Abstract 2171: Evidence that the Anti-Anginal Agent and Inhibitor of the Late Sodium Current, Ranolazine, Improves Post-Ischemic Stunned Myocardium in the Rabbit
Cellular Ca++ overload occurs in the myocardium during short periods of ischemia/reperfusion, even in the absence of necrosis, and may contribute to the mechanical dysfunction, myocardial stunning. The antianginal agent, ranolazine (R) inhibits the late sodium current and protects cells from intracellular sodium overload and subsequent Ca++ overload due to sodium-calcium exchange. The effects of R on stunned myocardium are unknown.
Methods: Myocardial stunning was induced in rabbits by 15 min of coronary artery occlusion (CAO) followed by 3 hrs reperfusion (rep). Ten min before CAO , rabbits were randomly assigned to vehicle (n = 15) or R (2 mg/kg bolus plus 60μg/kg/min infusion, I.V., n = 15). Myocardial stunning was assessed by left ventricular (LV) 2-D echocardiography using ischemic free-wall fractional thickening (FWft, [systolic wall thickness- diastolic wall thickness/diastolic wall thickness]) as a marker of severity. Regional ejection fraction (EF) was also assessed.
Results: During CAO FWft was similarly depressed in both groups, suggesting a similar degree of ischemic insult. (FWft was reduced from 0.62 ± 0.05 at baseline to .20±.06 in vehicle and from 0.73 ± 0.05 to 0.26 ± 0.07 in R, p = ns, R vs. vehicle). After rep, previously ischemic myocardium remained stunned, however FWft recovered significantly better in R (0.48 ± 0.05) than in vehicle (0.34 ± 0.03, p=0.027). Baseline EF was 0.65 ± 0.02 in the R and 0.68 ± 0.02 in vehicle (p=ns). During CAO EF was reduced by 36 ± 6% in vehicle vs. only 20 ± 6% in R (p<0.05). At the end of rep, EF remained depressed in both groups but the reduction in the vehicle group (25 ± 5%) was significantly worse than in R (9 ± 4%, p<0.02). Improvement in function was independent of necrosis (negligible) or differences in hemodynamics or regional myocardial blood flow (no significant differences between groups).
Conclusion: R reduced stunned myocardium following brief ischemia/rep suggesting that inhibiting the late sodium current may be a novel approach to treating stunning independent of effects on hemodynamics.