Clinical and molecular genetics of the short QT syndrome

Schimpf, Rainer; Borggrefe, Martin; Wolpert, Christian

doi:10.1097/hco.0b013e3282fbf756

Cited by 63 publications

(44 citation statements)

References 48 publications

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“…death (Schimpf et al 2008), and reduced HRV is also a known risk factor for cardiovascular events (Tsuji et al 1996). Whether a decrease from high doses of stimulants can have enduring effects on cardiac sympathetic function via altered striatal DAT and whether a dose reduction or discontinuation can possibly affect the QT interval may be worthy of further investigations.…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular Safety of Stimulants in Children with Attention-Deficit/Hyperactivity Disorder: A Nationwide Prospective Cohort Study

Dalsgaard

Kvist

Leckman

et al. 2014

Journal of Child and Adolescent Psychopharmacology

100

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Objective: The purpose of this study was to determine whether stimulant users are at higher risk of a later cardiovascular event than are non-users, examining this association in both a national cohort and a population-based sample of children and adolescents diagnosed with attention-deficit/hyperactivity disorder (ADHD). We also aim to examine a possible doseresponse relationship in such an association. Methods: We conducted a longitudinal, prospective cohort study of all children born in Denmark between 1990 and 1999. Within this cohort, children with ADHD were identified. Data from national health registers on psychiatric and somatic diagnoses, stimulant prescriptions, cardiovascular risk factors, pre-and perinatal and sociodemographic covariates in all children and their parents were merged, using the unique personal identification number. Hazard ratios (HR) for cardiovascular events were estimated using Cox regression, adjusted for other known risk factors. Results: In the total population (n = 714,258 contributing a total of 6,767,982 person-years) use of stimulants increased the risk of a cardiovascular event; adjusted HR = 1.83 (1.10-3.04). In children with ADHD (n = 8300) stimulant treatment also increased the risk of a cardiovascular event (adjusted HR = 2.20 [2.15-2.24]), with a complex time-dependent dose-response relationship. Conclusions: This is the first nationwide cohort study of the cardiovascular safety of stimulants in children and adolescents, and it represents, to our knowledge, the longest prospective follow-up study. Cardiovascular events were rare but twice as likely in stimulant users as in non-users, both in the total national population and in children with ADHD. We found a complex, time-and dose-dependent interrelationship between cardiovascular adverse events and stimulant treatment in children and adolescents. Our results suggest a safety signal with an increased risk of cardiovascular disease associated with stimulant treatment in children and adolescents, even after adjusting for a number of potential confounders.

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Section: Discussionmentioning

confidence: 99%

Cardiovascular Safety of Stimulants in Children with Attention-Deficit/Hyperactivity Disorder: A Nationwide Prospective Cohort Study

Dalsgaard

Kvist

Leckman

et al. 2014

Journal of Child and Adolescent Psychopharmacology

100

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“…[24][25][26] Likewise, little is known about the significance of acquired, e.g., drug-induced shortening of QTc and therapeutic consequences are uncertain. 23,27,28 Primidone and rufinamide can both shorten QTc, 29,30 but these drugs were not used in our patients. Although the use of carbamazepine could have influenced our results, this drug is associated with bradyarrhythmias and has only minor effects on QT intervals.…”

Section: Methodsmentioning

confidence: 99%

“…Shortening of QT is substantially mediated by circulating catecholamines and can be enhanced by hyperkalemia and acidosis. 23,27,28,33 All these conditions occur particularly during or shortly after GTCS. 18,19,34 Furthermore, chronic epilepsy patients display altered autonomic function with a presumably increased sympathetic tone and enhanced QT dispersion (spatial heterogeneity of cardiac repolarization), which are both independent predictors of cardiac mortality.…”

Section: Methodsmentioning

confidence: 99%

“…Short QTc syndrome with a genetic etiology has only recently been described. 23 Mutations in cardiac voltagegated potassium and calcium channels shorten QTc and thereby reduce ventricular refractory period as a potential cause for life-threatening re-entry ventricular tachyarrhythmia. Clinical data on the predictive value of short QT in otherwise healthy populations are, however, controversial.…”

Section: Methodsmentioning

confidence: 99%

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Enhanced QT shortening and persistent tachycardia after generalized seizures

Surges¹,

Scott²,

Walker³

2010

Neurology

139

111

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Objective: Generalized tonic-clonic seizures (GTCS) are a major risk factor for sudden unexpected death in epilepsy (SUDEP). We investigated whether ictal/postictal cardiac features were dependent on seizure type within individual patients.Methods: ECG data from patients with medically refractory temporal lobe epilepsy (TLE) undergoing presurgical investigation who had both complex partial seizures and secondarily GTCS during video-EEG telemetry were retrospectively reviewed. Peri-ictal heart rate (HR), corrected QT interval (QTc), HR variability, and cardiac rhythm were assessed.Results: Twenty-five patients were included in this study. Secondarily GTCS led to higher ictal HR, persistent postictal tachycardia, and decreased postictal HR variability. Moreover, abnormal shortening of QTc occurred in 17 patients mainly during the early postictal phase and significantly more often in secondarily GTCS. Abnormal QTc prolongation occurred in 3 patients with no significant association with GTCS. Benign cardiac arrhythmias occurred in 14 patients and were independent of seizure type. Conclusions:Our data suggest a substantial disturbance of autonomic function following secondarily generalized tonic-clonic seizures (GTCS) in patients with medically refractory temporal lobe epilepsy. The observed alterations could potentially facilitate sudden cardiac death and might contribute to the association of sudden unexpected death in epilepsy with GTCS. Neurology ® 2010;74:421-426 GLOSSARY CI ϭ confidence interval; CPS ϭ complex partial seizure; GTCS ϭ generalized tonic-clonic seizures; HR ϭ heart rate; HRV ϭ HR variability; QTc ϭ corrected QT interval; SUDEP ϭ sudden unexpected death in epilepsy; TLE ϭ temporal lobe epilepsy.Sudden unexpected death in epilepsy (SUDEP) is the most frequent epilepsy-related cause of death and is particularly prevalent in patients with chronic epilepsy.1 In younger people with epilepsy (age 20 -40 years), the risk for sudden death is increased about 24-fold compared to the general population.2 Peri-ictal cardiorespiratory alterations are likely to be involved in the pathophysiology of SUDEP and include tachyarrhythmias and bradyarrhythmias as well as central or obstructive hypoventilation and neurogenic pulmonary edema.1 Since generalized tonic-clonic seizures (GTCS) are a major risk factor for SUDEP, 3,4 then determining the specific cardiac characteristics of GTCS may give us a considerable insight into the mechanisms underlying SUDEP. Abnormalities in cardiac repolarization, persistent elevations of heart rate (HR) after exercise, and a decreased HR variability (HRV) are established predictors for cardiac mortality and sudden cardiac death in other medical conditions or in healthy populations. [5][6][7] Previous studies have suggested a greater impact of GTCS on cardiac excitability than nongeneralized seizures with higher ictal heart rates in chronic epilepsy and SUDEP patients 4,[8][9][10][11] and possibly more cardiac arrhythmias following GTCS. 8,10 These studies, however, are confou...

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“…By contrast, reggae (reg) mutants have a kcnh2 gain-of-function mutation leading to accelerated repolarization and, thus, can be considered a model for human short QT syndrome . Interestingly, reg mutants present with paroxysmal atrial fibrillation, a condition that has been found in human short QT syndrome (Schimpf et al, 2008). Slow mo (smo) is a mutant that is characterized by bradycardia (a slow heart rate).…”

Section: Primer Arrhythmiasmentioning

confidence: 99%

Fishing for the genetic basis of cardiovascular disease

Dahme

Katus

Rottbauer

2009

Disease Models &Amp; Mechanisms

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Cardiovascular disease (CVD) has recently overtaken infectious disease to become the biggest global killer. Genetic factors have emerged as being of major importance in the pathogenesis of CVD. Owing to disease heterogeneity, variable penetrance and high mortality, human genetic studies alone are not sufficient to elucidate the genetic basis of CVD. Animal models are needed to identify novel genes that are involved in cardiovascular pathology and to verify the effect of suspected disease genes on cardiovascular function. An intriguing model organism is the zebrafish danio rerio. Several features of the zebrafish, such as a closed cardiovascular system, transparency at embryonal stages, rapid and external development, and easily tractable genetics make it ideal for cardiovascular research. Moreover, zebrafish are suitable for forward genetics approaches, which allow the unbiased identification of novel and unanticipated cardiovascular genes. Zebrafish mutants with various cardiovascular phenotypes that closely correlate with human disease, such as congenital heart disease, cardiomyopathies and arrhythmias, have been isolated. The pool of zebrafish mutants, for which the causal gene mutation has been identified, is constantly growing. The human orthologues of several of these zebrafish genes have been shown to be involved in the pathogenesis of human CVD. Cardiovascular zebrafish models also provide the opportunity to develop and test novel therapeutic strategies, using innovative technologies such as high throughput in vivo small molecule screens.

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Clinical and molecular genetics of the short QT syndrome

Cited by 63 publications

References 48 publications

Cardiovascular Safety of Stimulants in Children with Attention-Deficit/Hyperactivity Disorder: A Nationwide Prospective Cohort Study

Cardiovascular Safety of Stimulants in Children with Attention-Deficit/Hyperactivity Disorder: A Nationwide Prospective Cohort Study

Enhanced QT shortening and persistent tachycardia after generalized seizures

Fishing for the genetic basis of cardiovascular disease

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