LAUSR

More than 2 decades ago, a novel sinoatrial (SA) node modulator, now known as ivabradine, was found in experimental preparations to decrease heart rate to a similar extent as beta-blockers but without depressing cardiac index or left ventricular function.1,2 The main mode of action was found to be strong rate-dependent inhibition of the “funny” current, If, which is responsible for the diastolic depolarization phase of the SA nodal action potential.2 If is a fascinating mixed sodium–potassium current that activates uniquely during hyperpolarization in the range of 260 to 270 mV. Over many years of investigation, ivabradine has been shown to exhibit beneficial pleiotropic actions through heart rate reduction and other influences, as depicted in Figure 1.3 The main clinical application for ivabradine, as approved by the European Medicines Agency (EMA) and the European Society of Cardiology, is for treatment of angina pectoris in individuals who are either intolerant of or inadequately managed by beta-blockers and whose heart rate is $70 beats/min4–6 (NCT00143507). Ivabradine has not received the Food and Drug Administration approval for this indication in the United States. Interest has been increasingly drawn to indications for ivabradine in patients with heart failure.7–9 The SHIFT trial (NCT02441218),8 which investigated ivabradine in patients with reduced left ventricular (LV) ejection fraction and elevated heart rate while receiving beta-blocker therapy, reported a 5% absolute risk reduction (hazard ratio, 0.82, 95% confidence interval, 0.75–0.9, P , 0.0001) in the composite endpoint of heart failure hospitalization and cardiovascular death. In 2015, ivabradine was approved by the Food and Drug Administration as a second-line therapy for patients with stable, chronic heart failure with reduced LV ejection fraction and sinus rhythm $70 beats/min.9 In the current issue of the journal, El-Naggar et al10 explored a logical extension of the existing experimental and clinical literature on heart failure, namely, whether or not ivabradine can afford protection against doxorubicin-induced heart failure in an intact rat model. This is an important, clinically relevant issue, given the extent to which doxorubicin is used as a broad-spectrum, anthracycline-class anticancer agent. In fact, heart failure is one of the most significant side effects of doxorubicin therapy.11 The cardiotoxicity is a consequence of multifold actions leading to severe myocardial and autonomic dysfunction. Effective therapy to combat doxorubicin-induced cardiomyopathy and heart failure is lacking. The choice of the present investigators to examine the usefulness of ivabradine is intriguing and has potential mechanistic underpinnings. Four groups were studied: saline, doxorubicin, ivabradine, and ivabradine plus doxorubicin. Doxorubicin was administered intraperitoneally as 6 equal injections of 2.5 mg/kg/2 days over a period of 2 weeks, with a cumulative dose of 15 mg/kg. Ivabradine was also administered intraperitoneally in 6 doses of 10 mg/kg/2 days for a total of 60 mg, either separately or along with doxorubicin. The animals were instrumented with chronic catheters and surface electrocardiogram electrodes to record an extensive array of measurements including heart rate, mean arterial pressure, LV dP/dt max, and the relaxation time constant Tau. Measures of autonomic tone and baroreceptor sensitivity were also assessed as well as cardiac troponin T and histopathologic changes. The results revealed relatively global benefits of ivabradine with respect to most of the parameters assessed. Overall, ivabradine was shown to produce salutary effects,