Beta blockers normalize QT hysteresis in long QT syndrome

Objectives This study was performed to evaluate the impact of beta blockers on QT adaptation to heart rate during the exercise and recovery phases of exercise testing in long QT syndrome. Background Long QT syndrome is characterized by familial syncope and sudden death in the context of sudden heart rate changes. QT hysteresis has been proposed as a phenotypic marker of long QT syndrome, suggesting altered QT adaptation to changes in heart rate. Methods Fourteen patients with long QT syndrome (aged 26 ± 16 years, 6 male) and 10 healthy volunteers (aged 37 ± 11 years, 9 male) underwent graded exercise testing with continuous lead II electrocardiographic monitoring. Long QT patients underwent repeat assessment after 1 month of beta blockade. QT intervals at matching heart rates were compared during exercise and recovery to determine the effect of beta blockade on QT hysteresis, defined as the recovery QT peak interval subtracted from the exercise QT peak interval. Results In the 14 long QT syndrome patients, beta blockers slowed the resting heart rate without affecting the corrected QT interval (502 ± 52 ms baseline vs 481 ± 40 ms beta blocker, P = .17). The increase in heart rate with exercise was similar in the 3 groups (P = .73). Exaggerated hysteresis of the QT interval was seen in the patients with long QT syndrome at baseline compared with controls (46 ± 19 ms vs 19 ± 11 ms 1 minute into recovery, P = .006). Beta blockers had minimal effect on the QT interval but markedly reduced hysteresis with minimal separation of the exercise and recovery QT/RR curves (25 ± 35 ms 1 minute into recovery, P = .027). The combined curve separation at all 6 time points analyzed was 165 ± 95 ms in patients with long QT syndrome at baseline, 40 ± 131 ms after beta blockade, and 29 ± 30 ms in control subjects (P = .002). Comparison of the beta blocker effect on hysteresis in the 2 genotypes suggested a greater reduction in hysteresis in the 3 patients with long QT syndrome 1 compared with the 11 patients with long QT syndrome 2. Conclusions Beta blockers reduce QT hysteresis in patients with long QT syndrome to values seen in normal patients. This improved QT adaptation to changes in heart rate may explain the clinical benefit of beta blockers in long QT syndrome. (Am Heart J 2002;143:528-34.)     

Long QT Syndrome: A Comprehensive Review of the Literature and Current Evidence

Long QT syndrome (LQT) represents a heterogeneous family of cardiac electrophysiologic disorders characterized by QT prolongation and T-wave abnormalities on the electrocardiogram. It is commonly associated with syncope, however, sudden cardiac death can occur due to torsades de pointes. LQT is a clinical diagnosis and should be suspected in individuals on the basis of clinical presentation, family history and ECG characteristics. Management is focused on the prevention of syncope and ultimately sudden death. Complete cessation of symptoms is the goal. Life-style modification, beta blockers and ICD implantation are the most important therapeutic modalities in proper management of patients with LQT. Awareness should be raised regarding possible circumstances that could increase the risk of QT prolongation. Advanced age, hypokalemia, a history of heart failure, and structural heart disease are often mentioned in this context. Prudent consideration is needed before making a decision to recommend an ICD implantation in a young, active patient. Medical and/or device therapy still represent important therapeutic modalities in the management of patients with LQT with careful clinical judgement for the substrate of patients who will benefit. Insights from benchside to bedside have facilitated progress toward better therapeutic strategies, there also remains a need for tailoring management toward individuals in a mechanism-specific manner to optimize care. In addition, continued progress toward fundamental understanding of mechanisms of ion channel function and drug-channel interaction will guide the development of more effective, mechanism-based molecular agents in the treatment of LQT.     

Ventricular tachycardia and exercise related syncope in children with structurally normal hearts: emphasis on repolarisation abnormality.

OBJECTIVE--To emphasize the importance of ventricular tachycardia associated with repolarisation abnormality in syncope associated with exercise. DESIGN--Retrospective analysis of data on children presenting with syncope between 1985 and 1993. PATIENTS--5 apparently normal children with recurrent exercise related syncope associated with electrocardiographically abnormal TU complexes. RESULTS--3 children were diagnosed as having an intermediate form of the long QT syndrome and catecholamine sensitive ventricular tachycardia because the abnormal TU complexes were associated with polymorphic ventricular tachycardia that was not typical of torsades de pointes. Tachycardia was induced by exercise in all patients and by isoprenaline in the one patient who was tested. One patient also had sinus node dysfunction. One child had incessant salvos of polymorphic ventricular arrhythmias and intermittent abnormal TU complexes suggestive of repolarisation abnormalities. The other had typical congenital long QT syndrome. Treatment was effective in three patients; two patients took a beta blocker alone and one took a beta blocker and low doses of amiodarone. One patient died suddenly, death being associated with sinus node dysfunction. In one patient with incessant ventricular arrhythmias treatment with a beta blocker, amiodarone, or Ic drugs was ineffective and always associated with proarrhythmia or syncope. He was not given further treatment and was asymptomatic despite having mild cardiomegaly. CONCLUSIONS--Ventricular tachycardia associated with repolarisation abnormality was an important cause of exercise related syncope in apparently normal children. TU complex abnormalities can be identified by repeated electrocardiography. beta Blockers are effective in preventing recurrent episodes. The role of amiodarone in this type of ventricular tachycardia needs further evaluation.     

Sodium-channel blockers might contribute to the prevention of ventricular tachycardia in patients with long QT syndrome type 2: a description of 4 cases

Four patients with long QT type 2, aged 11 to 18 years from unrelated families, with recurrent syncope and polymorhic ventricular tachycardia were studied. Long QT syndrome was diagnosed in these children at ages 4 to 7 years. Syncope, QT prolongation on electrocardiogram (corrected QT interval ≥ 490 milliseconds), notched T-wave morphology, bradycardia, and polymorphic ventricular arrhythmia were found in all of the patients. The KCNH2-L586M; KCNH2-G604S, KCNH2-L1045F; and a combined mutation KCNH2 T613M + SCN5A R190G were genotyped. Syncope, implantable cardioverter-defibrillator shocks, and tachycardia persisted in these patients, although they were receiving a full dose of β-blocker therapy. Adding a sodium-channel blocker (IC class) led to a reduction in the polymorphic ventricular arrhythmia. No syncope episodes were registered during the patients' 8 to 60 months of follow-up on the combined antiarrhythmic therapy. Further studies are needed to better define the possible role of sodium-channel blockers in patients with long QT type 2.     

Genotype‐Specific Risk Stratification and Management of Patients with Long QT Syndrome

Long QT syndrome (LQTS) is an inherited disorder associated with life‐threatening ventricular arrhythmias. An understanding of the relationship between the genotype and phenotype characteristics of LQTS can lead to improved risk stratification and management of this hereditary arrhythmogenic disorder. Risk stratification in LQTS relies on combined assessment of clinical, electrocardiographic, and mutations‐specific factors. Studies have shown that there are genotype‐specific risk factors for arrhythmic events including age, gender, resting heart rate, QT corrected for heart rate, prior syncope, the postpartum period, menopause, mutation location, type of mutation, the biophysical function of the mutation, and response to beta‐blockers. Importantly, genotype‐specific therapeutic options have been suggested. Lifestyle changes are recommended according to the prevalent trigger for cardiac events. Beta‐blockers confer greater benefit among patients with LQT1 with the greatest benefit among those with cytoplasmic loops mutations; specific beta‐blocker agents may provide greater protection than other agents in specific LQTS genotypes. Potassium supplementation and sex hormone–based therapy may protect patients with LQT2. Sodium channel blockers such as mexiletine, flecainide, and ranolazine could be treatment options in LQT3.     

Kongenitales Long-QT-Syndrom

The long QT syndrome is characterized by prolongation of the heart rate-corrected QT interval on the electrocardiogram and by the occurrence of life-threatening ventricular tachyarrhythmias of the torsade de pointes type. In most cases, the disorder becomes clinically manifest during childhood. Before these events, affected patients are typically considered healthy because no other symptoms occur. Sudden cardiac death without preceding syncope is rare. The diagnosis is based on the patient's history and the evaluation of the surface electrocardiogram. Genetic analysis is a relatively new diagnostic tool. The disease-causing gene can be identified in approximately 70-80% of patients. Symptomatic patients are treated with a beta-blocker. Implanted cardioverter defibrillators appear to be the most effective therapy for high-risk patients. High-risk patients are defined as those with aborted cardiac arrest or recurrent cardiac events (e. g., syncope or torsade de pointes) despite conventional therapy (i. e., beta-blocker alone).     

Positive head-up tilt table test in patients with the long QT syndrome.

AIMS: Syncope in patients with the long QT syndrome is commonly attributed to a ventricular arrhythmia (torsades de pointes). The susceptibility of patients with the long QT syndrome (LQTS) to neurally mediated syncope is currently unknown. METHODS AND RESULTS: Head-up tilt table testing (70 degrees) was performed in six patients with the long QT syndrome and a history of syncope. All patients had syncope with a mixed response. The RR interval was significantly decreased 2 min before the onset of syncope (980 +/- 125 ms vs 630 +/- 91 ms, P=0.003), and significantly increased during syncope (983.17 +/- 224.71; P=0.006). Non-significant changes in QT intervals were observed. Baseline QT was 513 +/- 86 ms and decreased to 450 +/- 59 ms 2 min before the onset of syncope (P=0.11). Although not statistically significant, QT intervals during syncope were longer than at 2 min before syncope (485 +/- 85 ms vs 450 +/- 59 ms; P=0.29). CONCLUSION: Our results suggest that patients with the LQTS are susceptible to neurally mediated syncope. Whether this susceptibility differs from control populations remains unresolved. From a clinical standpoint, neurocardiogenic syncope should be considered a diagnostic alternative in patients with LQTS.     

Asthma and the risk of cardiac events in the Long QT syndrome. Long QT Syndrome Investigative Group

While acquiring data for the International Long QT Syndrome Registry, we noticed that a number of patients referred for long QT syndrome (LQTS) were affected by asthma. The effect of asthma comorbidity on clinical course of LQTS has not been studied. This study aimed to evaluate the prevalence of asthma in patients with LQTS, determine the influence of asthma comorbidity on outcome of LQTS patients, and to investigate the confounding effects of beta mimetics and beta blockers on the occurrence of cardiac events in asthmatic patients. The influence of asthma on risk of cardiac events (syncope, aborted cardiac arrest, or LQTS death) was evaluated after accounting for age, gender, QTc, and RR interval duration, beta-blocker and beta-mimetic use. Asthma was identified in 226 (5.2%) of 4,310 studied LQTS family members. Longer QTc duration was associated with higher incidence of asthma (p <0.001). Asthma was independently associated with significantly increased risk of cardiac events in affected LQTS patients (hazard ratio 1.32; p = 0.048) and in borderline-affected family members (hazard ratio 2.08; p = 0.004) after adjustment for QTc, RR interval, and gender. An increased risk of cardiac events in asthmatic patients observed before beta-blocker therapy was reduced after initiation of treatment with beta blockers. In conclusion, the occurrence of asthma in LQTS patients increases with QTc duration. Asthma comorbidity in LQTS patients is associated with an increased risk of cardiac events. The asthma-associated increase in the risk of LQTS-related cardiac events is diminished after initiation of beta-blocker therapy, suggesting a possible role of beta-receptor modulation underlying asthma-LQTS association.     

Provocative testing and drug response in a patient with the long QT syndrome.

A girl of 14 with the long QT syndrome (LQTS) and torsades de pointes is reported. Isoprenaline or adrenaline infusions induced torsades de pointes and inversion of the TU wave. Changes in the TU wave during isoprenaline infusion were used to select effective drugs to treat this patient. A beta blocker and calcium channel blocker were selected and the patient had no episodes of syncope for two years. This electrocardiographically guided method may be useful for selecting effective drugs in patients with the LQTS.     

遗传性长 QT 综合征的药物及器械治疗

遗传性长 QT 综合征（long-QT syndrome,LQTS）以心电图上 QT 间期延长及其相关的尖端扭转型室性心动过速（torsade de pointes,TdP）为特征,易导致心脏性猝死。它的危险因素有 QTc 长度、基因型、晕厥史等。LQTS 的治疗手段包括β受体阻滞剂治疗、外科心脏左侧交感神经节切除术（LCSD）、心脏起搏治疗以及植入式心律转复除颤器（ICD）治疗。β受体阻滞剂治疗是 LQTS 治疗的基石;心脏起搏治疗适用于伴有心动过缓的 LQTS,可明显降低心脏事件的复发率,但不降低死亡率。对高危的 LQTS 应植入 ICD,皮下 ICD 并发症较少,值得推广。LCSD 技术实用性较差,更适用于 ICD 植入后频繁电击治疗的患者。     

A case of congenital long QT syndrome associated with T wave alternans]

A case was presented in which a rare T wave alternans occurred in association with congenital long QT syndrome. A 71-year-old woman, who had experienced several syncopal attacks per year for the previous forty years, was admitted for further evaluation of the syncope. She had a family history of sudden death (sister) and QT prolongation (son). Electrocardiogram showed a corrected QT interval of 0.68 seconds. Treadmill exercise-tolerance test revealed both T wave alternans immediately after exercise and torsades de pointes 150 seconds after exercise. The syncope was induced by the mental excitation. A prolonged corrected QT interval reduced from 0.70 seconds to 0.58 seconds by the correction of her serum potassium and magnesium. The effect of propranolol, verapamil, phenytoin or mexiletine on T wave alternans and ventricular arrhythmia was evaluated by the treadmill exercise-tolerance test. The treatment with propranolol was most effective.     

先天性QT延长综合征尖端扭转型室性心动过速的发作方式

目的　研究先天性QT延长的尖端扭转型室性心动过速 (室速 )发作方式及其临床意义。方法　回顾性分析 5 5例因反复晕厥而确诊为先天性QT延长综合征病人的心电图 ,其中 16例记录到尖端扭转型室速开始发作的图形。结果　共记录到尖端扭转型室速 14 9阵 ,130阵为间隙依赖性。结论　间隙依赖性尖端扭转型室速曾经被认为是后天获得性QT延长综合征标志 ,研究表明其在先天性QT延长综合征尖端扭转型室速发作中也起重要的作用     

Abnormal QT interval variability in patients with hypertrophic cardiomyopathy: can syncope be predicted?

We sought to determine QT variability pattern in patients with hypertrophic cardiomyopathy (HCM) and its relationship with the risk of syncope. QT interval variability was assessed from 24-hour Holter monitoring in 10 HCM patients with history of syncope, 10 HCM patients without history of syncope, and 10 healthy subjects. QT variability was higher in patients with HCM, in particular in those with history of syncope, than in healthy controls. Time domain QT variability did not vary between waking and sleeping hours in HCM patients, whereas it was significantly shorter while asleep in the control group. Increased QT SDANN identified HCM patients with history of syncope with an accuracy of 75%. Our data show that QT variability is abnormal in HCM patients and indirectly support the concept that arrhythmia-related syncope in these patients may be, at least in part, related to an altered control of repolarization.     

Sotalol,hypokalaemia, syncope,and torsade de pointes.

Thirteen patients developed syncope and a prolonged QTc interval while taking therapeutic doses of sotalol. Polymorphous ventricular tachycardia was observed in 12 patients, and criteria typical of torsade de pointes were present in 10. In 12 patients sotalol had been given with hydrochlorothiazide in a combined preparation, Sotazide, but with inadequate or no potassium supplementation. Serum potassium concentrations were reduced in eight patients. Four patients were taking other drugs known to prolong the QT interval, including disopyramide (three patients) and tricyclic antidepressants (two patients). The QT interval returned to normal in all patients after withdrawal of the drugs and correction of the hypokalaemia. Thus even in low dosage sotalol may be hazardous in the presence of hypokalaemia or when combined with drugs that also prolong the QT interval. The use of sotalol concurrently with potassium losing diuretics, such as the combined preparation Sotazide, may expose the patient to unnecessary risk and should be avoided unless the class III antiarrhythmic action of this unique beta adrenoreceptor blocking agent is also required.     

Prolonged QT and cardiac arrest after heart transplantation: inherited or acquired?

The long QT syndrome is an inherited arrhythmogenic disease characterized by prolongation of QT interval, syncope, and sudden cardiac death because of ventricular tachycardia, mainly in the form of Torsades de Pointes. We present an unusual case of prolonged QT interval and cardiac arrest caused by Torsades de Pointes in the early phase after orthotopic heart transplant.     

Torsade de pointes induced by ajmaline

Ajmaline, a reserpine derivative, is an effective class I antiarrhythmic agent. Herein we report two cases of ajmaline-induced abnormal QT prolongation accompanied by polymorphic ventricular tachycardia of the torsade de pointes type. Since ajmaline is increasingly used for the acute termination of wide complex tachycardia and as a diagnostic tool after syncope and in patients with idiopathic ventricular tachyarrhythmias, our observations suggest that caution should be exercised with regard to the effects of the drug on the QT interval and its potency to induce proarrhythmia of the torsade de pointes type.     

Sotalol, hypokalaemia, syncope, and torsade de pointes

Thirteen patients developed syncope and a prolonged QTc interval while taking therapeutic doses of sotalol. Polymorphous ventricular tachycardia was observed in 12 patients, and criteria typical of torsade de pointes were present in 10. In 12 patients sotalol had been given with hydrochlorothiazide in a combined preparation, Sotazide, but with inadequate or no potassium supplementation. Serum potassium concentrations were reduced in eight patients. Four patients were taking other drugs known to prolong the QT interval, including disopyramide (three patients) and tricyclic antidepressants (two patients). The QT interval returned to normal in all patients after withdrawal of the drugs and correction of the hypokalaemia. Thus even in low dosage sotalol may be hazardous in the presence of hypokalaemia or when combined with drugs that also prolong the QT interval. The use of sotalol concurrently with potassium losing diuretics, such as the combined preparation Sotazide, may expose the patient to unnecessary risk and should be avoided unless the class III antiarrhythmic action of this unique beta adrenoreceptor blocking agent is also required.     

Diagnosis, sudden death risk stratification, and treatment of main long QT syndrome molecular-genetic variants

Inherited long QT syndrome (LQTS) refers to the primary electrical diseases of the heart. It is characterized by QT prolongation on resting ECG and syncope due to life-threatening ventricular arrhythmias. This review focuses on diagnosis, differential diagnosis, risk stratification of sudden cardiac death, and treatment strategy of patients with most prevalent genetic fOrms of LQTS - LQT1, LQT2 and LQT3, which accounted for about 90% of all genetically confirmed cases. Recent advances in understanding of relationship between clinical, electrocardiographic features (on ECG, body surface mapping, stress test) and genetic variants of LQT presented. Characteristics of syncopal events and ECG features of LQTl, LQT2 and LQT3 in the majority of cases are helpful to make an appropriate choice for therapy, even before positive result of molecular genetic testing. Management has focused on the use of beta blockers as first-line treatment and exclusion of triggers of life-threatening arrhythmia which are specific for each molecular-genetic variant. Implantation of cardioverter defibrillator for secondary prevention of sudden death in the high-risk patients or patients with insufficient effect of antiarrhythmic therapy is required.     

Spontaneous onset of torsade de pointes in long-QT syndrome and the role of sympathovagal imbalance.

The net effects of sympathetic and vagal activity on the QT interval and the mode of spontaneous onset of torsade de pointes (TdP) are still unclear in long-QT syndrome. Two patients with long-QT syndrome had syncope while undergoing Holter ECG investigation. The spontaneous onset of TdP in these patients was analyzed with respect to the relation between the RR and QT intervals. Both patients were high-school students (16- and 17-year-old boys) who had been diagnosed as long-QT syndrome and followed up without medical treatment because they had had neither a history of syncope nor arrhythmia induction by treadmill exercise tests. The first episode of syncope in both patients occurred during ordinary daily life and was not related to exercise or psychological stress. The dynamic changes between the RR and QT intervals associated with the spontaneous onset of TdP were analyzed by Holter ECG. Both patients showed sinus tachycardia followed by abrupt sinus bradycardia immediately before the onset of TdP. The enhanced rate of the adaptive response of the QT interval that occurred during the deceleration of the heart rate preceded the onset of TdP. These observations suggest that the complex situation that follows sympathovagal imbalance may have an important role in the dynamic change in the QT interval and initiation of TdP in patients with long-QT syndrome.     

Drug-induced QT-interval prolongation and recurrent torsade de pointes in a child with heterotaxy syndrome and KCNE1 D85N polymorphism

We present a child case of heterotaxy syndrome (asplenia syndrome) after Fontan procedure that showed extreme prolongation of QT interval and torsade de pointes (TdP) after administration of sodium channel blockers for paroxysmal atrial tachycardia. Despite low serum concentration of the drugs, QT prolongation persisted and TdP attacks with unconsciousness recurred, possibly in association with junctional bradycardia and myocardial damage although he had never experienced QT prolongation during bradycardia before. Temporal cardiac pacing via a venous route to exclude possible implication of bradycardia in induction of TdP was difficult to apply due to total cavopulmonary connection (TCPC) circulation. Continuous intravenous administration of low-dose isoproterenol was started but an appropriate heart rate for prevention of TdP was difficult to obtain. Finally, we were urged to conduct implantation of a DDD pacemaker combined with ICD surgically with epicardial leads, resulting in successful suppression of TdP and syncope. Screening of the genotype disclosed the KCNE1 D85N polymorphism, which is known as one of the typical disease-causing gene variants in long-QT syndrome (LQTS).