Beta‐Blocker Efficacy in High‐Risk Patients with the Congenital Long‐QT Syndrome Types 1 and 2: Implications for Patient Management

β‐Blockers for LQTS Types 1 and 2. Background: Beta‐blockers are the mainstay therapy in patients with the congenital long‐QT syndrome (LQTS) types 1 and 2. However, limited data exist regarding the efficacy and limitations of this form of medical management within high‐risk subsets of these populations. Methods and Results: Multivariate analysis was carried out to identify age‐related gender‐ and genotype‐specific risk factors for cardiac events (comprising syncope, aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) from birth through age 40 years among 971 LQT1 (n = 549) and LQT2 (n = 422) patients from the International LQTS Registry. Risk factors for cardiac events included the LQT1 genotype (HR = 1.49, P = 0.003) and male gender (HR = 1.31, P = 0.04) in the 0–14 years age group; and the LQT2 genotype (HR = 1.67, P < 0.001) and female gender (HR = 2.58, P < 0.001) in the 15–40 years age group. Gender–genotype subset analysis showed enhanced risk among LQT1 males (HR = 1.93, P < 0.001) and LQT2 females (HR = 3.28, P < 0.001) in the 2 respective age groups. Beta‐blocker therapy was associated with a significant risk‐reduction in high‐risk patients, including a 67% reduction (P = 0.02) in LQT1 males and a 71% reduction (P < 0.001) in LQT2 females. Life‐threatening events (ACA/SCD) rarely occurred as a presenting symptom among beta‐blocker‐treated patients. However, high‐risk patients who experienced syncope during beta‐blocker therapy had a relatively high rate of subsequent ACA/SCD (>1 event per 100 patient‐years). Conclusions: The present findings suggest that beta‐blocker therapy should be routinely administered to all high‐risk LQT1 and LQT2 patients without contraindications as a first line measure, whereas primary defibrillator therapy should be recommended for those who experience syncope during medical therapy. (J Cardiovasc Electrophysiol, Vol. 21, pp. 893‐901, August 2010)     

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.     

Long QT syndrome associated with inflammatory degeneration of the stellate ganglia

A well-studied case of intermittent long QT syndrome in a 21-year-old female is presented. Electrophysiologic investigation repeated three times revealed changing sinoatrial and atrioventricular dysfunction and nonsustained ventricular tachycardia. The patient died 29 months after first hospitalization in a stage of electromechanical dissociation after runs of torsade de pointes although she had been treated with repeated anti-inflammatory therapy as well as high doses of propranolol. Postmortem examination demonstrated active inflammation of stellate ganglia. Myocardium appeared normal.     

获得性长QT综合征的心电图分析

目的探讨获得性QT间期延长（LQTS）伴尖端扭转型室速（TdP）的心电图特征、相关病因及诱因。方法选取获得性LQTS伴Tdp发作住院患者19例,观察其QT、QTc间期和TdP发作特征。结果 19例患者QTc间期变动在0.49-0.87s（平均0.63±0.09s）,伴随T波电交替4例,Niagara瀑布样T波3例,Tdp触发方式和发作时间不同。相关诱因和病因包括电解质紊乱8例,缓慢性心律失常7例,药物过量4例。15例患者抢救成功,4例发生院内死亡。结论 LQTs伴Tdp起病急骤,院内死亡率高,了解其心电图特点、相关诱因及其危险因素,及时防范,对于减少院内心脏恶性事件的发生意义重大。     

Microvolt T‐Wave Alternans during Holter Monitoring in Children and Adolescents

Background: Time‐domain microvolt T‐wave alternans (TWA) has been described as a noninvasive marker of sudden cardiac death in adults. The incidence of TWA in pediatric populations has not been defined well. The aim of the study was to determine peculiarities of TWA in children. Methods: We examined 68 healthy patients—newborns (20) and children in age group of 7–17 years (48)—and 85 pediatric patients: ventricular premature beats—65; dilated cardiomyopathy (DCMP)—2; long QT syndrome (LQTS)—10; Brugada syndrome (BrS)—5, catecholaminergic ventricular tachycardia (CVT)—3. All underwent Holter monitoring (HM) with definition of the peak value of TWA by modified moving average method. Results: In healthy newborns, TWA was 32 ± 8 (12–55) μV (HR 123–156 bmp). In healthy children (7–17 years) it was 30 ± 11 (10–l 55) μV, (HR 64–132 bmp) without any differences between boys and girls. In all group of patients, TWA were significantly higher (P < 0.05) than in healthy. Circadian peak of TWA was found (90%) in a second part of day and at sleep (8%). Among them 60% (LQTS, BrS, and DCPM) had TWA > 55 μV. Conclusion: Time‐domain TWA during HM in children was independent of age, gender, and heart rate. In 94% healthy children, values of TWA do not exceed 55 μV but 20–50% children with cardiac pathology had TWA more than 55 μV. Night circadian type of TWA in diseases with risk of life‐threatening arrhythmias associated with TWA was more than 55 μV. Ann Noninvasive Electrocardiol 2010;15(2):138–144     

Sudden Paradoxical QT‐Interval Prolongation Exacerbating T‐Wave Alternans in a Patient with Type 3 Long QT Syndrome

We report a case with type 3 congenital long QT syndrome, who exhibited a sudden paradoxical QT‐interval prolongation during a progressive increase in heart rate, which exacerbated T‐wave alternans.     

Successful Therapeutic Hypothermia in Patients with Congenital Long QT Syndrome

Therapeutic hypothermia has been shown to improve neurological outcomes in patients who remain comatose following resuscitation from cardiac arrest. While there are numerous reports of patients who have had a successful course after induction of therapeutic hypothermia, such therapeutic intervention has not been described in patients with congenital long QT syndrome (LQTS). We report outcomes in two patients with LQTS who had therapeutic hypothermia following a ventricular fibrillation arrest. Careful and routine monitoring of the QT interval in this patient population is necessary due to the potential for worsening electrical instability during induced hypothermia. Ann Noninvasive Electrocardiol 2011;16(1):100–103     

Occult T Wave Alternans in Long QT Syndrome

T Wave Alternans in LQTS. T wave alternans that is visually apparent on the ECG is a known risk factor for sudden death in idiopathic long QT syndrome (LQTS). To determine if occult and visually undetectable forms of T wave alternans are also present in LQTS, we measured T wave alternans from a 16-year-old girl with LQTS during exercise using spectral analysis methods and a recording system designed to minimize exercise-related noise. While there was no alternans at rest, statistically significant, yet visually inapparent T wave alternans were measured both during exercise and recovery. Using identical recording techniques, no significant T wave alternans was detected from the subject's mother, who had a prolonged QT interval but was not experiencing arrhythmias, nor from five healthy volunteers with normal QT intervals. This report suggests that electrocardiographically occult, yet prognostically important forms of T wave alternans may be present in patients with LQTS.     

QT Interval and Long‐Term Mortality Risk in the Framingham Heart Study

Background : The association between QT interval and mortality has been demonstrated in large, prospective population‐based studies, but the strength of the association varies considerably based on the method of heart rate correction. We examined the QT‐mortality relationship in the Framingham Heart Study (FHS). Methods : Participants in the first (original cohort, n = 2,365) and second generation (offspring cohort, n = 4,530) cohorts were included in this study with a mean follow up of 27.5 years. QT interval measurements were obtained manually using a reproducible digital caliper technique. Results : Using Cox proportional hazards regression adjusting for age and sex, a 20 millisecond increase in QTc (using Bazett's correction; QT/RR^1/2 interval) was associated with a modest increase in risk of all‐cause mortality (HR 1.14, 95% CI 1.10–1.18, P < 0.0001), coronary heart disease (CHD) mortality (HR 1.15, 95% CI 1.05–1.26, P = 0.003), and sudden cardiac death (SCD, HR 1.19, 95% CI 1.03–1.37, P = 0.02). However, adjustment for heart rate using RR interval in linear regression attenuated this association. The association of QT interval with all‐cause mortality persisted after adjustment for cardiovascular risk factors, but associations with CHD mortality and SCD were no longer significant. Conclusion : In FHS, there is evidence of a graded relation between QTc and all‐cause mortality, CHD death, and SCD; however, this association is attenuated by adjustment for RR interval. These data confirm that using Bazett's heart rate correction, QTc, overestimates the association with mortality. An association with all‐cause mortality persists despite a more complete adjustment for heart rate and known cardiovascular risk factors.     

Septic cardiomyopathy as a cause of long QT syndrome

A 63-year-old woman admitted with 2:1 infranodal atrioventricular block subsequently developed ventricular dysfunction incident to septic syndrome. Concomitant changes included an abnormally prolonged QTc interval (600 ms) and the occurrence of torsade de pointes. Restoration of a normal QTc interval and cessation of torsade de pointes was coincident with return of normal ventricular function and remission of sepsis. This report supports the view that sepsis-induced cardiomyopathy is another cause of the long QT syndrome.     

Short QT Syndrome

Short QT syndrome (SQTS) is an inheritable primary electrical disease of the heart, discovered in 1999. It is characterized by an abnormally short QT interval (<300 ms) and a propensity to atrial fibrillation and sudden cardiac death (SCD). Like in the case of long QT syndrome there is more than one genetic mutation that can lead to a short QT interval in the ECG and so far two have been identified. Shortening of the effective refractory period combined with increased dispersion of repolarization is the likely substrate for reentry and life threatening tachyarrhythmias. Only 22 people have been classified as having SQTS: 15 from the actual measurement of a short QT interval in their ECG and 7 by history, all having died from SCD. It is very likely that several cases, especially among children, have been overlooked, since the shortness of the QT interval only becomes apparent at heart rates <80 beats/min. The best form of treatment is still not known, but prevention of atrial fibrillation has been accomplished by propafenone, and an implantable cardioverter defibrillator is recommended for prevention of SCD.     

Microvolt T‐Wave Alternans for Risk Stratification in Athletes with Ventricular Arrhythmias: Correlation with Programmed Ventricular Stimulation

Background: Aim of our study is to evaluate the role of T‐wave alternans (TWA) to stratify the risk of sudden cardiac death in athletes (Ath) with complex ventricular arrhythmias (VA), and to document a possible correlation between TWA and electrophysiological testing (EPS) results. Methods : We studied 85 Ath with VA (61 M, mean age 32 ± 11 years). In all cases a cardiological evaluation was performed, including TWA and EPS. The patients were evaluated during a follow‐up of 30 ± 21 months. The end point was the occurrence of sudden death (SD) or malignant ventricular tachyarrhythmias (VT). Results: TWA was negative in 57 Ath (68%), positive in 15 (18%) and indeterminate in 13 (14%). All subjects with negative TWA did not show induction of VT at EPS, with significant correlation between negative TWA and negative EPS (P < 0.001). All Ath with positive TWA also had VT induced by a EPS, with significant correlation (P < 0.001). By contrast, our data did not show significant correlation between indeterminate TWA and positive or negative EPS. However, there was significant correlation between abnormal TWA test (positive + indeterminate) and inducibility of VT at EPS (P < 0.001). During follow‐up we observed a significant difference in end point occurrence (VT or SD) between Ath with negative or abnormal TWA and between Ath with negative or positive EPS. Conclusion: TWA confirm its role as a simple and noninvasive test, and it seems useful for prognostic stratification of Ath with VA.     

Assessment of Physiological Amplitude,Duration, and Magnitude of ECG T‐Wave Alternans

Background: An association between T‐wave alternans (TWA) and malignant ventricular arrhythmias is generally recognized. Because relatively low levels of TWA have also been observed in healthy (H) subjects, the question arises as to whether these are ascribable to noise and artifacts, or can be given the relevance of a physiological phenomenon characterizing a preclinical condition. Methods: To answer this question, in the present study 20‐minute not noisy, sinus ECG recordings, from 138 H‐subjects and 148 coronary artery diseased (CAD) patients, were submitted to our adaptive match filter (AMF) procedure to identify and parameterize TWA in terms of duration (TWAD), amplitude (TWAA), and magnitude (TWAM, defined as the product of TWAD times TWAA). The 99.5th percentiles of mean values of TWAA, TWAD, and TWAM over 20‐minute ECGs were used to define three threshold levels (THRD, THRA, and THRM), which allow discrimination of abnormal TWA levels. Results: Nonstationary TWA was found in all our H‐subjects and CAD‐patients. TWAD, TWAA, and TWAM levels were classified as being physiological in 99% of H‐subjects and 87% of CAD‐patients. A linear correlation (r =?0.52, P < 0.001) was found between TWAA and RR interval in the H‐population. Conclusions: Our results support the hypothesis of the existence of physiological TWA levels, which are to be considered in the effort to improve reliability of nonphysiological TWA levels discrimination.     

Cardiac Pacing in the Long QT Syndrome:

Cardiac Pacing in the Long QT Syndrome. A review of published data on cardiac pacing in the long QT syndrome (LQTS) is presented, in the hope that optimization of patient selection and pacemaker programming will prevent arrhythmic death. LQT3 patients may derive particular benefit from pacing because the dispersion of repolarization worsens steeply during bradycardia in this genotype. However, concluding that other genotypes will not benefit from pacing is premature. Pacing may he especially beneficial for patients with "pause-dependent" arrhythmias. Programming should include a sufficiently fast lower rate limit. Features that allow heart rate slowing beyond the lower rate limit or that may trigger pauses must he programmed "off" because pauses are proarrhythmic in this population. Pause-prevention pacing algorithms may he beneficial.     

Identification of Gender‐Related Normality Regions for T‐Wave Alternans

Background: T‐wave alternans (TWA), a harbinger of sudden cardiac death, associates to a broad variety of pathologies. In a previous study, we observed the presence of unstable and low‐amplitude TWA also in healthy subjects, and considered it as “physiological TWA.” The possible existence of different TWA characteristics between males and female is investigated in the present work. Methods: Resting ECG recordings from 142 control healthy subjects, 77 males and 65 females, were submitted to our adaptive match filter (AMF) based method for TWA detection and characterization in terms of duration, amplitude, and their product. The 99.5th percentile of these parameters distributions over the entire control population and over the male and female subgroups, were used to define thresholds which delimit a gender‐independent and male‐ and female‐related TWA normality regions, respectively, out of which abnormal TWA cases (TWA+) are expected to fall. Clinical usefulness of these regions was tested using a population of 151 coronary artery disease (CAD) patients, divided into 128 males and 23 females. Results: In our control‐female population, TWA duration was significantly longer than in control‐male population (65 ± 13 beat vs 52 ± 14 beat; P < 10^?6). Our gender‐related normality regions allowed identification of 36 (23.8%) TWA+ cases among the CAD patients, 17 more than those obtained from a gender‐independent region. All these 17 patients were CAD males with over‐threshold TWA duration. Conclusions: TWA is a gender‐related phenomenon. Definition of gender‐related TWA normality regions improves identification of patients at increased TWA stability (i.e., prolonged TWA duration) and, thus, at increased risk of arrhythmic events. Ann Noninvasive Electrocardiol 2010;15(4):328‐336