ZP123 Prevents Spontaneous Ventricular Arrhythmias and Reduces Infarct Size During Myocardial Ischemia/Reperfusion Injury in Open-Chest Dogs

Background: The antiarrhythmic and cardioprotective effect of inhibiting gap junction uncoupling or increasing gap junction intercellular communication during ischemia/reperfusion (I/R) injury has not been studied. ZP123 is a stable antiarrhythmic peptide that restores and maintains gap junction intercellular communication. Methods: I/R injury was produced in dogs subjected to a 60-min coronary artery occlusion and 4 hr reperfusion. ZP123 was administered IV 10-min before reperfusion as a bolus + IV infusion at doses of: 1ng/kg bolus + 10ng/kg/hr infusion (n=6); 10ng/kg bolus + 100ng/kg/hr infusion (n=6); 100ng/kg bolus + 1000ng/kg/hr infusion (n=7); 1000ng/kg bolus + 10µg/kg/hr infusion (n=6); vehicle control (n=6). Premature ventricular complexes (PVC) were counted for 2 min intervals every 5 min during the first 60 min of reperfusion. Four or more consecutive PVC’s was defined as ventricular tachycardia (VT). Infarct size was assessed after 4 hr of reperfusion and expressed as percent of left ventricle. Results: Total incidence of VT was reduced significantly after treatment with the two highest doses of ZP123 (20.3±10.9; 4.3±4.1 events; p<0.05) compared to controls (48.7±6.0). Total PVC’s expressed as % of total beats over time were reduced significantly from 25.1±4.2% in control animals to 11.0±4.4% and 1.7±1.3% at the two highest doses of ZP123. Analysis of PVC or VT incidence over time demonstrated a significant change in the trend of arrhythmia incidence (repeated measures ANOVA, p<0.01). ZP123 reduced infarct size significantly from 13.2±1.9% in controls to 7.1±1.0% (p<0.05) at the highest dose of ZP123. ZP123 had no effect on heart rate or arterial blood pressure. In separate canine safety studies ZP123 did not induce abnormal atrial or ventricular arrhythmia, QTc prolongation or morphologic ECG changes. PR, QRS, and QTc values were comparable to vehicle-treated controls. The pharmacokinetic profile of ZP123 after IV infusion is characterized by low volume of distribution, a moderate clearance and short half-life. Conclusion: ZP123 treatment reduced the incidence of VT and PVC’s and was associated with reduced infarct size. Our data suggest that ZP123 may be effective for the prevention of ischemia/reperfusion-induced arrhythmias.