Ranolazine ameliorates postresuscitation electrical instability and myocardial dysfunction and improves survival with good neurologic recovery in a rat model of cardiac arrest

Heart Rhythm. 2014 Sep;11(9):1641-7. doi: 10.1016/j.hrthm.2014.05.023. Epub 2014 May 22.

Abstract

Background: During ischemia, enhancement of the "late Na+ current" (I(NaL)) contributes to intracellular Ca2+ overload. Dysregulation of intracellular Ca2+ homeostasis plays a critical role in the pathophysiology of cardiac arrest and cardiopulmonary resuscitation (CPR), leading to ventricular arrhythmias and left ventricle (LV) dysfunction.

Objective: The purpose of this study was to investigate the effects of the I(NaL) blocker ranolazine on outcome of CPR in a rat model. We hypothesized that ranolazine might reduce postresuscitation arrhythmias and improve survival and recovery.

Methods: Eighteen rats were assigned to receive intravenous ranolazine 10 mg/kg or vehicle. Ventricular fibrillation was induced and untreated for 8 minutes. CPR then was performed for 8 minutes. ECG and arterial and right atrial pressures were monitored up to 3 hours after CPR. After resuscitation, LV function was monitored by echocardiography, and 72-hour survival with neurologic recovery was evaluated. Plasma was obtained for biomarkers of heart and brain injury.

Results: All animals in the ranolazine group were resuscitated and survived up to 72 hours, whereas 72% in the vehicle group were resuscitated but 54% survived. The period of postresuscitation arrhythmia with hemodynamic instability was shorter in the ranolazine group compared to vehicle group (P < .02). Seventy-two hours after resuscitation, LV systolic and diastolic functions were better in the ranolazine group compared to vehicle (P < .05). Full neurologic recovery was observed in all ranolazine animals, whereas neurologic impairment persisted in the vehicle group (P < .02).

Conclusion: In this model, ranolazine pretreatment reduced postresuscitation electrical and hemodynamic instability and improved 72-hour postresuscitation LV function and survival with good neurologic recovery.

Keywords: Cardiac arrest; Late Na(+) current blockade; Myocardial dysfunction; Neurologic recovery; Outcome; Postresuscitation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetanilides / therapeutic use*
  • Animals
  • Cardiomyopathies / drug therapy*
  • Cardiomyopathies / etiology
  • Cardiomyopathies / physiopathology
  • Cardiopulmonary Resuscitation*
  • Central Nervous System / drug effects
  • Central Nervous System / physiopathology*
  • Disease Models, Animal
  • Enzyme Inhibitors / therapeutic use
  • Heart Arrest / physiopathology*
  • Heart Arrest / therapy
  • Piperazines / therapeutic use*
  • Ranolazine
  • Rats
  • Rats, Sprague-Dawley
  • Sodium Channel Blockers
  • Treatment Outcome
  • Ventricular Dysfunction, Left / drug therapy*
  • Ventricular Dysfunction, Left / etiology
  • Ventricular Dysfunction, Left / physiopathology

Substances

  • Acetanilides
  • Enzyme Inhibitors
  • Piperazines
  • Sodium Channel Blockers
  • Ranolazine