Left cardiac sympathetic denervation for the treatment of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia using video-assisted thoracic surgery

Article Outline

• Abstract
• Introduction
• Methods
  • Case review
• Technique
• Results
• Discussion
• Conclusion
• Supplementary data
• References
• Copyright

Background

Long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) are two of the most common, potentially lethal, cardiac channelopathies. Treatment strategies for the primary and secondary prevention of life-threatening polymorphic ventricular tachycardia/fibrillation include pharmacotherapy with β-blockers, implantable cardioverter defibrillators, and left cardiac sympathetic denervation (LCSD).

Objectives

This study sought to report our institutional experience with LCSD using video-assisted thoracic surgery (VATS).

Methods

From November 2005 through November 2008, 20 patients (8 female, average age at surgery 9.1 ± 9.7 years, range 2 months to 42 years) underwent LCSD via either a traditional approach (N = 2) or VATS (N = 18). A total of 12 patients had genotype-positive LQTS (7 LQT1, 2 LQT2, 1 LQT3, 2 LQT1/LQT2), 2 had JLNS, 4 had genotype-negative LQTS, and 2 had CPVT1. Electronic medical records were reviewed for patient selection, perioperative complications, and short-term outcomes.

Results

LCSD was performed as a secondary prevention strategy in 11 patients (8 LQTS patients, average QTc 549 ms) and as primary prevention in 9 patients (average QTc 480 ms). There were no perioperative complications, including no intraoperative ectopy, no uncontrolled hemorrhage, and no VATS cases requiring conversion to a traditional approach. The average length of available follow-up was 16.6 ± 9.5 months (range 4 to 40 months). Among the 18 patients who underwent VATS-LCSD, the average time from operation to dismissal was 2.6 days (range 1 day to 15 days), the majority being next-day dismissals. Among those receiving LCSD as secondary prevention, there has been a marked reduction in cardiac events.

Conclusions

We present a series of 20 patients with LQTS and CPVT who underwent LCSD, 18 using VATS. The minimally invasive VATS surgical approach was associated with minimal perioperative complications, including no intraoperative ectopy and excellent immediate and short-term outcomes. Videoscopic denervation surgery, in addition to traditional LCSD, offers a safe and effective treatment option for the personalized medicine required for patients with LQTS/CPVT.

Keywords: Left cardiac sympathetic denervation, long QT syndrome, CPVT, VATS, denervation, LQTS

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Introduction 

Congenital long QT syndrome (LQTS) affects 1 in 2,500 people and was first described clinically in 1957 by Jervell and Lange-Nielsen.¹, ² The trademark dysrhythmia underlying LQTS is torsades de pointes (TdP), a potentially lethal polymorphic ventricular arrhythmia.³ The genetic understanding of LQTS has been advanced by the discovery of 12 LQTS susceptibility genes, which encode complex proteins that regulate sodium, potassium, and calcium ion flux across cardiac membranes to control ventricular repolarization.³ Mutations in potassium channel genes KCNQ1 (LQT1) and KCNH2 (LQT2) as well as the sodium channel gene SCN5A gene account for approximately 75% of patients with clinically definite LQTS and compose over 95% of genetically identifiable LQTS.⁴, ⁵, ⁶, ⁷

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an autosomal-dominant heritable arrhythmia syndrome first described in 1975.⁸ Patients with CPVT characteristically present with exertional syncope or sudden death.⁹ The 2 main genetic subtypes of CPVT are type 1 CPVT (CPVT1), caused by mutations in the RYR2-encoded cardiac ryanodine receptor/calcium release channel, and the rarer type 2 CPVT (CPVT2), caused by mutations in the CASQ2-encoded calsequestrin protein.⁹, ¹⁰, ¹¹, ¹² Patients with CPVT typically have a normal resting 12-lead electrocardiogram (ECG), but can have ventricular ectopy on exercise or catecholamine stress testing. Untreated, patients with CPVT have a risk of lethality as high as 30% to 50% by age 40.¹³, ¹⁴

The mainstay of medical therapy for both LQTS and CPVT patients is beta-blocker pharmacotherapy.¹⁴, ¹⁵ Moss et al¹⁵ showed a significant reduction in cardiac events in LQTS probands and affected patients and in affected family members during a 5-year period while on beta-blockers. In that same study, however, the investigators reported that symptomatic QT prolongation resulting in sudden death continues to occur on beta-blocker therapy. Implantable cardioverter defibrillators (ICDs) offer a more aggressive and effective sudden cardiac death counterattack strategy for LQTS and CPVT patients who present with aborted cardiac arrest (ACA), remain symptomatic despite beta-blocker therapy, or are intolerant of their medication.¹⁴, ¹⁶ Although arguably the most definitive means of sudden death prevention, ICDs are associated with significant comorbidities including device-related malfunction and recalls, infections, inappropriate therapies, and psychological sequelae.¹⁶

There has been renewed consideration of left cardiac sympathetic denervation (LCSD) originally described by Moss¹⁷ in 1971, in part because of the therapeutic and comorbidity gap between daily medications and an ICD, and in part because of LQTS specialists increasingly understanding and embracing its anti-fibrillatory potential. LCSD is known to raise the threshold for ventricular fibrillation¹⁸ and reduce the arrhythmias associated with acute myocardial ischemia in animal models¹⁹, ²⁰ without reducing heart rate or impairing myocardial contractility.²¹ A significant protective effect of LCSD among high-risk patients with LQTS was shown by Schwartz et al,²² who reported the outcome of LCSD in 147 LQTS patients. Almost half of the study cohort had a history of prior aborted cardiac arrest, and 75% of the patients had cardiac events despite beta-blocker therapy before LCSD. Surgically, LCSD involved resection of the lower half of the left stellate ganglion and the left-sided sympathetic chain at the level of T2, T3, and T4 (Figure 1A). Postoperatively, there was a >90% reduction in the frequency of cardiac events. Recently, LCSD has been used as an effective treatment option for patients with CPVT.²³ Herein, we describe our single-institution experience in performing video-assisted thoracic surgery (VATS)-LCSD for patients with either LQTS or CPVT.

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• Figure 1. 

  Anatomy of left cardiac sympathetic denervation (LCSD). A: An anatomical drawing of the left cardiac sympathetic chain after exposure through the pleura that is resected during VATS-LCSD. The stellate ganglion is located under the superior edge of the incision. The dashed line indicates the resection of the lower half of the left stellate ganglion occurring just above the major lower branches. B and C: Videoscopic still frames of VATS-LCSD before (B) and after (C) dissection of the pleura. VATS = video-assisted thoracic surgery.

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Methods 

Case review 

In this institutional review board–approved study, we identified all patients who had undergone LCSD surgery at our institution between November 1, 2005, and November 1, 2008. Patients were identified through Mayo Clinic's LQTS/CPVT clinic electronic medical records. A detailed retrospective review of the electronic medical record was performed, specifically looking at demographic variables, genotype, specific mutation (if available), indications for surgery, available follow-up, surgical complications, length of hospital stay, presence of ICD or pharmacologic therapy, and incidence of aborted cardiac arrest (ACA) or ICD shocks (appropriate and inappropriate). The surgery was considered secondary prevention if the patient had a history of either ACA or ventricular fibrillation (VF)-terminating ICD therapy. Follow-up was censored as of February 1, 2009.

For each patient, we calculated the corrected QT interval (QTc) using the standard Bazett formula.²⁴ Average QTc values, when reported, refer to patients with LQTS only. In this study, the reported QTc values are derived from the ECG the day before and the day after LCSD when available. All continuous variables were reported as the mean ± SD.

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Technique 

All patients underwent their procedures by a single surgeon (C.M.). Each patient was placed on the operating table with their right side down. After anesthetic induction, the right bronchus was selectively intubated and the left lung collapsed. The selective intubation allows for adequate visualization of the posterior mediastinum without using prone positioning or hemithorax CO₂ insufflation, which can irritate the pleura. Three small mid-axillary incisions were made in the left chest wall in each of 3 intercostal spaces. The camera was inserted into the 4th intercostal space incision at the anterior axillary line, the grasper was inserted in the 2nd intercostal space at the mid-axillary line, and the scissors were placed in the 4th or 5th intercostal space at the posterior axillary line. Via the videoscopic transthoracic approach, the sympathetic ganglia are identified through the pleura, which is then divided to expose the left-sided sympathetic chain from T4 to T1 (Figure 1, Video 1).

After application of a solution of lidocaine as previously described by other investigators,²² the ganglia were removed by dividing the major rami communicans and fully identifying the much smaller sympathetic nerve branches that travel toward the heart (Figure 1, Video 1). These nerves are divided sharply or with the aid of cautery. The left stellate ganglion is then divided along the anatomic fusion between its upper and lower poles, just above the major lower branches as seen in Figure 1 and Video 1. Often, but not always, a subtle variation in the size of the upper and lower halves of the stellate ganglion is seen in this area when visualized under magnification using high-definition equipment, helping the surgeon visualize this site of anatomic fusion. The upper half of the left stellate ganglion typically retracts back to its original anatomic position in the low neck once traction on the nerve trunk is released. The completely dissected nerve trunk and ganglia are then removed en bloc. The dissected materials are sent to pathology and read by frozen section to ensure that nerve and ganglions have been removed. If available, frozen section review by a surgical pathologist provides an important check and balance to verify/confirm the correct identification of the sympathetic chain, although this is not necessarily performed at all institutions. Once pathology is confirmed, the endotracheal tube is pulled back into the trachea and the left lung is inflated under direct vision. One port is placed under water seal to displace air temporarily. A postoperative chest radiograph is performed to confirm the absence of a significant pneumothorax, and the port is sealed. No chest tube is typically required. All patients were monitored postoperatively in either the adult or pediatric intensive care unit.

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Results 

Among the 450 patients with clinically and/or genetically established LQTS/CPVT who have been seen in our LQTS Clinic since July 2000, 20 patients (8 female, mean age 9.1 ± 9.7 years, range 2 months to 42 years, average QTc 518 ± 70 ms, range 430 to 687 ms) have had LCSD performed at our institution (Table 1, Table 2). An open thoracotomy approach was used in the first 2 patients, whereas VATS was used in the subsequent 18 patients. The 20 patients included 16 with autosomal dominant LQTS (12 with established genotype), 2 with Jervell and Lange-Nielsen syndrome (JLNS), and 2 with CPVT1. Among those with a known LQTS genotype, 7 had LQT1, 2 LQT2, 1 LQT3, and 2 had both LQT1 and LQT2. The average time of clinical follow-up was 16.6 ± 9.5 months. The average hospital stay was 3.5 ± 4.4 days. Three patients had prolonged stays over 8 days because of young age or prolonged weaning of intravenous medications. The other 17 patients had an average stay of 1.8 ± 1 days.

Table 1. Patient characteristics, LCSD secondary prevention: Summary of patients who received an LCSD at our institution as secondary preventative therapy

Patients 1 and 3 had procedures using open thoracotomy, whereas the remainder had VATS-LCSD performed. Patient 6 has a severely malignant form of LQTS, resulting in daily episodes of TdP for his 3 months of life before the LCSD and for the 21 months after surgery of which we have follow-up for him. QTc values that are reported were taken the day before and the day after LCSD, and may not represent the baseline QTc of the patient.

ACA = aborted cardiac arrest; LCSD = left cardiac sympathetic denervation; LQT− = Genotype negative LQTS; LQTS = long QT syndrome; mo = months; TdP = torsades de pointes; VATS-LCSD = video-assisted thoracic surgical approach for left cardiac sympathetic denervation.

Table 2. Patient characteristics, LCSD primary prevention: Summary of patients who received a prophylactic VATS-LCSD at out institution as primary preventative therapy

Patient 19 had seizures postoperatively, diagnosed by an epileptologist to be complex febrile seizures secondary to postoperative fever. Patients 12 and 13 are siblings. QTc values that are reported were taken the day before and the day after surgery, and may not represent the baseline QTc of the patient.

PVC = premature ventricular contraction; other abbreviations as in Table 1.

LCSD was performed in 11 patients for secondary prevention (4 females, average age 8.5 ± 12.6 years, range 0 to 42 years, average QTc 549 ± 75 ms, range 451 to 687 ms, Table 1) and in 9 patients for primary prevention (4 females, average age 9.8 ± 5.3 years, range 1 to 17 years, average QTc 480 ± 40 ms, range 430 to 536 ms, Table 2). Within this primary prevention subset, 7 patients had LCSD because of the presence of a high-risk phenotype, whereas 2 had LCSD recommended due to a moderate-risk phenotype but severe beta-blocker intolerance (i.e., unacceptable side effects necessitating discontinuation or significant reduction in dose of the medication). Eight patients in our cohort already had an ICD by the time of the surgery. Two patients had an ICD placed as a concomitant procedure during VATS-LCSD.

There were no significant surgical complications observed in any patient. As expected, clinically and hemodynamically insignificant tiny to small apical pneumothoraces were noted on the initial postoperative chest radiograph in 10 patients. All spontaneously resolved without symptoms or need for chest tube placement. No patients had persistent ptosis of the left eyelid at 2-week follow-up, and only 2 patients (10%) had transient ptosis after surgery. As such, no Horner syndrome has occurred either. One patient had asymmetric facial sweating on follow-up. One 2-month-old patient received a 10-ml/kg blood transfusion secondary to multiple postoperative phlebotomies unrelated to the surgery. One severely affected CPVT patient (case 7) was admitted on an intravenous lidocaine drip because of refractory ventricular arrhythmias, and needed a prolonged 9-day wean from this medication because of recurrent postoperative ventricular ectopy. There were no other perioperative or postoperative ventricular arrhythmias, and no VATS procedure required conversion to an open surgical approach.

In our secondary prevention cohort, appropriate ICD shocks were eliminated entirely after LCSD in 8 of 11 patients thus far (Table 1). Preoperatively, there were 3 patients who were dependent on intravenous lidocaine to prevent recurrent ventricular arrhythmias (cases 1, 3, 7). All 3 patients were able to resume an oral pharmacotherapy regimen after surgery, 2 within 24 hours after surgery. To date, the most dramatic response attributed to LCSD involved a 42-year-old woman with symptomatic LQT2 and at least 15 VF-terminating ICD therapies in the year before denervation (case 2). Now, 30 months later, she has had only one ICD shock, which occurred 28 months after her LCSD in December 2008. Another dramatic response was achieved in a 13-month-old female patient with gene-negative LQTS who had an out-of-hospital cardiac arrest (case 3). She was admitted and treated at an outside institution, where she required a continuous lidocaine infusion to prevent recurrent ventricular arrhythmias. Repeated attempts to wean her to oral mexiletine failed. She was transferred to our institution to have LCSD performed, after which she was weaned to oral pharmacotherapy within 24 hours.

There were 2 patients in whom we consider the anti-fibrillatory effect from VATS-LCSD to have been insufficient (patients 5 and 6). That is, the frequency of events/ICD shocks postoperatively has been reduced minimally. One of these patients was a neonate with an LQT3 genotype who had a QTc >800 ms at birth. This boy, now almost 2 years old, continued to have appropriate ICD shocks as well as numerous nonsustained ventricular arrhythmias despite the procedure. His clinical phenotype is exquisitely sensitive to appropriate levels of mexiletine and strict administration every 8 hours, a regimen first suggested by Schwartz et al.²⁵ The other suboptimal outcome was in a 6-year-old boy with JLNS who had documented TdP 4 months after LCSD, prompting a decision to proceed with an ICD. His post-ICD course was then complicated by lead-related right ventricle perforation 2 weeks after implantation, necessitating urgent median sternotomy, lead repositioning, and repair of the right ventricular puncture. This JLNS patient has since had 2 appropriate VF-terminating ICD therapies and continues on high-dose beta-blocker therapy.

Twelve-lead ECGs were performed on each patient the day before and the day after their LCSD. There was no significant difference noted between the average preoperative QTc value (518 ± 70 ms) and postoperative QTc values (508 ± 62 ms). Figure 2 provides an example of the potential QT attenuating affect that can accompany LCSD. Here, the patient's (case 8 from Table 1) QTc decreased almost immediately after LCSD, and at 6 months postoperatively, the QTc was 423 ms, compared with the preoperative QTc of 529 ms.

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• Figure 2. 

  Electrocardiogram of patient 8 before (A) and 6 months after (B) VATS-LCSD, showing a decrease in the QTc from 529 ms to 423 ms. VATS-LCSD = video-assisted thoracic surgery–left cardiac sympathetic denervation.

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Discussion 

In the setting of beta-blocker breakthroughs, intolerance to pharmacotherapy, and history of appropriate ICD therapies, LCSD should be considered as a viable treatment option for patients with a sudden-death-predisposing channelopathy such as LQTS or CPVT. Herein, we report a series of 20 genotypically and phenotypically diverse patients who have undergone LCSD at a single institution, 18 via VATS, without any perioperative complications and significant, albeit not universal, short-term success. This is consistent with previously published reports of the significant anti-fibrillatory effect of LCSD in both LQTS and CPVT.²², ²³

Aside from its anti-fibrillatory effect, Schwartz et al²² have observed a QT-attenuating effect after denervation, reporting a decrease in the QTc by an average of 39 ± 54 ms 6 months after denervation. We have not been able to confirm systematically this observation yet because most of the patients did not return for a 6-month follow-up evaluation. Nevertheless, as shown in Figure 2, impressive QT-attenuating effects at 6-month follow-up have been observed among some of our patients as well. Acutely, however, LCSD does not seem to affect or improve cardiac repolarization because no significant differences between QTc values, measured the day before and the day after surgery, were observed overall.

Atallah et al²⁶ recently described 9 VATS-LCSD cases at their institution. Of the 9 patients, 4 had LQTS (2 with JLNS), 4 had CPVT, and 1 had idiopathic ventricular tachycardia. The average hospital stay was 3 days, and there were no major surgical complications. Notably, 8 of their 9 patients underwent a high left cardiac sympathetic denervation without resection of the lower half of the stellate ganglion, whereas 1 patient had a stellate ganglionectomy performed. This patient did not have Horner syndrome postoperatively, but did have harlequin facial flushing noted. This had resolved by 5-year follow up. Although so far only 1 patient had recurrent arrhythmias postoperatively (immediately after the procedure),¹⁸ it should be noted that resection of the lower half of the left stellate ganglion is considered a critical part of the anti-fibrillatory effect of LCSD.²²

Li et al²⁷ also recently described 11 VATS-LCSD cases, 10 female and 1 male, all with LQTS. These investigators had provided previously the original case description of 4 patients undergoing VATS-LCSD for LQTS in 2003.²⁸ All patients underwent resection of the left T2-T5 sympathetic chain and the lower third of the stellate ganglion. There were no major postoperative complications, and the average length of hospital stay was 6 days. Seven of the 11 patients were free of cardiac events at follow-up, 2 patients had reduced frequency or duration of events, and 1 patient seems to have had an increase in events despite the denervation surgery. The only male patient in their study, a 6-year-old boy with malignant ventricular arrhythmias, died while playing approximately 1 to 2 years after denervation. This patient had ventricular tachycardia during the VATS-LCSD that ceased on clipping of the stellate ganglion. All patients remained on at least low-dose beta-blocker therapy postoperatively.²⁷

LCSD is a safe and effective option for high-risk patients in primary and secondary prevention.²² There are multiple effects of LCSD that contribute to its clinical efficacy.²⁹ LCSD raises the threshold for ventricular fibrillation, thus making it more difficult for a heart to fibrillate (i.e., the anti-fibrillatory effect of LCSD).¹⁸ LCSD reduces the arrhythmias associated with acute myocardial ischemia in anesthetized¹⁹ and in conscious animal models²⁰ for sudden death. LCSD does not produce post-denervation supersensitivity because it is a pre-ganglionic denervation,³⁰ and this explains why its effects are likely to be durable rather than transient. LCSD does not reduce heart rate—an effect particularly important for patients with LQT3—and does not impair myocardial contractility²¹ because the sympathetic control of heart rate on the sinus node is exerted by the right stellate ganglion and because the right-sided sympathetic chain provides sufficient compensation. In addition, it seems from our data that VATS is equally as safe and effective as the traditional open approach. Currently, VATS-LCSD is the preferred surgical approach at our institution. The use of thoracoscopy itself carries a lower risk profile compared with open thoracotomy, including reduced complication rates, shorter hospital and intensive care unit stay, and less pleural drainage time.³¹

There may be numerous technical advantages for using the thoracoscopic approach to LCSD specifically. Because of the magnification of the surgical field, the enhanced visualization may enable the surgeon to perform a more extensive sympathetic chain resection with identification of small sympathetic branches and anatomic variants. In addition, VATS not only leaves the patient with only 3 small scars in the axilla and left chest in lieu of a cervical scar, but minimizes the risk for Horner syndrome because less traction is applied to the stellate ganglion and sympathetic chain. In our experience, risk of postoperative ptosis seems to be age-dependent, and largely caused by traction on the stellate ganglion. The exposed stellate ganglion permits careful dissection along the anatomical fusion between upper and lower poles in most (but not all) patients, likely reducing further the risk of ptosis/Horner syndrome, neither of which has been observed in our first 20 patients. Furthermore, the VATS technique for LCSD does not use CO₂ for insufflation, thus limiting intrathoracic irritation and systemic hypercapnia. No chest tube has been required postoperatively so far, and the identified left pneumothoraces have been termed “questionable,” “tiny,” or “small.” They have all resolved spontaneously without any clinical manifestations. Ultimately, the most important consideration regarding the surgical approach to LCSD, open versus VATS, is surgical preference and competence.

Several precautions should be noted with VATS-LCSD. Direct stimulation of the ganglia by the electrocautery apparatus should be avoided because it can induce ectopy. This can be minimized by having an experienced anesthesia team perform selective right main-stem intubation, which decreases the likelihood of stimulating the ganglia. In addition, the exposed sympathetic chain is bathed in a lidocaine solution before en bloc resection. To date, no intraoperative ectopy has been observed. Finally, it is possible that if unexpected bleeding occurred, the surgical field may not be large enough to allow the surgeon to gain adequate hemostasis, ultimately requiring conversion to a traditional approach. Although reported anecdotally 15 years ago, the technique of minimally invasive video-assisted surgery has advanced considerably over the past 2 decades and this has not occurred in our patient cohort.

Possible limitations to this study include the short follow-up for a subset of the patients, with 10% of the patients having <6 months of follow-up. Despite this, early results for these patients are favorable. Furthermore, the lack of uniform time frames for each patient in this retrospective analysis makes the quantification of preoperative and postoperative frequency of cardiac events difficult and fraught with confounders, despite the obvious overall reduction in cardiac events seen in both our cohort and previous cohorts.²² Finally, the data on LCSD for patients with type 3 LQTS are limited in our cohort. However, Schwartz et al²² have reported favorable postoperative results in patients with this genetic subtype. A recent publication by the same author group has described their current approach of using LCSD in patients with LQT3 and QTc >500 ms, as well as a way to reduce ICD shocks in patients who have had prior defibrillator implantation.³²

Our group and others have shown that LCSD, using either traditional surgical techniques or minimally invasive video-assisted surgery, is an effective and safe treatment option for patients with LQTS and CPVT. In our LQTS/CPVT Clinic, the current indications for videoscopic denervation surgery include: (1) history of appropriate VF-terminating ICD therapy, (2) LQTS/CPVT breakthrough events while on adequate pharmacotherapy (in lieu of ICD implantation because of patient age, size, and comparative comorbidities), (3) pharmacotherapy intolerance (again as an option instead of ICD implantation), (4) perceived high-risk phenotype but risks associated with ICD therapy seem excessive, so-called “bridge-to-ICD”, and (5) care for high-risk patients without access to an ICD.

It is tempting to speculate that VATS-LCSD, in addition to beta-blocker therapy, may provide greater sudden death protection than beta-blockers alone and possibly near-ICD levels of protection secondary to its strong anti-fibrillatory effect with less comorbidity than ICD therapy. There has been some debate regarding whether LCSD could reduce the need for beta-blocker therapy in patients, or at least allow for lower dosing to decrease the risk of side effects, but data supporting this are currently unavailable in the literature. It would be interesting to determine the efficacy, comorbidities, and quality of life scores associated with a primary VATS-LCSD strategy (along with lower dose beta-blocker therapy) compared with either the current pharmacological gold standard of high-dose beta-blocker therapy or the current device gold standard of ICD therapy.

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Conclusion 

Videoscopic denervation surgery, in addition to traditional LCSD, offers a safe and effective treatment option for the personalized medicine required for infants, children, and adults with LQTS/CPVT, particularly for those with medically refractory arrhythmias, medication intolerance, or a history of appropriate ICD therapies. Additional studies are needed to further define the role and indications for videoscopic denervation surgery and to assess quality of life related to the various treatment modalities for patients with a potentially lethal cardiac channelopathy.

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Supplementary data 

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References 

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