Role Of Calcium Channel Blocker In T-wave Alternans Of The Rabbit Acute Myocardial Ischemia Model

Objective The malignant arrhythmia has a high incidence and mortality, so far treatment by every means proved not be as effective as expected. T-wave alternans is one of the most effective and independent predictive factor of malignant arrhythmia and sudden cardiac death, we expect that by using this index to monitor and intervene we could find a way to regulate malignant arrhythmia from upstream. In this research of the rabbit acute myocardiac ischemia model we study the difference between calcium channel blocker verapamil and nifedipine pretreatment on the effect of T-wave alternans, the change of electrophysiology parameter in relationship with repolarization under acute ischemia conditions, and the overlap effect of both ryanodine receptor agonist and verapamil. In this way we want to figure out the mechanism of verapamil on TWA, which could bring up with new method to preventing and intervening ischemic arrhythmia.Methods This research includes two parts as follows:(1) To compare the effect of verapamil and nifedipine on T-wave alternans in the left ventricular wedge preparations of acute myocardial ischemia rabbit model: Japanese white rabbits are randomized into four groups:control group, ischemia group, verapamil group and nifedipine group. Arterially perfused left ventricular wedge preparations are made, and action potentials (APs) of endocardium and epicardium and transmural ECG are simultaneously recorded. The control group was perfused with Tyrode’s solution, while the ischemia group undergoes15minutes non-perfusion before receiving a continuous stimulation at200ms basic cycle length, the verapamil group and nifedipine group undergo15minutes drug perfusion before15minutes non-perfusion, and finally receive a continuous stimulation at200ms basic cycle length. The incidence of T-wave alternans and ventricular tachycardia/fibrillation are observed, and the QRS, stimulus-action time of both endocardium and epicardium, QT interval, action potential duration of both endocardium and epicardium, transmuaral dispersion of depolarization and contractile curve are recorded.(2) To observe the change of verapamil’s effect on T-wave alternans by modifying Ryanodine receptor function in the left ventricular wedge preparations of acute myocardial ischemia rabbit model: Japanese white rabbits are randomized into five groups:control group, ischemia group, verapamil group, ryanodine group and verapamil+ryanodine group. Arterially perfused left ventricular wedge preparations are made, and action potentials (APs) of endocardium and epicardium and transmural ECG are simultaneously recorded. The control group was perfused with Tyrode’s solution, while the ischemia group undergoes15minutes non-perfusion before receiving a continuous stimulation at200ms basic cycle length, the drug pretreated group undergo15minutes drug perfusion before15minutes non-perfusion, and finally receive a continuous stimulation at200ms basic cycle length. The incidence of T-wave alternans and ventricular arrhythmia(tachycardia/fibrillation) are observed, and the QRS, stimulus-action time of both endocardium and epicardium, QT interval, action potential duration of both endocardium and epicardium, transmuaral dispersion of depolarization and contractile curve are recorded.Results (1) The incidence of T-wave alternans is0/10in control group,10/10in ischemia group,0/10in verapamil group and9/10in nifedipine group; the incidence of VT/VF is0/10in control group,5/10in ischemia group,0/10in verapamil group and3/10in nifedipine group, respectively. There is marked increase in QRS, stimulus-action time and TDR between ischemia group and control group(P<0.05). Verapamil can decrease incidence of T-wave alternans and ventricular arryhthmia(P<0.05), it also exhibits the ability of lowering QRS, stimulus-action time of epicardium and TDR during ischemia. There is no significant difference of the incidence of TWA, ventricular arryhthmia or electrophysiological parameters between nifedipine group and ischemia group.(2) The incidence of T-wave alternans is0/10in control group,10/10in ischemia group,0/10in verapamil group,10/10in ryanodine group and7/10in verapamil+ryanodine group; the incidence of ventricular arryhthmia is0/10in control group,5/10in ischemia group,0/10in verapamil group,6/10in ryanodine group and3/10in verapamil+ryanodine group, respectively. There is marked increase in QRS, stimulus-action time of ryanodine group compared with ischemia group(P<0.05), which is responsible for conduction blockade and reentray. There is no significant difference between verapamil+ryanodine group and ischemia group on the incidence of T-wave alternans and ventricular arryhthmia.Conclusion The increase of transmuaral dispersion of depolarization, decrease of conduction and after depolarization may play an important role in the formation of T-wave alternans. Verapamil is effective in suppressing TWA and ventricular arrhythmia during acute ischemia, whereas Nifedipine is unable to suppress T-wave alternans and ventricular arrhythmia, thus L-type calcium channel is not the unique target of TWA. Furthermore, modulation of Ryanodine receptor function is essential in TWA, we imply that acting on L type calcium channel and Ryanodine receptor at the same time may be the underlying mechanism of verapamil’s effect on TWA during acute myocardial ischemia.