Ivabradine Prevents Deleterious Effects of Dopamine Therapy in Heart Failure; No Role for HCN4 Overexpression

Abstract

Background: Exacerbations of chronic heart failure (CHF) are often treated with catecholamines to provide short term inotropic support, but this strategy is associated with long-term detrimental hemodynamic effects and increased ventricular arrhythmias (VA), possibly related to increased heart rate (HR). We hypothesized that ivabradine may prevent adverse effects of short-term dopamine treatment in CHF. Methods: Rats with post-myocardial infarction CHF received 2-week infusion of saline, dopamine(D), ivabradine(I) or DI cardiac function was assessed using echocardiography and pressure-volume loops while VA were assessed using telemetric ECG recording. Expression of HCN4, a potentially proarrhythmic channel blocked by ivabradine, was assessed in left ventricular (LV) myocardium. HCN4 expression was also assessed in human explanted normal and failing hearts and correlated with VA. Findings: Dopamine infusion had detrimental effects on hemodynamic parameters and LV remodeling and induced VA in CHF rats, while ivabradine completely prevented these effects. CHF rats demonstrated HCN4 overexpression in LV myocardium, and ivabradine and, unexpectedly, dopamine prevented this. Failing human hearts also exhibited HCN4 overexpression in LV myocardium that was unrelated to patient’s sex, CHF etiology, VA severity or plasma NT-proBNP. Interpretation: HR reduction offered by ivabradine may be a feasible strategy to extract benefits of inotropic support in CHF exacerbations, avoiding detrimental effects on CHF biology or VA. Ivabradine may offer additional beneficial effects in this setting, going beyond pure HR reduction, however prevention of ventricular HCN4 overexpression is unlikely to play a major role. Funding: This study was supported by National Institute of Cardiology and Polish Cardiac Society. Declaration of Interests: The authors have declared that no conflict of interest exists. Ethics Approval Statement: The study conformed to the Guide for the Care and Use of Laboratory Animals, US National Institutes of Health, ARRIVE 2.0 guidelines and was approved by the Second Warsaw Local Ethics Committee for Animal Experimentation. Study protocol conformed to the Declaration of Helsinki and was approved by the Institutional Ethics Committee. Each patient participating in the study had signed an informed consent form after being provided with detailed explanation of study principles.