Ranolazine Facilitates Termination of Ventricular Tachyarrhythmia Associated With Acute Myocardial Ischemia Through Suppression of Late <b><i>I</i></b>_Na-Mediated Focal Activity

Abstract

of Na + channel inactivation, may contribute to arrhythmogenesis in a variety of pathological conditions. 7-10 Late INa is small in normal cardiac myocytes and is enhanced by heart failure, exposure to oxidative stress, hypoxia and ischemia/reperfusion. 7-10 Late INa during the action potential (AP) plateau reduces repolarization reserve and may prolong AP duration (APD), which renders the membrane potential vulnerable for early afterdepolarization (EAD). In addition, increased late INa-dependent sarcolemmal Na + entry leads to intracellular Na + accumulation, which in turn produces Ca 2+ overload by reduced cellular Ca 2+ extrusion and increased Ca 2+ entry via the Na + /Ca 2+ exchanger. Ca 2+ overload is associated with increased diastolic Ca 2+ leak from the sarcoplasmic reticulum resulting in delayed afterdepolarization (DAD). 11 Moreover, Ca 2+ overload activates Ca 2+ /calmodulin-dependent protein kinase II (CaMKII), which enhances late INa. 9,11 Thus, such a late INa-mediated positive feedback loop might make a profound contribution V entricular tachyarrhythmia, including sustained ventricular tachycardia/fibrillation (VT/VF), associated with acute myocardial ischemia, is the most common immediate cause of sudden cardiac death. 1 In Japan, arrhythmic mortality in patients with acute myocardial infarction is approximately 14%, and the prevalence of coronary artery disease is increasing in step with the rapid aging of the population. 2,3 Although percutaneous coronary interventions have been well established as an effective first-line therapy for acute myocardial infarction, therapeutic strategy for ischemia-associated lethal ventricular arrhythmia remains to be developed.Acute myocardial ischemia is known to cause various changes in the electrophysiological characteristics of ventricular myocardium, and precise mechanisms of acute ischemia-associated arrhythmia are incompletely understood. 4-6 A number of recent reports suggest that late Na + current (INa), which is generated by dysfunctional regulation Background: Ventricular tachycardia/fibrillation (VT/VF) associated with acute myocardial ischemia is the most common cause of sudden cardiac death, but its underlying mechanisms are incompletely understood. It is hypothesized that late Na + current (INa) contributes to arrhythmogenic activity in ischemic myocardium.

Mechanisms of ranolazine pretreatment in preventing ventricular tachyarrhythmias in diabetic db/db mice with acute regional ischemia–reperfusion injury

“…Previously Ogawa et al showed that acute ranolazine perfusion facilitated the termination of ischemic VT/ VF by the suppression of I Na,L -dependent focal arrhythmogenic activity in isolated rabbit hearts 12 . Dhalla et al reported that ranolazine markedly reduced IR-induced VAs possibly via its I Na,L inhibitor property to reduce afterdepolarizations 11 .…”

Dose-Dependent Effects of Ranolazine on Reentrant Ventricular Arrhythmias Induced After Subacute Myocardial Infarction in Rabbits

“…Ranolazine's antiarrhythmic action during AMI has been shown to be mediated by inhibition of increased I NaL rather than by I Kr blockade. [5][6][7]9 This can be explained by a reduction in I NaL which in turn may decrease Na-dependent Ca 2þ overload, suggesting as a potential mechanism of EADs. However, since the arrhythmogenic substrate during the late post-MI period is different and the mechanism of VAs is more likely linked to reentry, I NaL blockade cannot effectively assist in preventing such arrhythmias solely on the basis of an EAD-suppressing mechanism.…”

“…2,3 Increased late sodium current (I NaL ) in the ischemically damaged myocardium may account as a mechanism for ectopic activity, generating after-potentials during repolarization due to sodium-overload mediated increased cytosolic calcium. 4 Although blockade of this current with ranolazine, a acetanilide and piperazine derivative that inhibits the I NaL at therapeutic doses, has been suggested to be responsible for a substantial antiarrhythmic effect against ventricular arrhythmias (VAs) observed during AMI, [5][6][7] its impact for VAs occurring several days postmyocardial infarction has not yet been explored.…”

Air Pollution and Cardiac Arrhythmias: From Epidemiological and Clinical Evidences to Cellular Electrophysiological Mechanisms

“…In addition to above experimental observations about the alteration in ionic currents upon exposure to CO, it should be noted that CO can also indirectly contribute to the cellular electrophysiological remodeling via myocardial ischemia. Under the ischemic condition, intracellular acidosis activates the Na + /H + exchanger to exclude hydrogen ions in exchange for sodium ions, and the elevated sodium is then exchanged for calcium through the Na + /Ca 2+ exchanger, which finally leads to intracellular Ca 2+ overload (115,116). Acidosis also inhibits I CaL , and this effect results in APD shortening together with the reduced I KATP by hypoxia (115).…”