C. N. Lang

Transgenic rabbit models to investigate the cardiac ion channel disease long QT syndrome

Long QT syndrome (LQTS) is a rare inherited channelopathy caused mainly by different mutations in genes encoding for cardiac K(+) or Na(+) channels, but can also be caused by commonly used ion-channel-blocking and QT-prolonging drugs, thus affecting a much larger population. To develop novel diagnostic and therapeutic strategies to improve the clinical management of these patients, a thorough understanding of the pathophysiological mechanisms of arrhythmogenesis and potential pharmacological targets is needed. Drug-induced and genetic animal models of various species have been generated and have been instrumental for identifying pro-arrhythmic triggers and important characteristics of the arrhythmogenic substrate in LQTS. However, due to species differences in features of cardiac electrical function, these different models do not entirely recapitulate all aspects of the human disease. In this review, we summarize advantages and shortcomings of different drug-induced and genetically mediated LQTS animal models - focusing on mouse and rabbit models since these represent the most commonly used small animal models for LQTS that can be subjected to genetic manipulation. In particular, we highlight the different aspects of arrhythmogenic mechanisms, pro-arrhythmic triggering factors, anti-arrhythmic agents, and electro-mechanical dysfunction investigated in transgenic LQTS rabbit models and their translational application for the clinical management of LQTS patients in detail. Transgenic LQTS rabbits have been instrumental to increase our understanding of the role of spatial and temporal dispersion of repolarization to provide an arrhythmogenic substrate, genotype-differences in the mechanisms for early afterdepolarization formation and arrhythmia maintenance, mechanisms of hormonal modification of arrhythmogenesis and regional heterogeneities in electro-mechanical dysfunction in LQTS.

Phase-contrast magnet resonance imaging reveals regional, transmural, and base-to-apex dispersion of mechanical dysfunction in patients with long QT syndrome

BACKGROUND Regional dispersion of prolonged repolarization is a hallmark of long QT syndrome (LQTS). We have also revealed regional heterogeneities in mechanical dysfunction in transgenic rabbit models of LQTS. OBJECTIVE In this clinical pilot study, we investigated whether patients with LQTS exhibit dispersion of mechanical/diastolic dysfunction. METHODS Nine pediatric patients with genotyped LQTS (12.2 ± 3.3 years) and 9 age- and sex-matched healthy controls (10.6 ± 1.5 years) were subjected to phase-contrast magnetic resonance imaging to analyze radial (Vr) and longitudinal (Vz) myocardial velocities during systole and diastole in the left ventricle (LV) base, mid, and apex. Twelve-lead electrocardiograms were recorded to assess the heart rate-corrected QT (QTc) interval. RESULTS The QTc interval was longer in patients with LQTS than in controls (469.1 ± 39.4 ms vs 417.8 ± 24.4 ms; P < .01). Patients with LQTS demonstrated prolonged radial and longitudinal time-to-diastolic peak velocities (TTP), a marker for prolonged contraction duration, in the LV base, mid, and apex. The longer QTc interval positively correlated with longer time-to-diastolic peak velocities (correlation coefficient 0.63; P < .01). Peak diastolic velocities were reduced in LQTS in the LV mid and apex, indicating impaired diastolic relaxation. In patients with LQTS, regional (TTPmax-min) and transmural (TTPVz-Vr) dispersion of contraction duration was increased in the LV apex (TTPVz_max-min: 38.9 ± 25.5 ms vs 20.2 ± 14.7 ms; P = .07; TTPVz-Vr: -21.7 ± 14.5 ms vs -8.7 ± 11.3 ms; P < .05). The base-to-apex longitudinal relaxation sequence was reversed in patients with LQTS compared with controls (TTPVz_base-apex: 14.4 ± 14.9 ms vs -10.1 ± 12.7 ms; P < .01). CONCLUSION Patients with LQTS exhibit diastolic dysfunction with reduced diastolic velocities and prolonged contraction duration. Mechanical dispersion is increased in LQTS with an increased regional and transmural dispersion of contraction duration and altered apicobasal longitudinal relaxation sequence. LQTS is an electromechanical disorder, and phase-contrast magnetic resonance imaging Heterogeneity in mechanical dysfunction enables a detailed assessment of mechanical consequences of LQTS.

Avoiding sports-related sudden cardiac death in children with congenital channelopathy : Recommendations for sports activities

For the past few years, children affected by an inherited channelopathy have been counseled to avoid (recreational) sports activities and all competitive sports so as to prevent exercise-induced arrhythmia and sudden cardiac death. An increased understanding of the pathophysiological mechanisms, better anti-arrhythmic strategies, and, in particular, more epidemiological data on exercise-induced arrhythmia in active athletes with channelopathies have changed the universal recommendation of “no sports,” leading to revised, less strict, and more differentiated guidelines (published by the American Heart Association/American College of Cardiology in 2015). In this review, we outline the disease- and genotype-specific mechanisms of exercise-induced arrhythmia; give an overview of trigger-, symptom-, and genotype-dependent guidance in sports activities for children with long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), or short QT syndrome (SQTS); and highlight the novelties in the current guidelines compared with previous versions. While it is still recommended for patients with LQT1 and CPVT (even when asymptomatic) and all symptomatic LQTS patients (independent of genotype) to avoid any competitive and high-intensity sports, other LQTS patients successfully treated with anti-arrhythmic therapies and phenotype-negative genotype-positive patients may be allowed to perform sports at different activity levels – provided they undergo regular, sophisticated evaluations to detect any changes in arrhythmogenic risk.ZusammenfassungBis vor Kurzem wurde Kindern mit angeborenen Ionenkanalerkrankungen die Teilnahme am Freizeit- oder Wettkampfsport meist strikt untersagt, um sportinduzierte Arrhythmien und den plötzlichen Herztod zu vermeiden. Verbesserte pathophysiologische Erkenntnisse über die zugrunde liegenden Erkrankungen, Fortschritte in der antiarrhythmischen Therapie und insbesondere epidemiologische Erfahrungen mit Rhythmusereignissen bei aktiven Athleten mit Ionenkanalerkrankungen haben zu weniger strengen, individualisierten Empfehlungen in den neuen amerikanischen Leitlinien der American Heart Association/des American College of Cardiology von 2015 geführt. Für die Beratung von Kindern mit Long-QT-Syndrom (LQTS), Brugada-Syndrom (BrS), katecholaminerger polymorpher ventrikulärer Tachykardie (CPVT) oder Short-QT-Syndrom (SQTS) beschreiben die Autoren die krankheits- und genotypspezifischen Mechanismen sportinduzierter Arrhythmien, geben einen Überblick über die Neuerungen im Vergleich zu älteren Leitlinien und erörtern die differenzierteren, trigger-, symptom- bzw. mutationsabhängigen Empfehlungen zu den einzelnen Krankheitsentitäten. Neben dem fortbestehenden Sportverbot im kompetitiven und hochintensiven Bereich für alle CPVT- und LQT1-Patienten sowie generell für alle symptomatischen LQTS-Patienten gibt es vor allem beim LQTS Patientengruppen, deren Sportverbot unter bestimmten Voraussetzungen gelockert werden kann. So können z. B. erfolgreich antiarrhythmisch behandelte und darunter asymptomatische LQTS-Patienten sowie mutations-positive phänotyp-negative LQTS-Patienten, die unter regelmäßiger Reevaluation ihres Risikoprofils von Spezialisten begleitet werden, durchaus zu sportlichen Aktivitäten zurückkehren.

Avoiding sports-related sudden cardiac death in children with congenital channelopathy

For the past few years, children affected by an inherited channelopathy have been counseled to avoid (recreational) sports activities and all competitive sports so as to prevent exercise-induced arrhythmia and sudden cardiac death. An increased understanding of the pathophysiological mechanisms, better anti-arrhythmic strategies, and, in particular, more epidemiological data on exercise-induced arrhythmia in active athletes with channelopathies have changed the universal recommendation of “no sports,” leading to revised, less strict, and more differentiated guidelines (published by the American Heart Association/American College of Cardiology in 2015). In this review, we outline the disease- and genotype-specific mechanisms of exercise-induced arrhythmia; give an overview of trigger-, symptom-, and genotype-dependent guidance in sports activities for children with long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), or short QT syndrome (SQTS); and highlight the novelties in the current guidelines compared with previous versions. While it is still recommended for patients with LQT1 and CPVT (even when asymptomatic) and all symptomatic LQTS patients (independent of genotype) to avoid any competitive and high-intensity sports, other LQTS patients successfully treated with anti-arrhythmic therapies and phenotype-negative genotype-positive patients may be allowed to perform sports at different activity levels – provided they undergo regular, sophisticated evaluations to detect any changes in arrhythmogenic risk.ZusammenfassungBis vor Kurzem wurde Kindern mit angeborenen Ionenkanalerkrankungen die Teilnahme am Freizeit- oder Wettkampfsport meist strikt untersagt, um sportinduzierte Arrhythmien und den plötzlichen Herztod zu vermeiden. Verbesserte pathophysiologische Erkenntnisse über die zugrunde liegenden Erkrankungen, Fortschritte in der antiarrhythmischen Therapie und insbesondere epidemiologische Erfahrungen mit Rhythmusereignissen bei aktiven Athleten mit Ionenkanalerkrankungen haben zu weniger strengen, individualisierten Empfehlungen in den neuen amerikanischen Leitlinien der American Heart Association/des American College of Cardiology von 2015 geführt. Für die Beratung von Kindern mit Long-QT-Syndrom (LQTS), Brugada-Syndrom (BrS), katecholaminerger polymorpher ventrikulärer Tachykardie (CPVT) oder Short-QT-Syndrom (SQTS) beschreiben die Autoren die krankheits- und genotypspezifischen Mechanismen sportinduzierter Arrhythmien, geben einen Überblick über die Neuerungen im Vergleich zu älteren Leitlinien und erörtern die differenzierteren, trigger-, symptom- bzw. mutationsabhängigen Empfehlungen zu den einzelnen Krankheitsentitäten. Neben dem fortbestehenden Sportverbot im kompetitiven und hochintensiven Bereich für alle CPVT- und LQT1-Patienten sowie generell für alle symptomatischen LQTS-Patienten gibt es vor allem beim LQTS Patientengruppen, deren Sportverbot unter bestimmten Voraussetzungen gelockert werden kann. So können z. B. erfolgreich antiarrhythmisch behandelte und darunter asymptomatische LQTS-Patienten sowie mutations-positive phänotyp-negative LQTS-Patienten, die unter regelmäßiger Reevaluation ihres Risikoprofils von Spezialisten begleitet werden, durchaus zu sportlichen Aktivitäten zurückkehren.

Apparent pacemaker dysfunction during peptide receptor radionuclide therapy for neuroendocrine tumor

This case is a reminder not to overlook rare causes of electrolyte shifts, which may cause reversible changes in pacemaker pacing thresholds.

Avoiding sports-related sudden cardiac death in children with congenital channelopathy@@@Vermeidung des sportbezogenen plötzlichen Herztods bei Kindern mit angeborenen Ionenkanalerkrankungen: Recommendations for sports activities@@@Empfehlungen für sportliche Aktivitäten

For the past few years, children affected by an inherited channelopathy have been counseled to avoid (recreational) sports activities and all competitive sports so as to prevent exercise-induced arrhythmia and sudden cardiac death. An increased understanding of the pathophysiological mechanisms, better anti-arrhythmic strategies, and, in particular, more epidemiological data on exercise-induced arrhythmia in active athletes with channelopathies have changed the universal recommendation of “no sports,” leading to revised, less strict, and more differentiated guidelines (published by the American Heart Association/American College of Cardiology in 2015). In this review, we outline the disease- and genotype-specific mechanisms of exercise-induced arrhythmia; give an overview of trigger-, symptom-, and genotype-dependent guidance in sports activities for children with long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), or short QT syndrome (SQTS); and highlight the novelties in the current guidelines compared with previous versions. While it is still recommended for patients with LQT1 and CPVT (even when asymptomatic) and all symptomatic LQTS patients (independent of genotype) to avoid any competitive and high-intensity sports, other LQTS patients successfully treated with anti-arrhythmic therapies and phenotype-negative genotype-positive patients may be allowed to perform sports at different activity levels – provided they undergo regular, sophisticated evaluations to detect any changes in arrhythmogenic risk.ZusammenfassungBis vor Kurzem wurde Kindern mit angeborenen Ionenkanalerkrankungen die Teilnahme am Freizeit- oder Wettkampfsport meist strikt untersagt, um sportinduzierte Arrhythmien und den plötzlichen Herztod zu vermeiden. Verbesserte pathophysiologische Erkenntnisse über die zugrunde liegenden Erkrankungen, Fortschritte in der antiarrhythmischen Therapie und insbesondere epidemiologische Erfahrungen mit Rhythmusereignissen bei aktiven Athleten mit Ionenkanalerkrankungen haben zu weniger strengen, individualisierten Empfehlungen in den neuen amerikanischen Leitlinien der American Heart Association/des American College of Cardiology von 2015 geführt. Für die Beratung von Kindern mit Long-QT-Syndrom (LQTS), Brugada-Syndrom (BrS), katecholaminerger polymorpher ventrikulärer Tachykardie (CPVT) oder Short-QT-Syndrom (SQTS) beschreiben die Autoren die krankheits- und genotypspezifischen Mechanismen sportinduzierter Arrhythmien, geben einen Überblick über die Neuerungen im Vergleich zu älteren Leitlinien und erörtern die differenzierteren, trigger-, symptom- bzw. mutationsabhängigen Empfehlungen zu den einzelnen Krankheitsentitäten. Neben dem fortbestehenden Sportverbot im kompetitiven und hochintensiven Bereich für alle CPVT- und LQT1-Patienten sowie generell für alle symptomatischen LQTS-Patienten gibt es vor allem beim LQTS Patientengruppen, deren Sportverbot unter bestimmten Voraussetzungen gelockert werden kann. So können z. B. erfolgreich antiarrhythmisch behandelte und darunter asymptomatische LQTS-Patienten sowie mutations-positive phänotyp-negative LQTS-Patienten, die unter regelmäßiger Reevaluation ihres Risikoprofils von Spezialisten begleitet werden, durchaus zu sportlichen Aktivitäten zurückkehren.