and survival in heart failure (HF) patients in a population that was 77% Caucasian.5 However, the response to carvedilol may vary among different ethnic groups6–9 and indeed, the dose of carvedilol for treatment in Japanese is 10–20 mg/day, which is less than half of the dose used in Western patients.10,11 In the Multicenter Carvedilol Heart Failure Dose Assessment (MUCHA) trial, low-dose carvedilol (5 mg/day group or 20 mg/day group) improved the LV ejection fraction (LVEF) and reduced cardiovascular hospitalization in Japanese patients with CHF.12 In addition, carvedilol therapy achieved a dose-related improvement in CHF and LVEF; cardiovascular hospitalization was markedly reduced. However, the relationship between the dose-dependent improvement of carvedilol and prognosis in Japanese patients with CHF remains unknown. Cardiac sympathetic nerve activity (CSA) plays an important role in the pathophysiology of CHF.13–17 We previously reported that CSA plays an important role in the pathophysiology of CHF, independent of hemodynamic overload, and that the transcardiac gradient of norepinephrine (NE) is a more reliable biomarker of CSA than the peripheral venous NE level.18,19 Moreover, carvedilol treatment has been reported as associated with a significant reduction in the transcardiac gradient of NE, without any changes in the plasma arterial NE, in patients with CHF.20 There has not previously been a study correlating the transcardiac gradient of NE, brain natriuretic peptide (BNP) and N-terminal BNP (NT-proBNP) with the dose of carvedilol. In the present study, we investigated the relationship of these parameters with the prognosis of CHF in the same population.