Effects And Mechanisms Of Imipramine In The Prevention And Treatment Of Ventricular Fibrillation

ObjectiveVentricular fibrillation(VF)is a leading cause of sudden cardiac death,and current treatment options are still inadequate,leading to complications and poor prognosis.Therefore,it is of great significance to seek new and effective therapeutic drugs.Imipramine is a tricyclic antidepressant commonly used in clinical practice.By monitoring the ECG of depression patients treated with imipramine,it was suggested that imipramine may have therapeutic effect on ventricular arrhythmia in heart disease patients,but its mechanism of action in VF remains unclear.This study aims to investigate the role and mechanism of imipramine in an induced VF model and explore its potential as a new treatment method for VF.MethodsTo study the anti-ventricular arrhythmia effect of imipramine,we used Langendorff perfusion method to establish the in vitro VF model of adult rats through ischemia and ventricular ectopic pacing(20Hz).Through ligation of the left anterior descending coronary artery and high-frequency electrical stimulation of the ventricle to establish the in vivo VF model of adult rats,the antiarrhythmic effect of imipramine was further tested.The effect of imipramine on ventricular muscle reentry activation during VF was evaluated by wholeheart perfusion of imipramine to detect its preventive and therapeutic effects.The ventricular myocytes of adult rats were isolated,and the action potential duration(APD),early after depolarization(EADs)and L-type calcium current(ICa,L)of ventricular myocytes with VF were recorded with patch clamp.Western blotting was used to detect the expression of ion channel protein in ventricular tissue of VF and VF treated with imipramine.Finally,human induced pluripotent stem cell-derived ventricular myocytes(hiPS-VCMs)were cultured,and the treatment of hiPS-VCMs by E-4031 was performed using the multielectrode array(MEA)and patch clamp recording to investigate the therapeutic effect of imipramine in simulating human VF.ResultsOur results demonstrate that the antidepressant imipramine has a preventive and therapeutic effect in the VF model of rats.Optical mapping confirmed that imipramine effectively terminated the reentrant excitation generated during VF.Patch clamp experiments revealed that imipramine shortened the APD prolongation of VF cells and eliminated EADs.Western blotting analysis showed that imipramine significantly reduced the level of calcium channel(Ca V1.2,the main subtype of the ventricle)protein,but had no significant effect on the expression of other ion channel proteins(Na V1.5,KV4.3).The typical ICa,L encoded by Ca V1.2 was further detected.The peak value of ICa,L in ventricular myocytes of VF treated with imipramine was significantly decreased,indicating that imipramine reduced APD prolongation by inhibiting Ca V1.2 and ICa,L.Additionlly,imipramine reduced the induction rate of arrhythmias in hiPSC-VCMs,further validating its therapeutic effect in human VF.ConclusionsImipramine is a commonly used antidepressant in clinic.In our study,we clarified the role of imipramine in the prevention and treatment of VF.Our study sheds light on the mechanisms may be through inhibiting the protein expression of calcium channel Ca V1.2 and down-regulating ICa,L,shorten APD and inhibit EAD,and achieve the goal of treating VF.