Bilateral cardiac sympathetic denervation in patients with congenital long QT syndrome.

BACKGROUND: Long QT syndrome (LQTS) is a potentially lethal yet treatable genetic heart disease for which left cardiac sympathetic denervation (LCSD) is a class I recommendation. Recent reports have suggested bilateral cardiac sympathetic denervation (BiCSD) as the initial surgical denervation therapy in LQTS. OBJECTIVE: The purpose of this study was to determine the frequency and settings in which BiCSD was used in a tertiary referral center with expertise in LCSD. METHODS: We performed a retrospective review of 234 out of 1638 patients with LQTS who underwent sympathetic denervation (14%) at our institution to identify the subset of patients who underwent BiCSD. Cardiac events (CEs) before LCSD, after LCSD, and after the completion of BiCSD were recorded and defined as being an appropriate implantable cardioverter-defibrillator shock, arrhythmic syncope, or sudden cardiac arrest. RESULTS: Only 11 patients (4.7%; 6 females [55%]) had BiCSD at our institution. Patients who received BiCSD trended toward being younger at diagnosis (6 ± 15 years vs 14 ± 13 years; P = .06) and being more likely to be symptomatic (73% vs 53%; P = .07) than the larger LCSD-only cohort. Continued CEs post-LCSD (3.8 CEs per patient on average) was the predominant determinant to return for BiCSD. Over 60 combined years of follow-up, 4 patients have not had a CE post-BiCSD while the other 7 patients average 3.6 nonlethal CEs. CONCLUSION: Less than 5% of all patients receiving denervation therapy underwent BiCSD. When BiCSD was chosen, it was almost always done in a staged sequential manner beginning with LCSD first and when driven by the arrhythmogenicity of the LQTS substrate, despite otherwise optimized guideline-directed therapies.

Left Cardiac Sympathetic Denervation for Long QT Syndrome: 50 Years' Experience Provides Guidance for Management.

OBJECTIVES: This study sought to report our single-center experience with left cardiac sympathetic denervation (LCSD) for long QT syndrome (LQTS) since 1973. BACKGROUND: LCSD is still underutilized because clinicians are often uncertain whether to use it versus an implantable cardioverter-defibrillator (ICD). METHODS: We performed LCSD in 125 patients with LQTS (58% women, mean QT interval corrected for frequency [QTc] 527 ± 60 ms, 90% on beta blockers) with a follow-up of 12.9 ± 10.3 years. They were retrospectively divided into 4 groups according to the clinical/genetic status: very high risk (n = 18, symptomatic in the first year of life or with highly malignant genetics), with aborted cardiac arrest (ACA) (n = 31), with syncope and/or ICD shocks on beta blockers (n = 45), in primary prevention (n = 31). RESULTS: After LCSD, 17% in the very high risk group remained asymptomatic, compared with 52%, 47%, and 97% in the other 3 groups (P < 0.0001), with an overall 86% decrease in the mean yearly cardiac event rate (P < 0.0001). Among 45 patients with only syncope/ICD shocks before LCSD, none had ACA/sudden death as first symptom after LCSD and a 6-month post-LCSD QTc <500 ms predicted excellent outcome. Patients with a QTc ≥500 ms have a 50% chance of shortening it by an average of 60 ms. LCSD results are not affected by common genotypes. CONCLUSIONS: We provide definitive evidence for the long-term efficacy of LCSD in LQTS. The degree of antiarrhythmic protection is influenced by patient's specificity and amount of QTc shortening. This novel approach to the analysis of the outcome allows cardiologists to rationally decide and tailor their management strategies to the individual features of their patients.

Cardiac sympathetic denervation in the prevention of genetically mediated life-threatening ventricular arrhythmias.

Proper management of patients affected by genetic disorders causing life-threatening arrhythmias is important for several reasons, including even societal ones, given the predominantly young age of those affected. Incorrect management often has dire consequences, ranging from unnecessary psychologic damage for the patients whose life becomes too limited by the fear of sudden death to equally avoidable tragedies when the entire armamentarium of effective therapies is not fully utilized. In this review, we focus primarily on long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) and deal specifically with the clinical impact of the most commonly used cardiac sympathetic denervation (CSD), namely left cardiac sympathetic denervation (LCSD). The two of us have used LCSD in the management of our patients with either LQTS or CPVT for a very long time and have been involved in ∼500 such interventions. It is on the basis of this personal and direct experience that we wish to share our views with clinical cardiologists and electrophysiologists, adult and paediatric, and with genetic cardiologists. We will begin by reviewing the history and rationale underlying sympathetic denervation therapy and will continue with a disease-specific intensification of therapy, and then with a discussion on how the impressive efficacy of LCSD should translate into guideline-directed therapy in both current and future guidelines, in order to upgrade the quality of care in the era of precision medicine.

Management of Congenital Long-QT Syndrome: Commentary From the Experts.

While published guidelines are useful in the care of patients with long-QT syndrome, it can be difficult to decide how to apply the guidelines to individual patients, particularly those with intermediate risk. We explored the diversity of opinion among 24 clinicians with expertise in long-QT syndrome. Experts from various regions and institutions were presented with 4 challenging clinical scenarios and asked to provide commentary emphasizing why they would make their treatment recommendations. All 24 authors were asked to vote on case-specific questions so as to demonstrate the degree of consensus or divergence of opinion. Of 24 authors, 23 voted and 1 abstained. Details of voting results with commentary are presented. There was consensus on several key points, particularly on the importance of the diagnostic evaluation and of ß-blocker use. There was diversity of opinion about the appropriate use of other therapeutic measures in intermediate-risk individuals. Significant gaps in knowledge were identified.

KCNQ1 G219E and TRPM4 T160M polymorphisms are involved in the pathogenesis of long QT syndrome: A case report.

RATIONALE: Long QT syndrome (LQTS) is an inheritable disease characterized by prolonged QT interval on the electrocardiogram. The pathogenesis of LQTS is related to mutations in LQTS-susceptible genes encoding cardiac ion channel proteins or subunits. PATIENT CONCERNS: Here, we reported a 37-year-old female Uygur patient with palpitation and loss of consciousness. DIAGNOSES: At the time of admission, a 12-lead electrocardiogram showed a QTc interval of 514 ms. Genetic analysis revealed KCNQ1 G219E and TRPM4 T160M mutations. INTERVENTIONS: Although beta-blockers remain the mainstay in treating LQTS, the patient underwent implantation of an automatic cardioverter defibrillator due to life-threatening arrhythmias. OUTCOMES: To explore the effect of the calcium ion antagonist verapamil on ion channels, we generated human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) from the peripheral blood mononuclear cells of the patient. The changes of action potential duration in response to verapamil were observed. LESSONS: Our results showed that patient-derived hiPSC-CMs could recapitulate the electrophysiological features of LQTS and display pharmaceutical responses to verapamil.

Potential therapeutic effects of electrogram-guided cardioneuroablation in long QT syndrome: case series.

BACKGROUND: A significant shortening of the corrected QT interval (QTc) in addition to parasympathetic denervation after cardioneuroablation (CNA) was recently demonstrated in patients with vagally mediated bradyarrhythmias and normal QTc range. This study assessed the effects of CNA on ventricular repolarization and heart rate by using QTc measurements in 2 patients with long QT syndrome (LQTS). METHODS: The case series included 2 consecutive patients with significant sinus bradycardia and refractory paroxysmal atrial fibrillation (AF). All atrial ganglionated plexus (GP) sites in addition to pulmonary vein isolation were successively targeted by using electrogram-guided strategy. QTc was calculated on 12-lead ECG before the procedure (time point 1), at post-ablation 24 h (time point 2), and at the last follow-up visit (time point 3), respectively. RESULTS: In the first case, QTc (Bazett) shortened from 612 to 551 msec between time points 1 and 2 and was 419 msec in time point 3. Similarly, QTc (Bazett) shortened from 480 to 401 msec between time points 1 and 3 in the second case. In both cases, minimum and mean heart rates were significantly increased after ablation. The parameters of which are used to estimate both sympathetic and parasympathetic changes in heart rate variability were significantly decreased after ablation. There were no arrhythmia-related symptoms during follow-up. CONCLUSIONS: The present case series reports a new ablation strategy systematically targeting autonomic GPs in LQTS patients. CNA shortens QTc (through sympathetic modulation) and increases heart rate. Although promising, these preliminary results need to be confirmed in the larger prospective study.

Video-thoracoscopic left cardiac sympathetic denervation for long-QT syndrome.

BACKGROUND: Congenital long-QT syndrome represents the most common cardiac channelopathy and manifests as potentially lethal ventricular arrhythmias. Prevention strategies include beta-blockade pharmacotherapy, implantable cardioverter-defibrillators, and left cardiac sympathetic denervation, which can increase the threshold for ventricular fibrillation. Herein, we report our experience with video-assisted thoracoscopic left cardiac sympathetic denervation. METHODS: We performed a retrospective review of the electronic medical records of all patients with congenital long-QT syndrome who underwent video-assisted thoracoscopic left cardiac sympathetic denervation at our institution. RESULTS: From September 2009 to May 2016, 6 patients with a mean age of 30.5 years (range 20-47 years) underwent video-assisted thoracoscopic left cardiac sympathetic denervation for medically refractory long-QT syndrome. All patients had an uneventful recovery and were discharged 1-3 days after the operation. At a median follow-up of 14 months (range 12-60 months), 4 patients had no cardiac events while 2 experienced 1 episode of arrhythmic syncope and 1 episode of appropriate implantable cardioverter-defibrillator shock. Following surgery, the mean annual cardiac events in the study cohort decreased from 2.13 to 0.33 (p = 0.004) and the mean corrected QT interval reduced from 560 ms to 491 ms (p = 0.006). CONCLUSIONS: Video-assisted thoracoscopic left cardiac sympathetic denervation is a safe and effective therapy in patients with congenital long-QT syndrome who continue to suffer from recurrent life-threatening arrhythmias or frequent implantable cardioverter-defibrillator discharges despite maximum tolerated doses of beta blockers.

Left Cardiac Sympathetic Denervation Monotherapy in Patients With Congenital Long QT Syndrome.

BACKGROUND: Videoscopic left cardiac sympathetic denervation (LCSD) is an effective antifibrillatory, minimally invasive therapy for patients with potentially life-threatening arrhythmia syndromes like long QT syndrome (LQTS). Although initially used primarily for treatment intensification following documented LQTS-associated breakthrough cardiac events while on beta-blockers, LCSD as 1-time monotherapy for certain patients with LQTS requires further evaluation. We are presenting our early experience with LCSD monotherapy for carefully selected patients with LQTS. METHODS: Among the 1400 patients evaluated and treated for LQTS, a retrospective review was performed on the 204 patients with LQTS who underwent LCSD at our institution since 2005 to identify the patients where the LCSD served as stand-alone, monotherapy. Clinical data on symptomatic status before diagnosis, clinical, and genetic diagnosis, and breakthrough cardiac events after diagnosis were analyzed to determine efficacy of LCSD monotherapy. RESULT: Overall, 64 of 204 patients (31%) were treated with LCSD alone (37 [58%] female, mean QTc 466±30 ms, 16 [25%] patients were symptomatic before diagnosis with a mean age at diagnosis 17.3±11.8 years, 5 had [8%] ≥1 breakthrough cardiac event after diagnosis, and mean age at LCSD was 21.1±11.4 years). The primary motivation for LCSD monotherapy was an unacceptable quality of life stemming from beta-blocker related side effects (ie, beta-blocker intolerance) in 56/64 patients (88%). The underlying LQTS genotype was LQT1 in 36 (56%) and LQT2 in 20 (31%). There were no significant LCSD-related surgical complications. With a mean follow-up of 2.7±2.4 years so far, only 3 patients have experienced a nonlethal, post-LCSD breakthrough cardiac event in 180 patient-years. CONCLUSIONS: LCSD may be a safe and effective stand-alone therapy for select patients who do not tolerate beta-blockers. However, LCSD is not curative and patient selection will be critical when potentially considering LCSD as monotherapy.

Left cardiac sympathetic denervation reduces skin sympathetic nerve activity in patients with long QT syndrome.

BACKGROUND: Although left cardiac sympathetic denervation (LCSD) is an effective antiarrhythmic therapy for patients with long QT syndrome (LQTS), direct evidence of reduced sympathetic activity after LCSD in humans is limited. OBJECTIVE: The purpose of this study was to assess skin sympathetic nerve activity (SKNA) in patients with LQTS undergoing LCSD. METHODS: We prospectively enrolled 17 patients with LQTS who underwent LCSD between 2017 and 2019. SKNA recordings from the left arm (L-SKNA) and chest (C-SKNA) leads were performed before and after LCSD. Mean SKNA, burst activity, and nonburst activity of L-SKNA and C-SKNA were analyzed. RESULTS: The mean patient age was 21 ± 9 years (8 men 47%). The longest baseline corrected QT value was 497 ± 55 ms at rest and 531 ± 38 ms on exercise stress testing. Five patients (29.4%) had previous LQTS-triggered cardiac events including syncope, documented torsades de pointes, and ventricular fibrillation. In the 24 hours after LCSD, mean L-SKNA decreased from 1.25 ± 0.64 to 0.85 ± 0.33 µV (P = .005) and mean C-SKNA from 1.36 ± 0.67 to 1.05 ± 0.49 µV (P = .11). The frequency of episodes of SKNA bursts recorded from the left-arm lead (2.87 ± 1.61 bursts per minute vs 1.13 ± 0.99 bursts per minute; P < .001) and mean L-SKNA during burst (1.82 ± 0.79 µV vs 1.15 ± 0.44 µV; P < .001) and nonburst (1.09 ± 0.60 µV vs 0.75 ± 0.32 µV; P = .03) periods significantly decreased after LCSD, while the frequency of episodes of SKNA bursts recorded from the chest lead (P = .57) and mean C-SKNA during burst (P = .44) and nonburst (P = .10) periods did not change significantly. No arrhythmic events were documented after 11.9 months (range 3.0-22.2 months) of follow-up. CONCLUSION: LCSD provides an inhibitory effect on cardiac sympathetic activity by suppressing burst discharge as measured by SKNA.

Left cardiac sympathetic denervation in the management of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia: A meta-regression.

BACKGROUND: Left cardiac sympathetic denervation (LCSD) has been proposed as useful therapy for long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT), in addition to anti-arrhythmic agents and implantable cardioverter defibrillators. This study aimed to assess the current evidence for LCSD and compare the open vs the video-assisted thoracoscopic surgery (VATS) approaches. METHODS: MEDLINE, Embase and Cochrane library databases were searched up to December 2018 for studies reporting the long-term outcomes of LCSD in LQTS, CPVT patients. The incidence of cardiac events (CEs) before and after surgery, the change in QTc interval, and surgical complications were pooled to estimate the efficacy of LCSD. Meta-regression was used to estimate the effects of surgical approach (open vs VATS) on outcomes following LCSD. RESULTS: Twenty-seven papers met our inclusion criteria (647 patients). VATS was used in 408 patients (63.1%), open surgery in 239 (36.9%). Mean follow-up was 32.3 ± 32.5 months. Postsurgery, 398/585 patients (68.0%) were free of CEs and QTc decreased from 522 ± 61.6 ms to 494 ± 52.3 ms. Meta-regression showed no differences between the two approaches in the incidence of CEs and surgical complications. VATS was associated with a smaller reduction in QTc (ß-coefficient -20.04, 95% CI -36.82 to -3.27, P = .019). CONCLUSIONS: LCSD was associated with a reduction in the incidence of CEs in LQTS, CPVT patients and in the duration of QTc. Open surgery was associated with a greater reduction in QTc. Due to the limitations that hindered our study, a randomized trial is warranted to fully establish LCSD safety and efficacy.

The Effect of Left Cardiac Sympathetic Denervation on Exercise in Patients With Long QT Syndrome.

OBJECTIVES: This study evaluated the effect of left cardiac sympathetic denervation (LCSD) on heart rate, cardiac contractility, and cardiopulmonary fitness in human subjects. BACKGROUND: The primary treatment for long QT syndrome (LQTS) is beta-blocker (BB) therapy, but some patients experience breakthrough cardiac events or intolerable side effects. LCSD provides a significant antifibrillatory, protective effect in LQTS. However, the effect of LCSD on cardiopulmonary fitness in humans has not been previously described. METHODS: A retrospective analysis of patients with LQTS and LCSD (2006 to 2017) who had both pre- and post-LCSD exercise stress tests (N = 55; 39 females; mean age at LCSD 22 ± 12 years; mean follow-up 5.1 ± 2.5 years; 36 patients with LQT1; 15 patients with LQT2). Forty patients (73%) were receiving BBs pre-LCSD. RESULTS: Mean peak heart rate before LCSD was 143 ± 23 beats/min, mean peak oxygen consumption (VO2) was 32 ± 10 ml/kg/min, and mean peak respiratory exchange ratio was 1.14 ± 0.12. There was no difference in peak heart rate, peak VO2, peak QTc, or respiratory exchange ratio pre- and post-LCSD. To evaluate the isolated effect of LCSD, the study performed a subset analysis of patients with LCSD monotherapy (n = 10) or no change in BB dose (n = 12). Patient-matched pre- and post-LCSD exercise testing showed no difference in heart rate, VO2, or left ventricular function following LCSD. CONCLUSIONS: LCSD provides increased protection from an LQTS-triggered event without negatively affecting peak heart rate, cardiopulmonary fitness, or cardiac contractility, as assessed by both treadmill exercise stress testing and echocardiography.