Accelerated Sinus Rhythm Prevents Catecholaminergic Polymorphic Ventricular Tachycardia in Mice and in Patients

Faggioni, Michela; Hwang, Hyun Seok; Werf, Christian van der; Nederend, Ineke; Kannankeril, I Prince J.; Wilde, Arthur A.M.; Knollmann, Björn C.

doi:10.1161/circresaha.111.300076

Cited by 52 publications

(47 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1), and other mouse SUDEP models also exhibit interictal spontaneous bradycardia and postictal death associated with bradycardia (4,5). In these models, seizure-induced death could be prevented by the parasympathetic blocker atropine, and the same treatment has also been effective for CPVT mice and human cases (52). Our data indicate that RyR2 facilitates presynaptic glutamate release in central parasympathetic dorsomotor vagal neurons.…”

Section: Rq Mutation Selectively Enhances Excitatory Synaptic Transmimentioning

confidence: 57%

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

Aiba

Wehrens

Noebels

2016

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

View full text Add to dashboard Cite

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 ...

show abstract

Section: Rq Mutation Selectively Enhances Excitatory Synaptic Transmimentioning

confidence: 57%

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

Aiba

Wehrens

Noebels

2016

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

View full text Add to dashboard Cite

show abstract

“…This is also consistent with the observation that increased heart rate alone (as in programmed electrical stimulation) can rarely trigger VTs in patients with CPVT (61). In contrast, accelerating heart rate (in the absence of excessive adrenergic stress) suppresses spontaneous Ca 2+ release and prevents VTs in both CPVT animal models and patients (62 alternans. Thus, RyR2 represents a promising therapeutic target for cardiac alternans.…”

Section: Discussionmentioning

confidence: 99%

The cardiac ryanodine receptor, but not sarcoplasmic reticulum Ca2+-ATPase, is a major determinant of Ca2+ alternans in intact mouse hearts

Sun

Wei

Zhong

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…We are obviously aware of the article by Faggioni et al, 2 which includes 1 of the coauthors of our article, Dr Wilde. We also have direct experience with a few CPVT patients who had a reduction or disappearance of the ventricular arrhythmias induced by exercise when heart rate increased further (usually to >140 bpm).…”

mentioning

confidence: 99%

Response to Letters Regarding Article, “Clinical Management of Catecholaminergic Polymorphic Ventricular Tachycardia: The Role of Left Cardiac Sympathetic Denervation”

et al. 2016

Self Cite

View full text Add to dashboard Cite

We are glad to have the opportunity to respond to the points kindly raised by Drs Patanè and Gow in reference to our recent article on catecholaminergic polymorphic ventricular tachycardia (CPVT). 1 We are obviously aware of the article by Faggioni et al, 2 which includes 1 of the coauthors of our article, Dr Wilde. We also have direct experience with a few CPVT patients who had a reduction or disappearance of the ventricular arrhythmias induced by exercise when heart rate increased further (usually to >140 bpm). We have not discussed atrial overdrive pacing simply because we do not believe that these data and observations have direct relevance to the ongoing clinical management of CPVT patients in everyday life. The concept of atrial high-rate pacing (>120 bpm) may be of potential value in the in-hospital management of emergencies, but we find it difficult to recommend that heart rate should be increased permanently, or during exercise, to >140 bpm. In addition, how would it be possible to exclude that such an intervention, activated in the out-of-hospital setting, would not precipitate ventricular tachycardia or ventricular fibrillation? Our article was focused on how to reduce the incidence of life-threatening arrhythmias in the safest way. Rate support of CPVT patients who have symptomatic bradycardia in response to therapeutic β-blockade is always a consideration in CPVT.We acknowledge the comments concerning the possibility of anatomic variations in the cervicothoracic ganglion. Dr Gow has downplayed the statements by a recognized expert in the field (Andrew Armour), 3 who wrote that "all major cardiopulmonary nerves were found to arise from the stellate ganglia" and focused on the conclusions by Marcer et al 4 and Pather et al, 5 largely based on embalmed cadavers and on fetuses, that in ≈20% of cases the inferior cervical ganglion and the first thoracic ganglion were separate. In our personal experience of >40 years in hundreds of patients in whom we performed left (and sometimes right) cardiac sympathetic denervation, we have always found the stellate ganglion to be the fusion of the last cervical and first thoracic ganglia. The current video-assisted thoracoscopic approach allows a clear and comprehensive visualization of the anatomy and excludes the possibility of missing a significant anatomic variant.Another part of Dr Gow's letter is clinically relevant. He suggests a correlation between the possibility of anatomic variations of the stellate ganglion and the recurrence of syncope, and very seldom of cardiac arrest, in CPVT patients (and in patients with long QT syndrome) treated with left cardiac sympathetic denervation. Although we consider the issue of anatomic variability of minor importance in favoring the occurrence of arrhythmia recurrences, the deliberate lack of removal of either T4 or of the lower part of the stellate ganglion (T1), to exclude any risk of Horner syndrome, is a true concern. Patients with intentionally incomplete denervation did show a much higher risk of recurrences than p...

show abstract

Accelerated Sinus Rhythm Prevents Catecholaminergic Polymorphic Ventricular Tachycardia in Mice and in Patients

Cited by 52 publications

References 45 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

The cardiac ryanodine receptor, but not sarcoplasmic reticulum Ca2+-ATPase, is a major determinant of Ca2+ alternans in intact mouse hearts

Response to Letters Regarding Article, “Clinical Management of Catecholaminergic Polymorphic Ventricular Tachycardia: The Role of Left Cardiac Sympathetic Denervation”

Contact Info

Product

Resources

About