Bilateral cardiac sympathetic denervation for refractory arrhythmia in an individual with catecholaminergic polymorphic ventricular tachycardia associated with T-cell-mediated ganglionitis

Abstract

The individual in our case was troubled with difficult to control arrhythmia in the context of RYR2-mutation positive catecholaminergic polymorphic ventricular tachycardia (CPVT) despite medication. Recurrent implantable cardioverter defibrillator (ICD) shocks occurred for ventricular tachycardia (VT) and ventricular fibrillation (VF) as well as inappropriate shocks as a result of rapidly conducted atrial fibrillation (AF). Catheter ablation was effective in controlling these episodes of AF. Despite left cardiac sympathetic denervation, episodes of ventricular arrhythmia and subsequent ICD shocks persisted. Contralateral sympathetic cardiac denervation was subsequently undertaken, with histology suggesting T-cell mediated ganglionitis. 18 months on, there have been no further episodes of ventricular arrhythmia.

Background

Individuals with catecholaminergic polymorphic ventricular tachycardia (CPVT) may suffer with ongoing arrhythmia which can be difficult to treat with pharmacotherapy alone. Autonomic imbalances prevalent in the disorder may predispose to other arrhythmia such as atrial fibrillation (AF). This can be particularly problematic in the context of implantable cardioverter defibrillator (ICD) therapy and the potential for inappropriate shocks. This case illustrates how catheter ablation can be useful for control of atrial arrhythmia to reduce the risk of inappropriate ICD therapies and improve quality of life. We demonstrate how bilateral cardiac sympathetic denervation can dramatically improve arrhythmia control.

Case presentation

Our patient is a woman in her 20s with a diagnosis of CPVT. This was diagnosed following a survived cardiac arrest at the age of 6, and she was found on genetic testing to possess the RYR2 mutation characteristic of CPVT1. She has a dual chamber implantable cardioverter defibrillator (ICD) in situ and has had appropriate shocks for episodes of ventricular tachycardia (VT) and ventricular fibrillation (VF; see figure 1). Her heart is structurally normal with good left ventricular function.

Figure 1.

Intracardiac electrograms (EGMs) recorded by the individual’s dual chamber implantable cardioverter defibrillator (ICD) with markers shown. An episode of atrial fibrillation with rapid ventricular rate degenerates into ventricular fibrillation, subsequently leading to a shock being delivered. A, atrial channel; V, ventricular channel.

Unfortunately, she has also been troubled with episodes of AF with high ventricular rates which are not only highly symptomatic (with presyncope and breathlessness) but have also led to inappropriate shocks, despite medical therapy including oral nadolol 120 mg once daily and oral flecainide 100 mg three times a day (see figure 2).

Figure 2.

Electrograms (EGMs) recorded by dual chamber implantable cardioverter defibrillator (ICD) with markers shown. Episode of atrial fibrillation with rapid ventricular response leads to an inappropriate shock (seen as double vertical lines) delivered during a sensed ventricular beat. This leads to ventricular fibrillation, leading to a further shock delivered. A, atrial channel; V, ventricular channel.

Treatment

To reduce this risk, she underwent pulmonary vein isolation by cryoballoon ablation at the start of last year. At the start of the case a three-wire electrophysiology (EP) study was undertaken which was unremarkable with no evidence of an accessory pathway or dual atrioventricular (AV) nodal physiology. AF recurrence was documented approximately 6 months post ablation, and she was listed for re-do radiofrequency ablation using electroanatomical three-dimensional mapping. This demonstrated reconnection of a pulmonary vein which was re-isolated.

Due to the high burden of VT despite maximum medical therapy she underwent left cervical sympathectomy via video-assisted thoracoscopic surgery at the end of last year. Histological examination of the excised sympathetic chain demonstrated mild mononuclear inflammatory infiltrate with scattered CD3+ T cells observed around small vessels and clusters of ganglion cells within nerve fibres and ganglia, in keeping with T-cell-mediated ganglionitis. Unfortunately, earlier this year she was re-admitted following a syncopal episode during which episodes of VT and VF were successfully treated with a second ICD shock after a failed first shock. The decision was made to undergo contralateral cervical sympathectomy. Excised right cervical sympathetic tissue showed histology consistent with previous findings.

Outcome and follow-up

Eighteen months on from the procedure, the individual has been asymptomatic with no further documented ventricular tachyarrhythmia.

Discussion

Catecholaminergic polymorphic ventricular tachycardia

CPVT is an autosomal dominant inherited cardiac syndrome and channelopathy. The most common gene mutation (RYR2) affects the ryanodine receptor (RYR), which is responsible for regulating calcium (Ca²⁺) release from the sarcoplasmic reticulum (SR). Most commonly, RYR2 mutations cause inappropriate release of intracellular Ca²⁺ from the SR in response to rises in SR Ca²⁺ content, in a process known as store-overload induced Ca²⁺ release (SOICR).¹ The less common, recessive form of CPVT, often referred to as CPVT2, involves a mutation of the CASQ2 gene which leads to disordered SR Ca²⁺ buffering and subsequent SOICR.

During the normal cardiac action potential, intracellular flux of Ca²⁺ primarily via activation of L-type Ca²⁺ channels triggers activation of SR Ca²⁺ release via RYR in a process known as Ca²⁺-induced Ca²⁺ release, a process which then leads to muscle contraction via excitation-contraction coupling. However, spontaneous Ca²⁺ release in the absence of depolarisation (such as that seen in SOICR) can itself trigger depolarisation (primarily via activation of the Na⁺- Ca²⁺ exchanger in its forward mode and subsequent Na⁺ influx). This inappropriate depolarisation has significant arrhythmogenic potential, largely in the form of early or delayed after depolarisations (EADs or DADs) which may reach the threshold to trigger an action potential. Additionally, SR Ca²⁺ release can lead to Ca²⁺ waves and Ca²⁺ alternans, leading to electrical alternans, re-entry and the polymorphic VT characteristic of CPVT.²

As catecholaminergic stimulation increases SR Ca²⁺ content, it follows that situations promoting β-adrenergic activity would increase the arrhythmic risk in patients with this form of CPVT. The typical presentation of CPVT is one of syncope or cardiac arrest elicited by situations involved intense emotional or exertional stress. Adrenergic stimulation leads to a pathognomonic bidirectional VT, and this is often tested for with exercise treadmill testing.

In patients with CPVT, increased sympathetic activation and autonomic imbalance has been linked to ventricular arrhythmia. Primarily, β-adrenergic receptor antagonists are used to counteract the effects of sympathetic neurotransmitters. However, these medications are in some instances either not effective in suppressing arrhythmia or poorly tolerated.

Left cardiac sympathetic denervation

Left cardiac sympathetic denervation (LCSD) was first performed in 1916 as a treatment for angina pectoris,³ and subsequently adapted in 1971 to treat patients with long QT syndrome (LQTS).⁴ It involves surgical resection of the left stellate ganglion and has shown to be effective in reducing the arrhythmic risk for CPVT^{5 6} as well as LQTS.⁷ The primary antiarrhythmic mechanisms of LCSD seem to be antagonism of cardiac catecholamines as well as an increase in cardiac parasympathetic tone,⁸ although there may be multiple other, complex, effects.⁹ It’s unclear to what extent right cardiac sympathetic denervation (RCSD) is effective: indeed, early work suggested that RCSD may even be proarrhythmic.^{10 11}

While RCSD alone remains an unconventional therapeutic option, bilateral cardiac sympathetic denervation has shown promise within small series in the treatment of refractory ventricular arrhythmia across a range of conditions including ischaemic and nonischaemic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy (ARVC) and Chagas disease,^12–16 with a randomised trial planned.¹⁷ However, there is a paucity of evidence for outcomes in patients with CPVT.

T-cell-mediated ganglionitis and refractory arrhythmia

Stellate ganglia tissue removed during LCSD for refractory arrhythmia caused by LQTS/CPVT in 12 patients demonstrated evidence of chronic T-cell mediated inflammation thought likely virally or immunologically mediated.¹⁸ Cardiac ganglionitis has been previously reported in postmortem histological analysis of sudden cardiac death victims with LQTS and high arrhythmic burden.^19–21 Whether ganglionitis increases arrhythmic risk and if so by what mechanism, remains unclear. Inflammatory mediators are known to affect neural circuits and neurotransmitter systems in the brain,^{22 23} with some suggestion they exert similar disruptive effects on cardiac neural tissue, with alterations in ventricular electrophysiology seen.²⁴ The link between ganglionitis and arrhythmogenesis merits future exploration.

Learning points.

• Refractory arrhythmia can have profound effects on quality of life for individuals with catecholaminergic polymorphic ventricular tachycardia (CPVT), including those suffering with recurrent implantable cardioverter defibrillator (ICD) shocks.

• Pharmacotherapy as well as catheter ablation can be useful tools in reducing arrhythmia burden and the risk of inappropriate ICD therapies.

• Bilateral cardiac sympathetic denervation appears to be a promising therapeutic option in those suffering despite maximum medical therapy but requires further study, particularly in the context of CPVT and long QT syndrome (LQTS).

• The role of ganglionitis in refractory arrhythmia remains poorly understood and merits investigation.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).