Impact of short-acting loop diuretic doses and cardiac sympathetic nerve abnormalities on outcomes of patients with reduced left ventricular function

Recent studies reported that high doses of short-acting loop diuretics are associated with poor outcomes in patients with heart failure (HF). Short-acting loop diuretics have been shown to activate the renin-angiotensin system (RAS) and have no favorable effects on cardiac sympathetic nervous system (SNS) activity. The goal of this study is to investigate the relationship between daily doses of furosemide and the outcomes of patients with left ventricular dysfunction (LVD) from the viewpoint of cardiac SNS abnormalities using iodine-123-labeled metaiodobenzylguanidine ((123)l-MIBG) myocardial scintigraphy. We enrolled 137 hospitalized patients (62.5 ± 14.2 years old, 103 men) with LVEF < 45% who underwent (123)l-MIBG myocardial scintigraphy. A delayed heart-to-mediastinum ratio (delayed HMR) was assessed using (123)l-MIBG scintigraphy. Cardiac events were defined as cardiac death or re-hospitalization due to the deterioration of HF. Cox proportional hazard analysis was used to identify predictors of cardiac events. Cardiac events occurred in 57 patients in a follow-up period of 33.1 ± 30 months. In a multivariate Cox proportional hazard analysis, delayed HMR and furosemide doses were identified as independent predictors of cardiac events (P = .0042, P = .033, respectively). Inverse probability of treatment weighting Cox modeling showed that the use of furosemide (≥40 mg /day) was associated with cardiac events with a hazard ratio of 1.96 (P = .003). In the Kaplan-Mayer analysis, the cardiac event-free survival rate was significantly lower in patients treated with high doses of furosemide (≥60 mg/day vs 40–60 mg/day vs <40 mg/day, the Log-rank test P < .0001). In a receiver-operating characteristic (ROC) analysis, the cut-off value for cardiac events was 40 mg/day of furosemide. The cardiac event-free rate was significantly lower in patients with delayed HMR <1.8 (median value) and receiving furosemide ≥40 mg/day than in other patients (the Log-rank test P < .0001). Significant differences in cardiac event rates according to furosemide doses among patients with delayed HMR <1.8 were observed among patients without β-blocker therapy (P = .001), but not among those with β-blocker therapy (P = .127). The present results indicate that a relationship exists between higher doses of furosemide and poor outcomes. The prognosis of HF patients with severe cardiac SNS abnormalities receiving high-dose short-acting loop diuretics is poor.