Ivabradine is as effective as metoprolol in the prevention of ventricular arrhythmias in acute non-reperfused myocardial infarction in the rat

Abstract

Ventricular arrhythmias are a major source of early mortality in acute myocardial infarction (MI) and remain a major therapeutic challenge. Thus we investigated effects of ivabradine, a presumably specific bradycardic agent versus metoprolol, a β-blocker, at doses offering the same heart rate (HR) reduction, on ventricular arrhythmias in the acute non-reperfused MI in the rat. Immediately after MI induction a single dose of ivabradine/ metoprolol was given. ECG was continuously recorded and ventricular arrhythmias were analyzed. After 6 h epicardial monophasic action potentials (MAPs) were recorded and cardiomyocyte Ca2+ handling was assessed. Both ivabradine and metoprolol reduced HR by 17% and arrhythmic mortality (14% and 19%, respectively, versus 33% in MI, p < 0.05) and ventricular arrhythmias in post-MI rats. Both drugs reduced QTc prolongation and decreased sensitivity of ryanodine receptors in isolated cardiomyocytes, but otherwise had no effect on Ca2+ handling, velocity of conduction or repolarization. We did not find any effects of potential IKr inhibition by ivabradine in this setting. Thus Ivabradine is an equally effective antiarrhythmic agent as metoprolol in early MI in the rat. It could be potentially tested as an alternative antiarrhythmic agent in acute MI when β-blockers are contraindicated.

Effect of Ivabradine on Cardiac Ventricular Arrhythmias: Friend or Foe?

“…Pacing to maintain unchanged HR essentially abolished protective effects of ivabradine, suggesting that HR reduction is the principal mechanism of its antiarrhythmic action [ 64 ]. Other experimental studies support this conclusion: we showed that ivabradine and metoprolol provided similar protection against VA induced by acute non-reperfused MI when given at doses that ensured identical HR reduction [ 57 ]. Similarly, ivabradine increased time to onset of ischemia-related conduction slowing and loss of electrical excitability and protected against development of VF during reperfusion in a model of 8-minute ischemia and reperfusion in an isolated rat heart [ 60 ].…”

“…Preclinical studies of ivabradine are summarized in Table 1 . Briefly, ivabradine reduced ventricular arrhythmias (VA, both ventricular tachycardia [VT]/ventricular fibrillation [VF] and premature ventricular complexes [PVC]), arrhythmic deaths and total mortality in the rat model of non-reperfused acute MI, both when given as prophylaxis [ 25 ] and within the first minutes of ischemia [ 57 ] and was as effective as metoprolol in the latter study. Furthermore ivabradine increased VF threshold during acute myocardial ischemia in the pig [ 58 , 59 ], reduced VA during ischemia and reperfusion in the isolated rat heart [ 60 ].…”

“…In the rat model of acute non-reperfused MI we showed that ivabradine prevented dispersion of electrical and biochemical properties between the infarct borderzone and the remote ventricular myocardium, essentially preventing early (within 45 min) ischemia-related shortening of AP and late (24 h) prolongation of AP related to downregulation of potassium channels (ERG and KVLQTI) in the infarct borderzone [ 25 ]. Despite the fact that ivabradine prevented striking differences in expression of various potassium channels (Kv4.3, KChIP2, ERG and KVLQTI) between the infarct borderzone and remote myocardium, it resulted in overall reduced expression of potassium channels, which could be responsible for QT prolongation observed at 24 h. Despite the fact that ivabradine did not affect parameters of Ca 2+ handling, such as SR Ca 2+ content, activity of major Ca 2+ transporting proteins (NCX, sarcoplasmic Ca 2+ -ATPase [SERCA]), it reduced RyR sensitivity to Ca 2+ , potentially preventing pro-arrhythmic diastolic SR Ca 2+ leak [ 25 , 57 ]. Moreover, in another rabbit ischemia and reperfusion study ivabradine increased FKBP12/12.6 expression and reduction of diastolic SR Ca 2+ leak [ 70 ].…”

“…Another potentially antiarrhythmic effect of ivabradine identified in our study was prevention of HCN4 overexpression in the ventricular cardiomyocytes as early as 24 h after MI induction [ 25 ], corroborating previous findings that ivabradine prevented HCN4 overexpression after 3 months of treatment in the post-MI rat [ 27 ]. However, due to the fact that in the setting of acute ischemia and reperfusion arrhythmias tend to occur early, before changes in ion channel expression could take place, [ 25 , 57 ], HCN4 overexpression is unlikely to play a major role in arrhythmogenesis in this setting.…”

Ivabradine protects rats against myocardial infarction through reinforcing autophagy via inhibiting PI3K/AKT/mTOR/p70S6K pathway

“…It has been revealed that Iva slows heart rate by reducing the slope of the diastolic depolarization of pacemaker action potential, without affecting cardiac inotropy or systemic vascular resistance [ 10 ]. Emerging evidence has proven the efficacy and safety of Iva in other cardiovascular diseases such as inappropriate sinus tachycardia [ 11 ] and ventricular arrhythmias [ 12 ]. However, the guidelines of Iva in the application of acute coronary syndromes has not been established.…”