Catecholaminergic Polymorphic Ventricular Tachycardia in Children

Leenhardt, Antoine; Lucet, V.; Denjoy, Isabelle; Grau, Francis; Ngoc, D. Do; Coumel, Philippe

doi:10.1161/01.cir.91.5.1512

Cited by 885 publications

(733 citation statements)

References 31 publications

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“…SD was evoked by three different methods: For K-SD, a 1 M KCl microejection pipette was placed at the slice surface. The KCl microinjection was started with a 10-ms pulse (constant 40 psi), and the ejection duration was incrementally escalated up to 500 ms (10,20,50, 100, 300, and 500 ms) every 3 min. OGD-SD was induced by exposure to ACSF with reduced glucose (2 mM glucose/8 mM sucrose or 5 mM glucose/5 mM sucrose) and saturated by nitrogen (95% N 2 /5% CO 2 ).…”

Section: Methodsmentioning

confidence: 99%

“…Most cases of sudden cardiac death in CPVT are considered to be due to ventricular tachycardia/fibrillation driven by sympathetic stimulation (47). Paradoxically, many patients show sinus bradycardia at rest (22,(48)(49)(50), and not a small fraction of death is related to AV block and bradycardia (51). The RQ mouse showed this bradycardia phenotype (Fig.…”

Section: Rq Mutation Selectively Enhances Excitatory Synaptic Transmimentioning

confidence: 99%

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Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death

Aiba

Wehrens

Noebels

2016

Proc. Natl. Acad. Sci. U.S.A.

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Cardiorespiratory failure is the most common cause of sudden unexplained death in epilepsy (SUDEP). Genetic autopsies have detected "leaky" gain-of-function mutations in the ryanodine receptor-2 (RyR2) gene in both SUDEP and sudden cardiac death cases linked to catecholaminergic polymorphic ventricular tachycardia that feature lethal cardiac arrhythmias without structural abnormality. Here we find that a human leaky RyR2 mutation, R176Q (RQ), alters neurotransmitter release probability in mice and significantly lowers the threshold for spreading depolarization (SD) in dorsal medulla, leading to cardiorespiratory collapse. Rare episodes of sinus bradycardia, spontaneous seizure, and sudden death were detected in RQ/+ mutant mice in vivo; however, when provoked, cortical seizures frequently led to apneas, brainstem SD, cardiorespiratory failure, and death. In vitro studies revealed that the RQ mutation selectively strengthened excitatory, but not inhibitory, synapses and facilitated SD in both the neocortex as well as brainstem dorsal medulla autonomic microcircuits. These data link defects in neuronal intracellular calcium homeostasis to the vulnerability of central autonomic brainstem pathways to hypoxic stress and implicate brainstem SD as a previously unrecognized site and mechanism contributing to premature death in individuals with leaky RYR2 mutations.sudden unexpected death in epilepsy | SUDEP | catecholaminergic polymorphic ventricular tachycardia | CPVT | ryanodine receptor U p to 10% of individuals with seizures of unknown cause and without known structural cardiac pathology die of sudden unexpected death in epilepsy (SUDEP), and this morbidity is second only to stroke in the number of life-years lost (1). Despite the high mortality rate, comparable to that of sudden infant death syndrome (SIDS), the exact causes are unclear, and there is no effective prediction or intervention. Cardiorespiratory dysfunction and collapse have been observed following generalized tonicclonic seizures in a small number of monitored cases (2), "near SUDEP" cases (3), and mouse SUDEP models (4-6). Genes linked with the most common cardiac LQT syndromes including LQT1 (KCNQ1), LQT2 (KCNH2/HERG), and LQT3 (SCN5A) are expressed in both the human heart and brain, where mutations in the kinetics of these membrane ion channels prolong depolarization and produce combined seizure, cardiac arrhythmia, and sudden death phenotypes (7,8). Because mutations in these ion channel genes currently explain only a small fraction of SUDEP cases (7), the search for additional genes and mechanisms is a high priority to understand and treat sudden death risk.Along with cardiac arrhythmia, recent findings in voltage-gated ion channelopathy models point to an extracardiac, central autonomic involvement of these genes in the events leading to sudden cardiac death. Spreading depolarization (SD) is a slow propagating wave of cellular depolarization that occurs in human brain and is known to contribute to transient neurological deficits during migraine ...

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Section: Methodsmentioning

confidence: 99%

Section: Rq Mutation Selectively Enhances Excitatory Synaptic Transmimentioning

confidence: 99%

Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death

Aiba

Wehrens

Noebels

2016

Proc. Natl. Acad. Sci. U.S.A.

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confidence: 99%

“…10,11 Mortality rates are high, reaching 30% to 50% in patients aged Յ30 years. 12 The original definition of CPVT described children with stress-induced ventricular arrhythmias that are predominantly bidirectional ventricular tachycardias, 10 whereas the FPVT patients have predominantly polymorphic ventricular tachycardia. 8 Priori et al 7 reported 4 RyR2 missense mutations, 3 of which (S2246L, R2474S, and N4104K) were sporadic and one (R4497C) of which was found in a family with 5 clinically affected mutation carriers.…”

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confidence: 99%

Clinical Implications of Cardiac Ryanodine Receptor/Calcium Release Channel Mutations Linked to Sudden Cardiac Death

Marks

2002

Circulation

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“…95 Familial history of syncope or sudden death exists in 30% of patients. 95 The gene encoding the ryanodine receptor regulates intracellular calcium flux and is affected in autosomal dominant CPVT. 96,97 Evaluation for premature CAD, cardiac catheterization for anomalous coronary arteries, and echocardiogram or MRI for ARVD and other etiologies should be considered in patients with exercise precipitated syncope.…”

Section: Catecholminergic Polymorphic Ventricular Tachycardia (Cpvt)mentioning

confidence: 99%

Evaluation and Management of Syncope

Bindra

Marchlinski

Lin

2008

Clinical medicine. Circulatory, respiratory and pulmonary medic

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Context Syncope is a commonly encountered by primary care physicians and cardiologists. Etiology is frequently not apparent, and patients may undergo unnecessary tests. Treatment must be tailored to the likely etiology. Complexities of diagnosis and treatment often warrant referral to a specialist. Objective To highlight the evolving recommendations for managing syncope in a clinically and cost effective manner. Evidence Acquisition An electronic literature search was undertaken of the Medline database from January 1996 to April 2006, using the Medical Subject Heading syncope, defibrillators, pacemakers, echocardiogram, cardiomyopathy, long QT syndrome, Arrhythmogenic right ventricular dysplasia, and Brugada syndrome. Abstracts and titles were reviewed to identify English-language trials. Bibliographies from the references as well as scientific statements from the Heart Rhythm Society, American Heart Association, and American College of Cardiology were reviewed. Evidence Synthesis A methodical approach to syncope can improve diagnosis, limit testing, and identify patients at risk of fatal outcome. A thorough history, physical exam and electrocardiogram are critical to the initial diagnosis. Presence of heart disease determines the extent of work-up and treatment. A trans-thoracic echocardiogram should be performed in patients with an unclear diagnosis and a positive cardiac history or an abnormal ECG. Ventricular arrhythmias are the most common cause of syncope in patients with structural heart disease. Patients with an ejection fraction less than 30 percent should receive an implantable defibrillator with few exceptions. An electrophysiology study may assist risk stratification in syncopal patients with borderline ventricular function. In patients without structural heart disease, the presence of a well defined arrhythmia syndrome consistent with a genetically determined risk of sudden death must be sought. The 12-lead electrocardiogram, family history and clinical presentation will identify most high-risk patients. Patients without structural heart disease can often be managed conservatively with well defined strategies for preventing neurocardiogenic syncope. Conclusions Managing syncope requires a methodical approach. An understanding of the limitations of the diagnostic tools and treatments is important. Lethal causes of syncope make it imperative to recognize the appropriate timing of referring patients to specialists.

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Catecholaminergic Polymorphic Ventricular Tachycardia in Children

Cited by 885 publications

References 31 publications

Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death

Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death

Clinical Implications of Cardiac Ryanodine Receptor/Calcium Release Channel Mutations Linked to Sudden Cardiac Death

Evaluation and Management of Syncope

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