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.

Paediatric and adult congenital cardiology education and training in Europe.

BACKGROUND: Limited data exist on training of European paediatric and adult congenital cardiologists. METHODS: A structured and approved questionnaire was circulated to national delegates of Association for European Paediatric and Congenital Cardiology in 33 European countries. RESULTS: Delegates from 30 countries (91%) responded. Paediatric cardiology was not recognised as a distinct speciality by the respective ministry of Health in seven countries (23%). Twenty countries (67%) have formally accredited paediatric cardiology training programmes, seven (23%) have substantial informal (not accredited or certified) training, and three (10%) have very limited or no programme. Twenty-two countries have a curriculum. Twelve countries have a national training director. There was one paediatric cardiology centre per 2.66 million population (range 0.87-9.64 million), one cardiac surgical centre per 4.73 million population (range 1.63-10.72 million), and one training centre per 4.29 million population (range 1.63-10.72 million population). The median number of paediatric cardiology fellows per training programme was 4 (range 1-17), and duration of training was 3 years (range 2-5 years). An exit examination in paediatric cardiology was conducted in 16 countries (53%) and certification provided by 20 countries (67%). Paediatric cardiologist number is affected by gross domestic product (R2 = 0.41). CONCLUSION: Training varies markedly across European countries. Although formal fellowship programmes exist in many countries, several countries have informal training or no training. Only a minority of countries provide both exit examination and certification. Harmonisation of training and standardisation of exit examination and certification could reduce variation in training thereby promoting high-quality care by European congenital cardiologists.

Mutation location and IKs regulation in the arrhythmic risk of long QT syndrome type 1: the importance of the KCNQ1 S6 region.

AIMS: Mutation type, location, dominant-negative IKs reduction, and possibly loss of cyclic adenosine monophosphate (cAMP)-dependent IKs stimulation via protein kinase A (PKA) influence the clinical severity of long QT syndrome type 1 (LQT1). Given the malignancy of KCNQ1-p.A341V, we assessed whether mutations neighbouring p.A341V in the S6 channel segment could also increase arrhythmic risk. METHODS AND RESULTS: Clinical and genetic data were obtained from 1316 LQT1 patients [450 families, 166 unique KCNQ1 mutations, including 277 p.A341V-positive subjects, 139 patients with p.A341-neighbouring mutations (91 missense, 48 non-missense), and 900 other LQT1 subjects]. A first cardiac event represented the primary endpoint. S6 segment missense variant characteristics, particularly cAMP stimulation responses, were analysed by cellular electrophysiology. p.A341-neighbouring mutation carriers had a QTc shorter than p.A341V carriers (477 ± 33 vs. 490 ± 44 ms) but longer than the remaining LQT1 patient population (467 ± 41 ms) (P < 0.05 for both). Similarly, the frequency of symptomatic subjects in the p.A341-neighbouring subgroup was intermediate between the other two groups (43% vs. 73% vs. 20%; P < 0.001). These differences in clinical severity can be explained, for p.A341V vs. p.A341-neighbouring mutations, by the p.A341V-specific impairment of IKs regulation. The differences between the p.A341-neighbouring subgroup and the rest of LQT1 mutations may be explained by the functional importance of the S6 segment for channel activation. CONCLUSION: KCNQ1 S6 segment mutations surrounding p.A341 increase arrhythmic risk. p.A341V-specific loss of PKA-dependent IKs enhancement correlates with its phenotypic severity. Cellular studies providing further insights into IKs-channel regulation and knowledge of structure-function relationships could improve risk stratification. These findings impact on clinical management.

Video-assisted thoracoscopic pacemaker lead placement in children with atrioventricular block.

BACKGROUND: The pacemaker lead placement is presented as one of the most appropriate procedures in children with a complete atrioventricular block (AVB). Despite the fact that video-assisted thoracic surgery (VATS) for epicardial lead placement has demonstrated positive results as to the feasibility, safety, and efficacy in adults, its role in pacemaker implantation in children remains unclear. AIM: This study sought to assess the intermediate-term outcomes of video-assisted thoracoscopic pacemaker lead placement in children with complete AVB. MATERIALS AND METHODS: From May 2017 to November 2019, five children with complete AVB underwent minimally invasive left ventricular (LV) lead placements via thoracoscopic video assistance approach. The procedure was performed under complex intratracheal anesthesia with single-lung ventilation, all pacing parameters were evaluated in perioperative and follow-up periods. RESULTS: The median age of children at implantation was 3 years (range: 2 to 4 years), the median weight was 13 kg (range: 12-15 kg). All procedures were completed successfully, pacing thresholds for the active lead measured 0.3-1.1V, with R-wave amplitude of 8-18 mV and impedance of 560-1478 Ohm. CONCLUSION: Thoracoscopic pacemaker lead placement may provide a potential alternative to the transthoracic approach of epicardial lead placement in children with AVB.

Prevalence, correlates, and mortality impacts of ventricular arrhythmia among older men and women: a population-based cohort study in Moscow.

BACKGROUND: In Russia, cardiovascular disease (CVD) mortality is high and the mortality gap between men and women is large. Conventional risk factors cannot explain these phenomena. Ventricular arrhythmia (VA) is an important contributor to the death toll in community-based populations. The study examines the prevalence and the mortality impacts of VA in men and women and the role of VA in the male mortality excess at older ages. METHODS: This is a secondary analysis of data from the Stress, Aging, and Health in Russia (SAHR) study that was fielded in 2007-9 in Moscow (1800 individuals, mean age 68.8 years), with mean mortality follow-up of 7.4 years (416 deaths, 248 CVD deaths). Indicators reflecting the frequency and the complexity of VA were derived from 24-h ambulatory ECG recordings. Other covariates were: socio-demographic characteristics, conventional risk factors, markers of inflammation, reported myocardial infarction, and stroke. The impacts of VA and other variables on CVD and all-cause mortality among men and women were estimated with the proportional hazard models. We assessed the contributions of VAs to the male-female mortality gap using hazard models that do and do not include groups of the predictors. Logistic models were used to assess the associations between VA and other biomarkers. RESULTS: VAs were about twice as prevalent among men as among women. In both sexes, they were significantly associated with CVD and all-cause mortality independently of conventional risk factors. The highest hazard ratios (HRs) for CVD death were found for the runs of ventricular premature complexes (VPCs) HR = 2.45, 95% CI 1.63-3.68 for men and 2.75, 95% CI 1.18-6.40 for women. The mortality impacts of the polymorphic VPCs were significant among men only (HR = 1.50, 95% CI 1.08-2.07). VA indicators can potentially explain 12.3% and 9.1% of the male-female gaps in mortality from CVD and all causes, respectively. VAs were associated with ECG-registered ischemic problems and reported MI, particularly among men. CONCLUSIONS: VA indicators predicted mortality in older Muscovites independently of other risk factors, and have the potential to explain a non-trivial share of the excess male mortality. The latter may be related to more severe coronary problems in men compared to women.

Atrial fibrillation among Russian men and women aged 55 years and older: prevalence, mortality, and associations with biomarkers in a population-based study.

OBJECTIVE: To examine the prevalence of atrial fibrillation (AF), its impacts on cardiovascular disease (CVD) and all-cause mortality, and the associations between AF and inflammatory and serum biomarkers in a population-based sample of Muscovites. METHODS: The study is a secondary analysis of data from the Stress, Aging and Health in Russia (SAHR) survey that includes information on 1800 individuals with an average age of 68.5 years at baseline, and on their subsequent mortality during 7.4 years on average. AF is detected by 12-lead electrocardiogram (ECG) and 24-hour Holter monitoring. The statistical analysis includes proportional hazard and logistic regression models. RESULTS: Of the 1732 participants with relevant Holter data, AF was detected in 100 (74 by ECG and Holter, 26 by Holter only). The prevalence of AF was 5.8% for men and 7.4% for women. The fully adjusted model showed strongly elevated hazard of CVD and all-cause mortality in men and women with long non-self-limiting AF (LAF). LAF was found to be negatively associated with elevated total and low-density lipoprotein cholesterol and to be positively associated with elevated markers of inflammation in women. CONCLUSIONS: The study assessed for the first time the prevalence and the risks of death related to AF among older Russians. LAF was shown to be a strong and independent predictor of CVD and all-cause mortality. AF is unlikely to contribute to the large excess male mortality in Russia. The finding that one-quarter of AF cases were detected only by Holter monitoring demonstrates the usefulness of diagnostics with prolonged ECG registration.

Handgrip strength and its prognostic value for mortality in Moscow, Denmark, and England.

BACKGROUND: This study compares handgrip strength and its association with mortality across studies conducted in Moscow, Denmark, and England. MATERIALS: The data collected by the Study of Stress, Aging, and Health in Russia, the Study of Middle-Aged Danish Twins and the Longitudinal Study of Aging Danish Twins, and the English Longitudinal Study of Ageing was utilized. RESULTS: Among the male participants, the age-standardized grip strength was 2 kg and 1 kg lower in Russia than in Denmark and in England, respectively. The age-standardized grip strength among the female participants was 1.9 kg and 1.6 kg lower in Russia than in Denmark and in England, respectively. In Moscow, a one-kilogram increase in grip strength was associated with a 4% (hazard ratio [HR] = 0.96, 95% confidence interval [CI]: 0.94, 0.99) reduction in mortality among men and a 10% (HR = 0.90, 95%CI: 0.86, 0.94) among women. Meanwhile, a one-kilogram increase in grip strength was associated with a 6% (HR = 0.94, 95%CI: 0.93, 0.95) and an 8% (HR = 0.92, 95%CI: 0.90, 0.94) decrease in mortality among Danish men and women, respectively, and with a 2% (HR = 0.98, 95%CI: 0.97, 0.99) and a 3% (HR = 0.97, 95%CI: 0.95, 0.98) reduction in mortality among the English men and women, respectively. CONCLUSION: The study suggests that, although absolute grip strength values appear to vary across the Muscovite, Danish, and English samples, the degree to which grip strength is predictive of mortality is comparable across national populations with diverse socioeconomic and health profiles and life expectancy levels.

Sex Differences in Biological Markers of Health in the Study of Stress, Aging and Health in Russia.

BACKGROUND: The apparent contradiction that women live longer but have worse health than men, the so called male-female health-survival paradox, is very pronounced in Russia. The present study investigates whether men in Moscow are healthier than women at the level of biomarkers, and whether the associations between biomarkers and subjective health have sex-specific patterns. MATERIALS: Previously collected data in the study of Stress, Aging, and Health in Russia (SAHR, n = 1800) were used to examine sex differences in biomarkers and their associations with physical functioning and self-rated health. RESULTS: The present study found mixed directions and magnitudes for sex differences in biomarkers. Women were significantly disadvantaged with regard to obesity and waist circumference, whereas men had a tendency toward higher prevalence of electrocardiographic abnormalities. No sex differences were indicated in the prevalence of immunological biomarkers, and mixed patterns were found for lipid profiles. Many biomarkers were associated with physical functioning and general health. Obesity and waist circumference were related to lower physical functioning among females only, while major Q-wave abnormalities with high probabilities of myocardial infarction and atrial fibrillation or atrial flutter were associated with physical functioning and self-rated health among males only. CONCLUSION: No clear patterns of sex differences in prevalence of high-risk levels of biomarkers suggest that the male-female health-survival paradox is weaker at the level of health biomarkers. We found some evidence that certain biomarkers reflecting pathophysiological changes in the organism that do not possess acute health risks, but over many years may lead to physical disability, are associated with physical functioning and self-rated health in women, whereas others reflecting more serious life-threatening pathophysiological changes are associated with physical functioning and self-rated health in men.

Clinical Management of Catecholaminergic Polymorphic Ventricular Tachycardia: The Role of Left Cardiac Sympathetic Denervation.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic disorder causing life-threatening arrhythmias whenever sympathetic activity increases. ß-Βlockers are the mainstay of therapy; when they fail, implantable cardioverter-defibrillators (ICDs) are used but often cause multiple shocks. Preliminary results with flecainide appear encouraging. We proposed left cardiac sympathetic denervation (LCSD) as useful additional therapy, but evidence remains anecdotal. METHODS AND RESULTS: We report 63 patients with CPVT who underwent LCSD as secondary (n=54) or primary (n=9) prevention. The median post-LCSD follow-up was 37 months. The 9 asymptomatic patients remained free of major cardiac events. Of the 54 patients with prior major cardiac events either on (n=38) or off (n=16) optimal medical therapy, 13 (24%) had at least 1 recurrence: 0 patients had an aborted cardiac arrest, 2 patients had syncope only, 10 patients had ≥1 appropriate ICD discharges, and 1 patient died suddenly. The 1- and 2-year cumulative event-free survival rates were 87% and 81%. The percentage of patients with major cardiac events despite optimal medical therapy (n=38) was reduced from 100% to 32% (P<0.001) after LCSD, and among 29 patients with a presurgical ICD, the rate of shocks dropped by 93% from 3.6 to 0.6 shocks per person per year (P<0.001). Patients with an incomplete LCSD (n=7) were more likely to experience major cardiac events after LCSD (71% versus 17%; P<0.01) than those with a complete LCSD. CONCLUSIONS: LCSD is an effective antifibrillatory intervention for patients with CPVT. Whenever syncope occurs despite optimal medical therapy, LCSD could be considered the next step rather than an ICD and could complement ICDs in patients with recurrent shocks.

Recalibration of the SCORE risk chart for the Russian population.

Persisting high levels of cardiovascular mortality in Russia present a specific case among developed countries. Application of cardiovascular risk prediction models holds great potential for primary prevention in this country. Using a unique set of cohort follow-up data from Moscow and Saint Petersburg, this study aims to test and recalibrate the Systematic Coronary Risk Evaluation (SCORE) methods for predicting CVD mortality risks in the general population. The study is based on pooled epidemiological cohort data covering the period 1975-2001. The algorithms from the SCORE project were used for the calibration of the SCORE equation for the Moscow and St. Petersburg populations (SCORE-MoSP). Age-specific 10-year cumulative cardiovascular mortality rates were estimated according to the original SCORE-High and SCORE-Low equations and compared to the estimates based on the recalibrated SCORE-MoSP model and observed CVD mortality rates. Ten-year risk prediction charts for CVD mortality were derived and compared using conventional SCORE-High and recalibrated SCORE-MoSP methods. The original SCORE-High model tends to substantially under-estimate 10-year cardiovascular mortality risk for females. The SCORE-MoSP model provided better results which were closer to the observed rates. For males, both the SCORE-High and SCORE-MoSP provided similar estimates which tend to under-estimate CVD mortality risk at younger ages. These differences are also reflected in the risk prediction charts. Using non-calibrated scoring models for Russia may lead to substantial under-estimation of cardiovascular mortality risk in some groups of individuals. Although the SCORE-MoSP provide better results for females, more complex scoring methods involving a wider range of risk factors are needed.

Latent time-varying factors in longitudinal analysis: a linear mixed hidden Markov model for heart rates.

Longitudinal data are often segmented by unobserved time-varying factors, which introduce latent heterogeneity at the observation level, in addition to heterogeneity across subjects. We account for this latent structure by a linear mixed hidden Markov model. It integrates subject-specific random effects and Markovian sequences of time-varying effects in the linear predictor. We propose an expectationU-maximization algorithm for maximum likelihood estimation, based on data augmentation. It reduces to the iterative maximization of the expected value of a complete likelihood function, derived from an augmented dataset with case weights, alternated with weights updating. In a case study of the Survey on Stress Aging and Health in Russia, the model is exploited to estimate the influence of the observed covariates under unobserved time-varying factors, which affect the cardiovascular activity of each subject during the observation period.

Perceived stress and biological risk: is the link stronger in Russians than in Taiwanese and Americans?

Allostatic load theory implies a relationship between exposure to psychological stress and multi-system physiological dysregulation. We used data from population-based samples of men and women in Russia (Moscow; n = 1800; age, mean 68.6 years), Taiwan (n = 1036; 65.6 years) and the United States (US; n = 1054; 58.0 years) -- which are likely to vary widely with respect to levels of stress exposure and biological markers -- to determine the magnitude of the association between perceived stress and physiological dysregulation. The measure of overall dysregulation was based on 15 markers including standard cardiovascular/metabolic risk factors as well as markers of inflammation and neuroendocrine activity. Subjective psychological stress was measured by the perceived stress scale. Only the Moscow sample demonstrated a positive association with overall dysregulation in both sexes. In the US, we found an association among women but not men. Among the Taiwanese, who report the lowest perceived stress, there was no association in women but an unexpected inverse relationship in men. The effects also varied across system-level subscores: the association with perceived stress was most consistent for standard cardiovascular/metabolic factors. Perceived stress was associated with inflammation and neuroendocrine activity in some samples. Although the evidence that perceived stress is the primary source of physiological dysregulation is generally modest, it was stronger in Russia where the level of perceived stress was particularly high. For Russia only, we had information about heart function based on a 24 h ambulatory electrocardiogram; perceived stress was consistently associated with heart rate dysregulation in Russian men and women.

To what extent do biomarkers account for the large social disparities in health in Moscow?

The Russian population continues to face political and economic challenges, has experienced poor general health and high mortality for decades, and has exhibited widening health disparities. The physiological factors underlying links between health and socioeconomic position in the Russian population are therefore an important topic to investigate. We used data from a population-based survey of Moscow residents aged 55 and older (n = 1495), fielded between December 2006 and June 2009, to address two questions. First, are social disparities evident across different clusters of biomarkers? Second, does biological risk mediate the link between socioeconomic status and health? Health outcomes included subscales for general health, physical function, and bodily pain. Socioeconomic status was represented by education and an index of material resources. Biological risk was measured by 20 biomarkers including cardiovascular, inflammatory, and neuroendocrine markers as well as heart rate parameters from 24-h ECG monitoring. For both sexes, the age-adjusted educational disparity in standard cardiovascular risk factors was substantial (men: standardized ß = -0.16, 95% CI = -0.23 to -0.09; women: ß = -0.25, CI = -0.32 to -0.18). Education differences in inflammation were also evident in both men (ß = -0.17, CI = -0.25 to -0.09) and women (ß = -0.09, CI = -0.17 to -0.01). Heart rate parameters differed by education only in men (ß = -0.10, CI = -0.18 to -0.02). The associations between material resources and biological risk scores were generally weaker than those for education. Social disparities in neuroendocrine markers were negligible for men and women. In terms of mediating effects, biological risk accounted for more of the education gap in general health and physical function (19-36%) than in bodily pain (12-18%). Inclusion of inflammatory markers and heart rate parameters-which were important predictors of health outcomes-may explain how we accounted for more of the social disparities than previous studies.

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 ß-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.

Prevalence, components, and correlates of metabolic syndrome (MetS) among elderly Muscovites.

The goal of this study is to estimate the prevalence of MetS, together with its components and correlates, among elderly Russians. Our population-based sample included randomly selected residents of Moscow aged 55 and older: 955 women with an average age of 67.6, and 833 men with an average age of 68.9. MetS was defined according to National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII). The prevalence of MetS was found to be 41.7% in women and 26.8% in men. It tended to decrease with age in men, but not in women. MetS was inversely related to education in women, but not in men. The most prevalent individual components of MetS were as follows: hypertension (64.4%), abdominal obesity (55%), and decreased high density lipoprotein cholesterol (HDL C) (46%) for women; and hypertension (71%) and fasting hyperglycemia (35.2%) for men. An elevated level of triglycerides (TG) was the rarest MetS component, affecting 23.5% of women and 22.1% of men. The higher female prevalence of MetS was attributable to abdominal obesity. MetS was found to be associated with markers of insulin resistance (IR), low-grade inflammation, and insufficient fibrinolysis. Although the metabolic burden is an important contributor to high levels of ill-health and cardiovascular mortality among elderly Russians (especially women), it does not explain why cardiovascular mortality is much higher in Russia than in other industrialized countries.

Biological mechanisms of disease and death in Moscow: rationale and design of the survey on Stress Aging and Health in Russia (SAHR).

BACKGROUND: Prior research has revealed large differences in health and mortality across countries, socioeconomic groups, and individuals. Russia experiences one of the world's highest levels of all-cause and cardiovascular mortality, great mortality differences within the population, and a heavy burden of ill health. Psychological stress has been suggested as a likely explanation of health loss and premature death in Russia and Eastern Europe. However, physiological mechanisms connecting stress with health in Russia remain unclear since existing epidemiological data are scarce and limited to conventional risk factors. METHOD AND DESIGN: The survey on Stress Aging and Health in Russia (SAHR) is addressing this knowledge gap by collecting an unusually rich database that includes a wide range of reported information, physical and cognitive health outcomes, and biomarkers in a sample of Muscovite men and women aged 55 and older. The total planned sample size is 2,000 individuals. The sample was randomly selected from epidemiological cohorts formed in Moscow between the mid-1970s and the 1990s and from medical population registers. The baseline data collection was carried out from December 2006 to June 2009. Interviews and medical tests were administered at hospital or at home according to standardized protocol. Questionnaire information includes health, socio-demographic characteristics, economic well-being, cognitive functioning, and batteries on stress and depression. Biomarkers include anthropometry, grip strength, resting ECG, conventional cardiovascular factors of risk such as lipid profile and blood pressure, and other biochemical parameters such as those related to inflammation, glucose and insulin resistance, coagulation, fibrinolysis, and stress hormones. In addition to these measurements, SAHR includes dynamic biomarkers provided by 24-hour ECG (Holter) monitoring. This method continuously registers the beat-to-beat heart rate in naturalistic conditions without restrictions on normal daily activities. It provides information about heart functioning, including heart rate variability and ischemic and arrhythmic events.Re-examination of the study subjects will be conducted in 2009-2011 and will focus on health, functional status, economic conditions, behaviors, and attitudes towards aging. The subjects are also followed up for mortality and non-fatal health events. DISCUSSION: The SAHR will produce a valuable set of established and novel biomarkers combined with self-reported data for the international research community and will provide important insights into factors and biological mechanisms of mortality and health losses in Russia.

The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome.

BACKGROUND: Data on the Jervell and Lange-Nielsen syndrome (J-LN), the long-QT syndrome (LQTS) variant associated with deafness and caused by homozygous or compound heterozygous mutations on the KCNQ1 or on the KCNE1 genes encoding the I(Ks) current, are still based largely on case reports. METHODS AND RESULTS: We analyzed data from 186 J-LN patients obtained from the literature (31%) and from individual physicians (69%). Most patients (86%) had cardiac events, and 50% were already symptomatic by age 3. Their QTc was markedly prolonged (557+/-65 ms). Most of the arrhythmic events (95%) were triggered by emotions or exercise. Females are at lower risk for cardiac arrest and sudden death (CA/SD) (hazard ratio, 0.54; 95% CI, 0.34 to 0.88; P=0.01). A QTc >550 ms and history of syncope during the first year of life are independent predictors of subsequent CA/SD. Most mutations (90.5%) are on the KCNQ1 gene; mutations on the KCNE1 gene are associated with a more benign course. beta-Blockers have only partial efficacy; 51% of the patients had events despite therapy and 27% had CA/SD. CONCLUSIONS: J-LN syndrome is a most severe variant of LQTS, with a very early onset and major QTc prolongation, and in which beta-blockers have limited efficacy. Subgroups at relatively lower risk for CA/SD are identifiable and include females, patients with a QTc < or =550 ms, those without events in the first year of life, and those with mutations on KCNE1. Early therapy with implanted cardioverter/defibrillators must be considered.