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Address reprint requests and correspondence: Dr Satoshi Nagase, Department of Advanced Arrhythmia and Translational Medical Science, National Cerebral and Cardiovascular Center, 6-1 Kishibe-shinmachi, Suita, Osaka 564-8565, Japan.
The efficacy of quinidine in multifocal ectopic Purkinje-related premature contractions (MEPPC) had been reported previously. However, quinidine sometimes causes side effects such as gastrointestinal intolerance and QT prolongation. In this MEPPC case, despite low-dose quinidine administration with low blood concentration, quinidine in combination with verapamil markedly suppressed ventricular arrhythmia.
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Previous ablations had already demonstrated conduction disturbances in the right and the left fascicles. Because Purkinje and bundle of His potentials had variable sequences that preceded PVCs, ablation for multiple Purkinje/His discharges is concerning owing to the severe impairment of atrioventricular conduction in MEPPC.
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If MEPPC is suspected, genetic testing should be performed promptly for an accurate diagnosis, and pharmacologic therapy, which is generally contraindicated in low cardiac function but is effective in MEPPC, should be initiated immediately.
Introduction
A mutation in the SCN5A gene is associated with several phenotypes, such as dilated cardiomyopathy (DCM) as well as long QT syndrome, Brugada syndrome, sick sinus syndrome, and atrial fibrillation. “Multifocal ectopic Purkinje-related premature contractions” (MEPPC), which is generally caused by the SCN5A mutation, is characterized by DCM and hyperexcitability of the fascicular–Purkinje system–mediated multifocal premature ventricular contraction (PVC) and polymorphic ventricular tachycardia.
However, quinidine administration, especially in high doses, is sometimes associated with side effects such as gastrointestinal intolerance and QT prolongation, and long-term administration is usually difficult. Moreover, the combination of quinidine administered with another drug in MEPPC is rare,
and reports on detailed cardiac electrophysiology are similarly scarce.
Here, we report the first case of a patient with MEPPC with the SCN5A variant, multifocal PVCs, and DCM in whom the combination of low-dose quinidine and verapamil was effective for both arrhythmia and heart failure. Characteristic electrophysiological findings are also presented.
Case report
A 32-year-old male patient was admitted to our institution owing to frequent multiform PVCs (Figure 1) and left ventricular (LV) dysfunction in January 2022. His grandfather had an implantable cardioverter-defibrillator owing to hypertrophic cardiomyopathy, and his younger brother also had frequent PVCs. Frequent PVCs and nonsustained ventricular tachycardia (NSVT) were first observed when the patient was 15 years old. At that time, PVC accounted for 39% of the total heartbeats in a 24-hour Holter electrocardiogram (ECG) and echocardiogram revealed normal LV function without obvious structural abnormalities. Mexiletine and propranolol were initiated, but failed to suppress PVCs. In 2005, the first catheter ablation was performed because PVC accounted for 63% of the total heartbeats on a Holter ECG. Radiofrequency application at the right ventricular apex area failed to eliminate PVC and NSVT, and verapamil and pilsicainide failed to suppress PVCs. In 2008, a second ablation was performed and radiofrequency application at the right ventricular apex and LV septum area partially suppressed PVC. The first and second ablation had been performed long ago and the details were no longer available. Sotalol also failed to suppress PVCs. Owing to patient refusal, amiodarone was not administered. Because bepridil partially suppressed PVCs, bepridil and bisoprolol were administered after the second ablation.
Figure 1Surface electrocardiogram in an electrophysiological study. Multiform premature ventricular contractions (PVCs) were observed. Major QRS morphology of PVC was the right bundle branch block type with right axis deviation. ∗ indicates PVC.
In 2021, genetic analysis revealed a previously reported SCN5A mutation (exon5, c.611C>A, p.A204E) in this patient, which led to the diagnosis of MEPPC.
Echocardiogram revealed a marked decrease in the LV function with an LV ejection fraction (LVEF) of 37%, end-diastolic diameter of 67 mm, and end-systolic diameter of 51 mm, and a Holter ECG revealed frequent PVC (84,371/day; 60% of total heartbeats) and polymorphic NSVT. Cardiac magnetic resonance imaging showed that LVEF was 19.7%, left ventricular end-diastolic volume index was 155.7 mL/m2, and late gadolinium enhancement was absent. Coronary computed tomography showed no particular abnormalities.
A third ablation was attempted on January 11, 2022. Surface ECG in an electrophysiological study (EPS) showed complete right bundle branch (RBB) block and slight right axis deviation during sinus rhythm, which may represent severe conduction impairment of RBB and left posterior fascicle (LPF) associated with previous ablations (Figure 1). Recording with multipolar catheters revealed that the HV interval was 62 ms and the bundle of His and/or left anterior fascicular (LAF) potentials preceded almost all PVCs (Figure 2). The RBB potential and LPF potential were damaged by previous ablation and could not be found by detailed mapping. Because the sequence of ectopic His and LAF discharges were variable, we considered that multifocal His–Purkinje discharges from both ventricles demonstrated multiple PVCs/NSVT (Figure 2, Supplemental Figure 1). Atrial constant pacing could not suppress PVCs (Supplemental Figure 2). Because PVCs preceded by residual LAF potentials appeared relatively frequently, ablation was performed using activation mapping as an index (Figure 3), but was ineffective, and ablation was abandoned owing to concerns about complete atrioventricular block. An implantable cardioverter-defibrillator was placed after ablation owing to NSVT and severe LV dysfunction.
Figure 2Surface electrocardiogram and intracardiac electrogram during electrophysiological study. Multipolar catheters were positioned to record the right-side bundle of His electrogram (HBE) in the right ventricle and left anterior fascicular (LAF) electrogram in the left ventricle. The catheter position is shown in Figure 3A. The red dotted line indicates the onset of the QRS complex in each premature ventricular contraction (PVC). The black arrow indicates the sequence of HBE and LAF electrogram in each PVC. HBE and LAF potentials appeared to be unrelated to each other, and the LAF sequences and their precedence over PVCs were not constant. Some PVCs were not preceded by HBE and LAF electrogram, which are expected to originate from the remote nonrecorded Purkinje network.
Figure 3A: Left intracardiac electrograms show left anterior fascicular (LAF) potentials (arrows) in a sinus rhythm and premature ventricular contractions (PVC). Right schema shows catheter position and activation mapping during PVC in the right anterior oblique view. HBE(rt.) indicates the right-side bundle of His electrogram and HBE(lt.) indicates the most proximal left bundle potential. Many PVCs with right bundle branch block type and right axis deviation originated from the LAF 4–5 area. However, radiofrequency applications (ABL) to this area failed to eliminate these PVCs. B: The left electrocardiogram (ECG) shows PVCs (∗), and the right ECG shows pace mapping at the ABL site. The QRS morphology with pacing at a cycle length of 400 ms is similar to that with PVC.
Although quinidine reduced PVCs (Supplemental Figure 3), the quinidine dose was limited to 300 mg/d owing to mild and tolerable diarrhea after consultation with the patient. Finally, the combination of 300 mg/d of quinidine and 240 mg/d of verapamil remarkably suppressed PVC/NSVT (Supplemental Figure 4). A Holter ECG showed that the number of PVCs was 4040 per day (4% of the total heartbeats). The BNP level decreased from 145.0 to 11.2 pg/mL. A follow-up echocardiogram showed that the LVEF was 32% and end-diastolic diameter / end-systolic diameter was 60 mm / 50 mm 2 weeks after quinidine and verapamil administration. The quinidine blood concentration was as low as 0.9 μg/mL.
Discussion
Previous reports
Since it was first reported in 2012, there have been several reports on MEPPC.
You cannot ablate the Lernaean Hydra: SCN5A mutation in a patient with multifocal ectopic Purkinje-related premature contractions syndrome treated with Flecainide and an implant of a subcutaneous defibrillator-a case report.
Multifocal atrial and ventricular premature contractions with an increased risk of dilated cardiomyopathy caused by a Na(v)1.5 gain-of-function mutation (G213D).
The G213D variant in Nav1.5 alters sodium current and causes an arrhythmogenic phenotype resulting in a multifocal ectopic Purkinje-related premature contraction phenotype in human-induced pluripotent stem cell-derived cardiomyocytes.
Electrophysiological considerations remain scarce, and treatment options are not fully established. The efficacy of ablation therapy is controversial, and information on pharmacological therapy remains insufficient.
In MEPPC, SCN5A mutation leads to a gain of function of the sodium channel responsible for hyperexcitability of the broad His-Purkinje network. This mechanism is expected to lead to the emergence of multifocal PVCs with multiple QRS morphologies and junctional beats. In fact, previous reports have shown that multifocal Purkinje potentials in extensive regions of both ventricles preceded each PVC.
You cannot ablate the Lernaean Hydra: SCN5A mutation in a patient with multifocal ectopic Purkinje-related premature contractions syndrome treated with Flecainide and an implant of a subcutaneous defibrillator-a case report.
Patients may present with frequent palpitations, syncope, dyspnea, or sudden cardiac death. High burden of multifocal PVCs can demonstrate DCM. There have been several reports on catheter ablation, all of which have been ineffective.
You cannot ablate the Lernaean Hydra: SCN5A mutation in a patient with multifocal ectopic Purkinje-related premature contractions syndrome treated with Flecainide and an implant of a subcutaneous defibrillator-a case report.
The G213D variant in Nav1.5 alters sodium current and causes an arrhythmogenic phenotype resulting in a multifocal ectopic Purkinje-related premature contraction phenotype in human-induced pluripotent stem cell-derived cardiomyocytes.
Thus, antiarrhythmic therapy with sodium channel blockers (quinidine, flecainide, and amiodarone) is generally recommended (Supplemental Table 1). Flecainide is the most commonly used drug,
You cannot ablate the Lernaean Hydra: SCN5A mutation in a patient with multifocal ectopic Purkinje-related premature contractions syndrome treated with Flecainide and an implant of a subcutaneous defibrillator-a case report.
Multifocal atrial and ventricular premature contractions with an increased risk of dilated cardiomyopathy caused by a Na(v)1.5 gain-of-function mutation (G213D).
The G213D variant in Nav1.5 alters sodium current and causes an arrhythmogenic phenotype resulting in a multifocal ectopic Purkinje-related premature contraction phenotype in human-induced pluripotent stem cell-derived cardiomyocytes.
Multifocal atrial and ventricular premature contractions with an increased risk of dilated cardiomyopathy caused by a Na(v)1.5 gain-of-function mutation (G213D).
You cannot ablate the Lernaean Hydra: SCN5A mutation in a patient with multifocal ectopic Purkinje-related premature contractions syndrome treated with Flecainide and an implant of a subcutaneous defibrillator-a case report.
In this case, we performed EPS/ablation and initiated drug treatment for MEPPC with the previously reported SCN5A variant. Surface ECG and EPS revealed prolongation of the HV interval and severe conduction impairment of RBB and LPF, probably owing to multiple previous ablations. Purkinje potentials originating from the LAF and/or bundle of His potential preceded most PVCs. Additionally, Purkinje and His potential sequences preceding the PVCs varied, and some discharge from the bundle of His showed exit block (Supplemental Figure 1). Thus, further radiofrequency current application was abandoned owing to concerns about the development of complete atrioventricular block. Moreover, in this patient, left bundle branch block–type PVCs, which should originate from the right ventricle, were also observed despite complete RBB. This also suggests that complete fascicular block is inappropriate as an endpoint for ablation to eliminate multiple PVCs in MEPPC. Unlike the previous report, atrial pacing performed during EPS was ineffective.
There are no reports of detailed EPS and detailed mapping of the earliest activation sites of the preceding Purkinje potentials using a multipolar catheter with a 3D mapping system, as in the present case.
In this case, although the blood concentration of quinidine was low, combination with verapamil markedly suppressed ventricular arrhythmia and improved heart failure. To date, there have been no reports of the combination of verapamil and low-dose quinidine being effective in MEPPC. Multiple antiarrhythmic agents were ineffective in this patient. Because he was diagnosed with MEPPC, we introduced quinidine this time, which was reported to be effective.
However, because quinidine showed a mild diarrhea tendency at 300 mg/d, the dose was not increased further, and PVCs were well controlled when verapamil (240 mg/d) was added. The blood concentration of quinidine was as low as 0.9 μg/mL. We did not try flecainide administration in this case,
You cannot ablate the Lernaean Hydra: SCN5A mutation in a patient with multifocal ectopic Purkinje-related premature contractions syndrome treated with Flecainide and an implant of a subcutaneous defibrillator-a case report.
Multifocal atrial and ventricular premature contractions with an increased risk of dilated cardiomyopathy caused by a Na(v)1.5 gain-of-function mutation (G213D).
The G213D variant in Nav1.5 alters sodium current and causes an arrhythmogenic phenotype resulting in a multifocal ectopic Purkinje-related premature contraction phenotype in human-induced pluripotent stem cell-derived cardiomyocytes.
Pilsicainide, a class Ic antiarrhythmic drug that is identical to flecainide, was ineffective in the present case. Side effects caused by quinidine are a concern because long-term administration is essential, and it is important to prevent these side effects using a small dose of quinidine in combination with another drug. Although the amount of quinidine was small and the blood concentration was low in our patient, it was useful in combination with verapamil. Furthermore, some class Ia or Ic antiarrhythmic drugs, which are generally contraindicated in heart failure, are remarkably effective in MEPPC. Thus, if MEPPC is suspected, it is important to perform genetic testing, make a reliable diagnosis, and initiate appropriate drug treatment.
Multifocal PVCs originating from Purkinje fibers may be suppressed using a combination of quinidine and verapamil regardless of its etiology, as we have previously reported.
Multifocal Purkinje-related premature contractions and electrical storm suppressed by quinidine and verapamil in a case with short-coupled ventricular fibrillation.
Frequent His-Purkinje discharges with longitudinal dissociation in a case with multiple premature ventricular contractions suppressed by co-treatment with verapamil and quinidine.
This hypothesis needs to be confirmed in more cases in the future. Generally, MEPPC is associated with the SCN5A variant, as in this case. However, it can be categorized as “MEPPC syndrome” or more broadly as “Purkinjopathy” based on a common phenotype including electrophysiologic data and effective antiarrhythmic drugs.
To the best of our knowledge, this is the first report showing that the combination of low-dose quinidine and verapamil was effective in treating MEPPC.
Intracardiac electrograms in EPS. Immediately after the second PVC, spontaneous excitation of the His potential (H) and exit block to the surroundings is observed.
Surface ECGs during constant atrial pacing at pacing cycle lengths (PCLs) of 500 ms (A) and 375 ms (B). Atrial constant pacing could not suppress PVCs.
You cannot ablate the Lernaean Hydra: SCN5A mutation in a patient with multifocal ectopic Purkinje-related premature contractions syndrome treated with Flecainide and an implant of a subcutaneous defibrillator-a case report.
Multifocal atrial and ventricular premature contractions with an increased risk of dilated cardiomyopathy caused by a Na(v)1.5 gain-of-function mutation (G213D).
The G213D variant in Nav1.5 alters sodium current and causes an arrhythmogenic phenotype resulting in a multifocal ectopic Purkinje-related premature contraction phenotype in human-induced pluripotent stem cell-derived cardiomyocytes.
Multifocal Purkinje-related premature contractions and electrical storm suppressed by quinidine and verapamil in a case with short-coupled ventricular fibrillation.
Frequent His-Purkinje discharges with longitudinal dissociation in a case with multiple premature ventricular contractions suppressed by co-treatment with verapamil and quinidine.
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