Response Of QT Interval Research Articles

Cardiac Implications in Dravet Syndrome: Can Electrocardiogram and Echocardiography Detect Hidden Risks?

Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy associated with loss-of-function variants in the SCN1A gene. Although predominantly expressed in the central nervous system, SCN1A is also expressed in the heart, suggesting a potential link between neuronal and cardiac channelopathies. Additionally, DS carries a high risk of sudden unexpected death in epilepsy (SUDEP). This study investigates electrocardiographic (EKG) and echocardiographic findings in patients with DS to assess potential cardiac risks. This prospective study recruited 34 patients with DS with confirmed SCN1A pathogenic variants during the 2024 family meeting of the Dravet Syndrome Foundation Spain. Participants underwent standard 12-lead EKG, high-lead EKG for Brugada pattern detection, and a standing test to evaluate QT interval response. When available, echocardiogram data were collected. QTc and P wave dispersion were calculated. To establish a basis for comparison, cases were matched with age- and sex-matched epileptic patients without DS. No significant EKG abnormalities suggesting long QT syndrome or Brugada syndrome were detected. However, QT and P wave dispersion, previously reported as markers of autonomic dysfunction associated with arrhythmias and SUDEP risk, were elevated. Echocardiograms in 21 patients showed normal cardiac structure, even in those on fenfluramine. Although no significant EKG or echocardiographic abnormalities were identified, elevated QTc and P wave dispersion, along with the elevated risk of SUDEP and past reports of arrhythmias, suggest the need for continued cardiac surveillance. Further studies are essential to explore the predictive value of QTc and P wave dispersion in assessing SUDEP and arrhythmia risk, and to identify other potential cardiac markers.

Proceed with caution: Standard protocol exercise stress tests fail to replicate the diagnostic utility of supine-stand tests for long QT syndrome.

Long QT syndrome (LQTS) is a sudden death predisposing condition characterized by ECG-derived prolongation of the QT interval. Previous studies have demonstrated that the supine-stand test may aid in the diagnosis of LQTS as patients fail to shorten their QT interval in response to standing up. The aim of this study was to evaluate the diagnostic accuracy of ECG data derived from standard protocol, clinically performed treadmill exercise stress tests (TESTs) in their ability to mimic the formal supine-stand test. We performed a retrospective review of 478 TESTs from patients evaluated for LQTS. Patients referred for evaluation of LQTS but who were dismissed as normal served as controls. Heart rate & QT values were obtained from standard protocol TESTs. Overall, 243 patients with LQTS (125 LQT1, 63 LQT2, 55 LQT3; 146 [60%] female, mean age at TEST 30±17 years) and 235 controls (142 [60%] female, mean age 24±15 years) were included. The paired ΔQTc (QTcStand -QTcSupine ) was similar between LQTS (-5±26) and controls (-2±25; p=.2). During position change, the QT interval shortened by ≥20ms in 33% of LQTS patients, remained unchanged in 62%, and increased in 5% of LQTS patients which was similar to controls (shortened in 40%, unchanged in 54%, and increased in 6% of controls; p=.2). Receiver-operator curve analysis to test the diagnostic ability of supine-stand ΔQT performed poorly in differentiating LQTS from controls with an of AUC 0.52 (p=.4). TESTs should be used with caution when trying to interpret supine-stand changes for diagnosis of LQTS.

The role of β-adrenergic stimulation in QT interval adaptation to heart rate during stress test.

The adaptation lag of the QT interval after heart rate (HR) has been proposed as an arrhythmic risk marker. Most studies have quantified the QT adaptation lag in response to abrupt, step-like changes in HR induced by atrial pacing, in response to tilt test or during ambulatory recordings. Recent studies have introduced novel methods to quantify the QT adaptation lag to gradual, ramp-like HR changes in stress tests by evaluating the differences between the measured QT series and an estimated, memoryless QT series obtained from the instantaneous HR. These studies have observed the QT adaptation lag to progressively reduce when approaching the stress peak, with the underlying mechanisms being still unclear. This study analyzes the contribution of β-adrenergic stimulation to QT interval rate adaptation in response to gradual, ramp-like HR changes. We first quantify the QT adaptation lag in Coronary Artery Disease (CAD) patients undergoing stress test. To uncover the involved mechanisms, we use biophysically detailed computational models coupling descriptions of human ventricular electrophysiology and β-adrenergic signaling, from which we simulate ventricular action potentials and ECG signals. We characterize the adaptation of the simulated QT interval in response to the HR time series measured from each of the analyzed CAD patients. We show that, when the simulated ventricular tissue is subjected to a time-varying β-adrenergic stimulation pattern, with higher stimulation levels close to the stress peak, the simulated QT interval presents adaptation lags during exercise that are more similar to those measured from the patients than when subjected to constant β-adrenergic stimulation. During stress test recovery, constant and time-varying β-adrenergic stimulation patterns render similar adaptation lags, which are generally shorter than during exercise, in agreement with results from the patients. In conclusion, our findings support the role of time-varying β-adrenergic stimulation in contributing to QT interval adaptation to gradually increasing HR changes as those seen during the exercise phase of a stress test.

Heart-Rate-Corrected QT Interval Response to Ramosetron during Robot-Assisted Laparoscopic Prostatectomy: A Randomized Trial.

Ramosetron, often used to prevent postoperative nausea and vomiting, might cause heart-rate-corrected (QTc) interval prolongation, as might robot-assisted laparoscopic prostatectomy (RALP), which requires a steep Trendelenburg position and CO2 pneumoperitoneum. This study aimed to determine how ramosetron administration affects the QTc interval in patients treated with RALP. Fifty-six subjects were randomly assigned to ramosetron (n = 28) or control (n = 28) groups. The ramosetron group received 0.3 mg of ramosetron after anesthetic induction, whereas the control group received normal saline. The QTc interval was measured before and after induction; after 5, 30, and 60 min of being placed in the Trendelenburg position; immediately after being returned to a supine position; and at the end of surgery. Linear mixed models were used to compare QT intervals between groups. QTc intervals did not differ significantly between groups over time (Pgroup×time = 0.111). However, they increased significantly in both groups after placement in the Trendelenburg position compared with before induction (Ptime < 0.001). This increase in QTc continued until the end of surgery in both groups. Based on these findings, ramosetron can be safely administered for the prevention of postoperative nausea and vomiting among patients undergoing RALP.

PO-639-06 PROCEED WITH CAUTION: STANDARD PROTOCOL EXERCISE STRESS TESTS DO NOT RECREATE THE DIAGNOSTIC UTILITY OF THE SUPINE-STAND TESTS FOR LONG QT SYNDROME

The treadmill exercise stress test (TEST) can unmask concealed long QT syndrome (LQTS), especially LQT1, by identifying a maladaptive QT response during the TEST’s recovery phase. Additionally, the supine-stand test may aid in LQTS diagnosis as patients fail to shorten their QT interval in response to standing up, and instead show a paradoxical increase of QT. However, as the supine-stand test protocol requires patients to be supine and then standing for ≥ 5 minutes, this often does not match the standard TEST protocols and as such, the clinical utility needs to be validated.

Temporary prolongation of corrected QT interval after cardioneuroablation for functional bradyarrhythmias

Abstract Background There are controversial reports on QT interval response to ganglionic plexi ablation that are selectively targeted during cardioneuroablation (CNA) or occurs as collateral lesion during left atrial ablation procedures. Both shortening or prolongation of the heart-rate corrected QT interval (QTc) with therapeutic or safety implications were described. Purpose In this retrospective study, we investigated longitudinal changes of QTc after CNA. Methods The study included 108 patients (age: 39±12 years, 60% males) who underwent biatrial cardioneuroablation (radiofrequency time: 15.5±6.7 min) for symptomatic functional bradyarrhythmias. Surface ECG examinations were performed on the day before the CNA (N=108), 1 hour after the CNA (N=106), on the 1st post-ablation day (N=50), at the 3-month (N=99), and 1-year (N=63) follow-up visits. Automated measurements of QT interval were employed for the analysis. Four formulas (Bazett, Framingham, Fridericia, and Hodges) were used for the correction of QT interval to instant heart rate. Results QTc significantly prolonged immediately after the CNA with rapid return to baseline values (Figure and Table). This was particularly valid for QT correction by Framingham formula (and similarly for Fridericia and Hodges formulas). The QTc by Bazett formula, which is known to overestimate QT at higher heart rates, returned to baseline more slowly and incompletely. Several mechanisms may contribute to observed QTc dynamics: (1) direct effect of autonomic denervation with recovery phenomenon; (2) QT hysteresis with an extremely long time constant; or (3) artifact due to suboptimum QT correction to a substantial change of heart rate. Conclusions The study suggests that CNA produces acute prolongation of QTc interval with rapid decay and virtual normalization in 3 months. CNA in otherwise healthy subjects is not likely associated with substantial long-term risk of long-QT-associated arrhythmias. In the same way, we cannot confirm earlier observations of clinically significant QTc shortening effect of ganglionated plexi ablation. Funding Acknowledgement Type of funding sources: None. Figure 1Table 1

Development of a Patient-Specific p.D85N-Potassium Voltage-Gated Channel Subfamily E Member 1–Induced Pluripotent Stem Cell–Derived Cardiomyocyte Model for Drug-Induced Long QT Syndrome

Prior epidemiological studies demonstrated that the p.D85N-Potassium voltage-gated channel subfamily E member 1 (KCNE1) common variant reduces repolarization reserve and predisposes to drug-induced QT prolongation/torsades de pointes. We sought to develop a cellular model for drug-induced long QT syndrome using a patient-specific induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM). p.D85N-KCNE1 iPSCs were generated from a 23-year-old female with an exaggerated heart rate-corrected QT interval response to metoclopramide (ΔQTc of 160 ms). Clustered regularly interspaced short palindromic repeats-associated 9 technology was used to generate gene-corrected isogenic iPSCs. Field potential duration and action potential duration (APD) were measured from iPSC-CMs. At baseline, p.D85N-KCNE1 iPSC-CMs displayed significantly longer field potential duration (281±15 ms, n=13 versus 223±8.6 ms, n=14, P<0.01) and action potential duration at 90% repolarization (APD90; 579±22 ms, n=24 versus 465±33 ms, n=26, P<0.01) than isogenic-control iPSC-CMs. Dofetilide at a concentration of 2 nM increased significantly field potential duration (379±20 ms, n=13, P<0.01) and APD90 (666±11 ms, n=46, P<0.01) in p.D85N-KCNE1 iPSC-CMs but not in isogenic-control. The effect of dofetilide on APD90 (616±54 ms, n=7 versus 526±54 ms, n=10, P<0.05) was confirmed by Patch-clamp. Interestingly, treatment of p.D85N-KCNE1 iPSC-CMs with estrogen at a concentration of 1 nM exaggerated further dofetilide-induced APD90 prolongation (696±9 ms, n=81, P<0.01) and caused more early afterdepolarizations (11.7%) compared with isogenic control (APD90: 618±8 ms, n=115 and early afterdepolarizations: 2.6%, P<0.05). This iPSC-CM study provides further evidence that the p.D85N-KCNE1 common variant in combination with environmental factors such as QT prolonging drugs and female sex is proarrhythmic.

Genetic Basis and Prognostic Value of Exercise QT Dynamics.

Abnormal QT interval responses to heart rate (QT dynamics) is an independent risk predictor for cardiovascular disease in patients, but its genetic basis and prognostic value in a population-based cohort have not been investigated. QT dynamics during exercise and recovery were derived in 56 643 individuals from UK Biobank without a history of cardiovascular events. Genome-wide association studies were conducted to identify genetic variants and bioinformatics analyses were performed to prioritize candidate genes. The prognostic value of QT dynamics was evaluated for cardiovascular events (death or hospitalization) and all-cause mortality. Heritability of QT dynamics during exercise and recovery were 10.7% and 5.4%, respectively. Genome-wide association studies identified 20 loci, of which 4 loci included genes implicated in mendelian long-QT syndrome. Five loci did not overlap with previously reported resting QT interval loci; candidate genes included KCNQ4 and KIAA1755. Genetic risk scores were not associated with cardiovascular events in 357 882 unrelated individuals from UK Biobank. We also did not observe associations of QT dynamics during exercise and recovery with cardiovascular events. Increased QT dynamics during recovery was significantly associated with all-cause mortality in the univariate Cox regression analysis (hazard ratio, 1.09 [95% CI, 1.05-1.13], P=2.28×10-5), but the association was not significant after adjusting for clinical risk factors. QT interval dynamics during exercise and recovery are heritable markers but do not carry independent prognostic information for clinical outcomes in the UK Biobank, a population-based cohort. Their prognostic importance may relate to cardiovascular disease cohorts where structural heart disease or ischemia may influence repolarization dynamics. The strong overlap between QT dynamics and resting QT interval loci suggests common biological pathways; however, nonoverlapping loci suggests alternative mechanisms may exist that underlie QT interval dynamics.

Quantitative Assessment of the Physiological Parameters Influencing QT Interval Response to Medication: Application of Computational Intelligence Tools.

Human heart electrophysiology is complex biological phenomenon, which is indirectly assessed by the measured ECG signal. ECG trace is further analyzed to derive interpretable surrogates including QT interval, QRS complex, PR interval, and T wave morphology. QT interval and its modification are the most commonly used surrogates of the drug triggered arrhythmia, but it is known that the QT interval itself is determined by other nondrug related parameters, physiological and pathological. In the current study, we used the computational intelligence algorithms to analyze correlations between various simulated physiological parameters and QT interval. Terfenadine given concomitantly with 8 enzymatic inhibitors was used as an example. The equation developed with the use of genetic programming technique leads to general reasoning about the changes in the prolonged QT. For small changes of the QT interval, the drug-related IKr and ICa currents inhibition potentials have major impact. The physiological parameters such as body surface area, potassium, sodium, and calcium ions concentrations are negligible. The influence of the physiological variables increases gradually with the more pronounced changes in QT. As the significant QT prolongation is associated with the drugs triggered arrhythmia risk, analysis of the role of physiological parameters influencing ECG seems to be advisable.

Non-Invasive Acoustical sensing of Drug-Induced Effects on the Contractile Machinery of Human Cardiomyocyte Clusters.

There is an urgent need for improved models for cardiotoxicity testing. Here we propose acoustic sensing applied to beating human cardiomyocyte clusters for non-invasive, surrogate measuring of the QT interval and other characteristics of the contractile machinery. In experiments with the acoustic method quartz crystal microbalance with dissipation monitoring (QCM-D), the shape of the recorded signals was very similar to the extracellular field potential detected in electrochemical experiments, and the expected changes of the QT interval in response to addition of conventional drugs (E-4031 or nifedipine) were observed. Additionally, changes in the dissipation signal upon addition of cytochalasin D were in good agreement with the known, corresponding shortening of the contraction-relaxation time. These findings suggest that QCM-D has great potential as a tool for cardiotoxicological screening, where effects of compounds on the cardiomyocyte contractile machinery can be detected independently of whether the extracellular field potential is altered or not.

The challenges and excitement of liver transplantation.

The challenges and excitement of liver transplantation.

Abstract 18740: Influence of Oral Progesterone Administration on QT Interval Response to Ikr Inhibition

Introduction: Evidence from pre-clinical and human studies suggests that higher serum progesterone concentrations may be protective against drug-induced QT interval lengthening. Hypothesis: Oral progesterone administration attenuates QT interval response to I Kr inhibition. Methods: In this prospective, double-blind, crossover study, 15 healthy female volunteers ages 21-40 years were randomized to receive progesterone 400 mg or matching placebo orally once daily for 7 days timed to the menses phase of the menstrual cycle (between-phase washout period = 52 days). On day 7, a low dose of ibutilide (0.003 mg/kg) was infused over 10 minutes, after which QT intervals were recorded and blood samples serially collected for 12 hours post-infusion. Prior to the treatment phases, subjects underwent ECG monitoring for 12 hours to calculate individualized heart rate-corrected QT intervals (QT c I). Results: There was no significant difference in maximum serum ibutilide concentrations between the progesterone and placebo phases. (1291±910 vs 1328±718 pg/mL, p=0.87). ECG data are reported from lead II; results are similar from leads V 1 and V 5 . There was no significant difference in pre-ibutilide QT c I between the progesterone and placebo phases (Table). Maximum ibutilide-associated QT c I, maximum % change in QT c I, and % change in area under the effect (QT c I) curve during the first hour following ibutilide administration (AUEC 0-1 , s-hr) were significantly lower during the progesterone phase. Progesterone-associated adverse effects were mild, predominantly fatigue/general malaise. Ibutilide-associated adverse effects during the progesterone and placebo phases included bradycardia [3/15 (20%) vs 2/15 (13%)], burning at infusion site [1/15 (7%) vs 1/15 (7%)], and transient (&lt; 1 minute) Bazett’s-corrected QT c &gt; 500 ms [0/15 vs 1/15 (7%). Conclusions: Oral progesterone administration attenuates QT c I lengthening associated with I Kr inhibition

62 * The response of the QT interval to standing in children with long QT syndrome

Background & Aims: Patients with Long QT Syndrome (LQTS) often display paradoxical prolongation of the QT interval in response to an increase in heart rate. Studies in adults have shown that the tachycardia induced by standing can be a useful aid in the investigation and diagnosis of LQTS. However, data on the response of the QT interval to standing in the paediatric LTQS population are limited. This study, therefore, aimed to observe the changes in the QT interval invoked by the action of standing in children with LQTS. Methods: 64 consecutive children from 56 families with LQTS (aged <18 years; median 12.8 years [interquartile range 7.4-14.9]; 55% female), followed up in a specialist referral centre for paediatric inherited cardiovascular disease underwent supine 12-lead ECG followed by a second ECG immediately after standing. Corrected QT interval (QTc) was measured in lead II using Bazett's and Fridericia's formula. 48 patients from 43 families (75%) had undergone genetic testing (LQT1 n=14, 29%; LQT2 n=8, 17%, LQT3 n=2, 4%, variants of uncertain significance n= 7, 15%). Results: The corrected QT interval (QTc) was 429ms supine vs. 452ms standing (mean increase of 23ms [+/−51ms]) in lead II. When subdivided by genotype, impairment of the QT response was most pronounced in LQT1 (416ms supine vs. 463ms standing; mean increase of 38ms [+/−54ms]) compared to LQT2 patients who showed appropriate QTc shortening (447ms supine vs. 430ms standing; mean decrease 16ms [+/−30ms] p=0.006 compared to LQT2 patients). In patients with a diagnosis of LQTS but a normal QTc at rest, QTc was 406ms supine vs. 439ms standing (mean increase of 33ms [+/−49ms]). Conclusions: This study shows that the QTc increases in children with LQTS on standing, particularly in children with LQT1. This may improve diagnostic accuracy in children in whom a diagnosis of LQTS is suspected.

Response of QT interval in methadone maintenance treated patients to the rapid changes in heart rate provoked by brisk standing: Comparison to healthy controls and patients with long QT syndrome

BackgroundPatients on methadone maintenance therapy are somehow similar to patients with congenital long QT syndrome (LQTS) because they have malfunction of potassium channels caused by a drug that cannot be easily discontinued. We tested patients on methadone therapy with the “stand-up” test, which has been shown to unravel pathologic QT-prolongation in congenital long-QT patients. Methods“Stand-up” test results of methadone-users, healthy volunteers and congenital LQTS patients were compared. Methadone serum levels and doses were collected. The prognostic value of the test was evaluated after 4years of follow-up. ResultsThe QT-response of methadone-users to the “stand-up” test resembled that of healthy volunteers more than the response of LQTS-patients. Differences in the QTc of methadone treated patients and controls, which were statistically significant at baseline, became no longer significant after standing. Within 52months of follow-up, one patient had suffered unexplained death and one had documented ventricular tachycardia. ConclusionsThe QT-response of methadone-users to the “stand-up” test is similar to that of healthy volunteers, not to that of LQTS-patients.

The phenomenon of “QT stunning”: The abnormal QT prolongation provoked by standing persists even as the heart rate returns to normal in patients with long QT syndrome

Patients with long QT syndrome (LQTS) have inadequate shortening of the QT interval in response to the sudden heart rate accelerations provoked by standing-a phenomenon of diagnostic value. We now validate our original observations in a cohort twice as large. We also describe that this abnormal QT-interval response persists as the heart rate acceleration returns to baseline. To describe a novel observation, termed "QT stunning" and to validate previous observations regarding the "QT-stretching" phenomenon in patients with LQTS by using our recently described "standing test." The electrocardiograms of 108 patients with LQTS and 112 healthy subjects were recorded in the supine position. Subjects were then instructed to stand up quickly and remain standing for 5 minutes during continuous electrocardiographic recording. The corrected QT interval was measured at baseline (QTc(base)), when heart rate acceleration without appropriate QT-interval shortening leads to maximal QT stretching (QTc(stretch)) and upon return of heart rate to baseline (QTc(return)). QTc(stretch) lengthened significantly more in patients with LQTS (103 ± 80 ms vs 66 ± 40 ms in controls; P <.001) and so did QTc(return) (28 ± 48 ms for patients with LQTS vs -3 ± 32 ms for controls; P <.001). Using a sensitivity cutoff of 90%, the specificity for diagnosing LQTS was 74% for QTc(base), 84% for QTc(return), and 87% for QTc(stretch). The present study extends our previous findings on the abnormal response of the QT interval in response to standing in patients with LQTS. Our study also shows that this abnormal response persists even after the heart rate slows back to baseline.

Applying the “Viskin test”: QT interval in response to standing in elite athletes

Applying the “Viskin test”: QT interval in response to standing in elite athletes

Effect of β-adrenergic stimulation on QT interval accommodation

QT interval correction formulas are based on instantaneous heart rate (HR), but QT interval adaptation to sudden HR change occurs gradually. In humans, the QT interval has been reported to reach a new steady-state value in about 2 minutes. This study sought to assess β-adrenergic stimulation effects on QT interval response to HR change. Ten subjects (42.1 ± 15.3 years, 3 men) undergoing radiofrequency ablation of supraventricular tachycardia were studied. Atrial pacing for 5 minutes at an HR ranging from 60 to 140 beats/min was performed before and during dobutamine infusion (10 μg/kg/min). The QT response to sudden HR change was evaluated. The QT response to sudden HR change consists of an immediate response (IR), followed by a gradual monoexponential course to the new steady-state value. Linear function results in inferior fit of QT adaptation course (P < .05 compared with exponential). The time constant of the exponential is approximately 1 minute (50.9 ± 11.4 seconds). The IR magnitude is approximately 3% of the RR interval change (2.97% ± 2.01%). Dobutamine shortens steady-state QT at given HR (from 301.8 ± 11.2 ms to 290.6 ± 13.2 ms at 120 beats/min; P < .001) and increases IR magnitude (to 13.28% ± 8.99% of RR change; P < .01). During sinus rhythm, QT variability and QT variability index were significantly increased by dobutamine. QT adaptation has 2 distinct phases, which might have different mechanisms. The effect of β-adrenergic stimulation on IR may increase QT variability by increasing the immediate response to HR variability. These results may be important in the assessment of drug effects on repolarization and for understanding of QT variability.

QT interval response: Comparison of the telemetered guinea pig, dog and monkey

QT interval response: Comparison of the telemetered guinea pig, dog and monkey

Therapeutic Strategies for Long-QT Syndrome

The discovery of genetic defects underlying long-QT syndrome (LQTS) has allowed to identify important genotype-phenotype correlations that are now being used for risk stratification. The next challenge is to exploit the new information on the pathophysiology of the disease derived from molecular genetics to devise more effective therapies. The successful response of LQT1 patients to β-blockers, the QT-shortening action of sodium channel blockers in at least some LQT3 patients, and the importance of maintaining adequate plasma potassium levels in LQT2 patients clearly demonstrate the importance of selecting therapy in the context of the molecular substrate. The hurdles on the road toward the development of novel therapeutic strategies are represented by the variable expressivity of the disease, the high prevalence of “private” mutations, and the role of genetic and nongenetic factors that act as modifiers of the phenotype. Given the large number of mutations identified and their phenotypic complexity, it is clearly impossible to anticipate a scenario in which each mutation will be managed through a specific therapy. However, the evidence that mutations in the LQTS gene may be clustered based on their electrophysiological profile and on their response to specific drugs may provide the rationale for the development of mutation-specific therapies. In this article, we will review the most relevant genotype-phenotype features of LQTS and the strategies explored to develop novel therapeutic approaches. ### Definition and Prevalence The congenital LQTS is an inherited arrhythmogenic disease characterized by abnormally prolonged QT interval leading to life-threatening arrhythmias in the presence of a structurally normal heart.1 Different clinical variants of LQTS have been identified. Romano Ward syndrome, transmitted as an autosomal dominant trait, is the most common form of LQTS and presents only a cardiac phenotype. Less prevalent variants of LQTS, such as Andersen and Timothy syndromes or the recessive Jervell and Lange-Nielsen syndromes, also present …

Electrophysiological Interventions for Inherited Arrhythmia Syndromes

IInherited arrhythmia syndromes are electrical myopathies with genetic origins and risk of sudden death. They may present from infancy through adulthood, although the specific diseases have stereotypic but variable phenotypic onset and severity. There is clinical and genetic overlap among the syndromes, with variable penetrance and expressivity. Although underlying mechanisms of arrhythmogenesis may differ between syndromes, the electrophysiological (EP), pharmacological, and interventional options overlap. Specifics of the genetics, pharmacological therapies, and lifestyle modifications have been reviewed recently and are beyond the scope of this article, which focuses on interventional electrophysiology for inherited arrhythmias. The congenital long-QT syndromes (LQTSs) are the prototypic group of inherited arrhythmias. They were initially described as autosomal-recessive LQTSs with congenital sensorineural hearing loss, Jervell and Lange-Nielson (JLN) syndrome,1 and the more common autosomal-dominant LQTS with normal hearing, Romano-Ward syndrome.2,3 LQTS is caused by mutations in ion channel (or related anchoring protein) –encoding genes,4–6 presenting with prolonged QTc, stress-induced syncope, ventricular arrhythmias, or sudden cardiac death (SCD). The diagnosis is ascertained from clinical symptom complex, family history, ECG manifestations (at baseline or with provocative stimulation), and genetic testing. The principal treatment is pharmacological for most LQTS patients.7,8 ### Interventions for Congenital Long-QT Syndromes #### Catheter Ablation There is little role for diagnostic EP testing in LQTS. Studies have shown that programmed ventricular stimulation, QT interval response to pacing, and infusion of β-blocking medication in LQTS are of limited value.9 Monophasic action potential studies demonstrated afterdepolarizations but were not prognostic, and proarrhythmia can occur with ventricular stimulation.10 #### Left Cardiac Sympathetic Denervation Left cardiac sympathetic denervation (LCSD) can reduce cardiac events in LQTS but is not commonly performed at many institutions.11 Indications for LCSD include failure of medical therapy or frequent implantable cardioverter-defibrillator (ICD) shocks. Clinical results vary, likely because of the level of sympathetic denervation and operator experience. Left cervicothoracic sympathectomy involves resection of …