Nifekalant Hydrochloride, a Novel Class III Antiarrhythmic Agent

CASE REPORTS Circ J 2003; 67: 712–714

Nifekalant Hydrochloride, a Novel Class III Antiarrhythmic Agent, Suppressed Postoperative Recurrent Ventricular Tachycardia in a Patient Undergoing Coronary Artery Bypass Grafting and the Dor Approach

Makoto Sahara, MD; Kouichi Sagara, MD; Takeshi Yamashita, MD; Hiroyuki Iinuma, MD; Long-Tai Fu, MD; Hiroshi Watanabe, MD

A patient with 3-vessel coronary artery disease and left ventricular aneurysm underwent coronary artery bypass grafting combined with the Dor approach. Five days later, ventricular tachycardia following short-coupled ventricular premature contractions suddenly occurred and was not responsive to class IB drugs (lidocaine and mexiletine), requiring frequent electrical cardioversion. After the administration of a novel class III drug, nifekalant hydrochloride, this electrical storm of ventricular tachycardia was completely suppressed together with the dis- appearance of ventricular premature contractions. Nifekalant hydrochloride (MS-551), a pure K+ channel blocker, might be effective for postoperative recurrent ventricular tachyarrhythmias that are refractory to other antiarrhythmic agents. (Circ J 2003; 67: 712–714) Key Words: Dor approach; Electrical storm; Myocardial infarction; Nifekalant hydrochloride; Postoperative ventricular tachyarrhythmias

ifekalant hydrochloride is a novel class III antiar- saphenous vein grafts and endoventricular circular patch rhythmic agent that has been developed in Japan plasty (the Dor approach) for the left ventricular aneurysm N and has attracted much attention in recent years were performed. because it has a unique function of selectively blocking the In the early morning on the ﬁfth day after the operation, rapid component of the delayed rectiﬁer K+ current (IKr) at ventricular tachycardia (VT) suddenly occurred, despite the a therapeutic concentration.1–3 In experimental models of absence of preoperative sustained VT or syncope. Mono- myocardial infarction, nifekalant has proved to be effective morphic non-sustained VT triggered by ventricular prema- in suppressing ventricular tachyarrhythmias without aggra- ture contractions (VPCs) with short coupling intervals vating the hemodynamics.4,5 We present a patient with (240–270ms) appeared incessantly (Fig2A) and was trans- unstable angina pectoris, old myocardial infarction and left formed into monomorphic sustained VT successively ventricular aneurysm who underwent coronary artery (Fig2B). Because the VT could not be suppressed by intra- bypass grafting (CABG) combined with the Dor approach venous administration of boluses of class IB antiarrhythmic and who had a postoperative electrical storm of ventricular agents (lidocaine 2.0 mg/kg and mexiletine 2.0mg/kg), tachycardia that was refractory to class IB drugs. We discuss the effect of nifekalant in this case report.

Case Report A 77-year-old man with an old myocardial infarction, left ventricular aneurysm and severe ventricular dysfunction (ejection fraction (EF): 24%) was admitted because of unstable angina pectoris in October 2000. On admission, his ECG showed no remarkable changes compared with his previous records (Fig1), but coronary angiography (CAG) revealed progression of 3-vessel coronary artery disease in addition to 75% stenosis of the left main trunk. Therefore, emergency CABG to all three coronary arteries with

(Received November 19, 2001; revised manuscript received February 4, 2002; accepted February 27, 2002) The Cardiovascular Institute Hospital, Tokyo, Japan Fig1. Twelve-lead ECG on admission shows right axis deviation, Mailing address: Makoto Sahara, MD, The Cardiovascular Institute complete right bundle branch block, abnormal Q wave and ST Hospital, 7-3-10 Roppongi, Minato-Ku, Tokyo 106-0032, Japan. segment elevation in leads I, aVL and V1–6, which were similar ﬁnd- E-mail: [email protected] ings to previous ECG recordings.

Circulation Journal Vol.67, August 2003 Nifekalant and Postoperative VT 713

Fig 3. Clinical course. EC, electrical cardioversion; Mono-VT, Fig2. (A) Incessant monomorphic non-sustained VT triggered by monomorphic ventricular tachycardia; NSVT, non-sustained ventric- ventricular premature contractions with short coupling times (240– ular tachycardia; Poly-VT, polymorphic ventricular tachycardia. 270ms) (arrow). (B) Non-sustained VT was successively transformed into monomorphic sustained VT. (C) Early next morning, monomorphic sustained VT triggered by the short-coupled VPC re-appeared and was transformed into polymorphic VT successively. electrical cardioversion was frequently required. Beta blockers and class IA antiarrhythmic agents could not be administered because of his low cardiac function. Although the continuous intravenous administration of lidocaine (1.0 mg·kg–1·h–1) and AAI pacing (rate = 100 /min) suppressed the occurrence of sustained VT for approx 22h, early the next morning, monomorphic sustained VT triggered by the short-coupled VPC re-appeared and was transformed into polymorphic VT successively (Fig2C), again requiring electrical cardioversion. There were no signifi- cant changes in cardiac enzymes, serum electrolytes, ECG and echocardiogram. Moreover, emergency CAG revealed good patency of all the bypass grafts, so it was unlikely that Fig4. Preoperative (A, B) and postoperative (C, D) left ventriculog- myocardial ischemia and/or infarction were associated raphy showing a decrease in the left ventricular end-diastolic volume index (215.4 to 113.8ml/m2) and an increase in the left ventricular EF with the VT. After beginning intravenous administration of (19.5 to 50.5%). (A) and (C) End diastole, (B) and (D) end systole. nifekalant, at a maintenance dose of 0.40mg·kg–1·h–1 in the afternoon of that day, the VPC completely disappeared and the electrical storm of VT was suppressed. Although the substrate. During an electrophysiologic study, sustained QTc intervals were prolonged from 0.43s to 0.49s, there VT could not be induced by triple extrastimuli from the was no sign of proarrhythmia related to nifekalant and no right ventricular apex. He was discharged on amiodarone aggravation of his hemodynamics [pulmonary artery pres- (200mg/day) and was without recurrence of VT for the sure (systole/diastole; mmHg):(pre) 22/12, (24h after the next 5 months. loading of nifekalant) 23/10; cardiac output (L/min):(pre) 4.87, (24h after the loading of nifekalant) 4.91]. On the third day after the administration of nifekalant, we began Discussion oral amiodarone at a loading dose of 600mg/day (Fig3) It has been reported that 0.68–3.1% of patients under- and when nifekalant was discontinued after 1 week, VT did going open heart surgery, including CABG, experience not recur. unexpected postoperative de novo sustained ventricular Postoperative cardiac catheterization 1 month later tachyarrhythmias (sustained VT and/or fibrillation),6–9 demonstrated good patency in all bypass grafts, decreased particularly in the first 7 postoperative days.8 The Dor left ventricular end-diastolic volume index (215.4 to approach (ie, endoventricular circular patch plasty) had 113.8ml/m2), increased left ventricular EF (19.5 to 50.5%) been reported to improve hemodynamics and significantly (Fig4) and improved hemodynamics (pulmonary capillary suppress the occurrence of postoperative ventricular tachy- wedge pressure: 23 to 18 mmHg; cardiac index: 1.6 to cardia when combined with cryotherapy.10,11 We consider 1.8L·min–1·m–2). Although his preoperative signal-aver- that the postoperative aggravated late potentials, which aged ECG had showed late potentials (filtered QRS were possibly associated with the surgical procedures, but complex duration (fQRS) 154 ms; low amplitude signal this is not exactly clear, were one of the factors inducing <40μV (LAS 40) 50ms; root mean square in the last 40ms the electrical storm of VT, and particularly because preop- of the filtered QRS complex (RMS 40) 10.5μV), his post- erative late potentials were recorded, cryotherapy should operative signal-averaged ECG showed an increase in all have been performed in this case. these parameters (fQRS: 179ms; LAS 40: 62ms; RMS 40: The electrical storm following VPCs with short coupling 12μV), indicating deterioration of the arrhythmogenic intervals suddenly occurred on the fifth postoperative day

Circulation Journal Vol.67, August 2003 714 SAHARA M et al. after successful surgery and could not be controlled by drug, on programmed stimulation-induced ventricular arrhythmias, class IB antiarrhythmic agents, but was successfully sup- electrophysiology, and hemodynamics in a canine myocardial infarction model. J Cardiovasc Pharmacol 1994; 23: 674–680. pressed by nifekalant. Nifekalant (MS-551; 1,3-dimethyl- 5. Friedrichs GS, Chi L, Gralinski MR, Black SC, Basler GC, Mu DX, 6-{2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl)-propylamino] et al. MS-551 protects against ventricular fibrillation in a chronic ethylamino}-2,4 (1H,3H)-pyrimidinedione hydrochloride) canine model of sudden cardiac death. J Cardiovasc Pharmacol is a novel class III drug that selectively blocks IKr at a ther- 1995; 25: 314–323. 1–3 6. Kron IL, DiMarco JP, Harman PK, Crosby IK, Mentzer RM, Nolan apeutic concentration. It also increases defibrillation effi- SP, et al. Unanticipated postoperative ventricular tachyarrhythmias. 12–14 cacy similar to other class III drugs and effectively sup- Ann Thorac Surg 1984; 38: 317–322. presses ventricular tachyarrhythmias in canine models of 7. Topol EJ, Lerman BB, Baughman KL, Platia EV, Griffith LS. De myocardial infarction.4,5 Although class III antiarrhythmic novo refractory ventricular tachyarrhythmias after coronary revascu- agents generally terminate reentry by prolonging cardiac larization. Am J Cardiol 1986; 57: 57–59. 8. Tam SK, Miller JM, Edmunds LH. Unexpected, sustained ventricu- repolarization and the refractory period, this prolongation lar tachyarrhythmia after cardiac operations. J Thorac Cardiovasc can lead to proarrhythmic actions inducing VPC, torsades Surg 1991; 102: 883–889. de pointes and/or ventricular fibrillation. Nifekalant has 9. Steinberg JS, Gaur A, Sciacca R, Tan E. New-onset sustained ven- been shown to aggravate adrenaline-induced arrhythmias,15 tricular tachycardia after cardiac surgery. Circulation 1999; 99: 903–908. the mechanism of which is thought to be abnormal auto- 10. Dor V, Sabatier M, Di Donato M, Maioli M, Toso A, Montiglio F. maticity and/or triggered activity.16 Conversely, nifekalant Late hemodynamic results after left ventricular patch repair associ- has been shown in an electrophysiologic study to inhibit ated with coronary grafting in patients with postinfarction akinetic or and prevent reentrant VT inhumans.17 On the basis of those dyskinetic aneurysm of the left ventricle. J Thorac Cardiovasc Surg 1995; 110: 1291–1299. findings, nifekalant would be effective for reentry VT, but 11. Dor V, Sabatier M, Di Donato M, Montiglio F, Toso A, Maioli M. ineffective for other types. In the present case, considering Efficacy of endoventricular patch plasty in large postinfarction the effectiveness of nifekalant and the presence of late akinetic scar and severe left ventricular dysfunction: Comparison potentials, we can assume that the VT was reentry type. with a series of large dyskinetic scars. J Thorac Cardiovasc Surg 1998; 116: 50–59. Although we believe that in the present case nifekalant sup- 12. Echt DS, Black JN, Barbey JT, Coxe DR, Cato E. Evaluation of anti- pressed the VT clinically by preventing the occurrence of arrhythmic drugs on defibrillation energy requirements in dogs: the triggering short-coupled VPCs, its true functional Sodium channel block and action potential prolongation. Circulation mechanism is still unclear. 1989; 79: 1106–1117. Recently, it was reported that nifekalant suppressed 13. Dorian P, Wang M, David I, Feindel C. 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Circulation Journal Vol.67, August 2003