Complex atrial arrhythmias as first manifestation of catecholaminergic polymorphic ventricular tachycardia: an unusual course in a patient with a new mutation in ryanodine receptor type 2 gene

2013 ◽  
Vol 24 (4) ◽  
pp. 741-744 ◽  
Author(s):  
Wolfgang Lawrenz ◽  
Otto N. Krogmann ◽  
Marcus Wieczorek
Keyword(s):  
Ventricular Tachycardia ◽  
Ryanodine Receptor ◽  
Sinus Node ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Receptor Type ◽  
Polymorphic Ventricular Tachycardia ◽  
Atrial Arrhythmias ◽  
Initial Manifestation ◽  
Life Threatening

AbstractCatecholaminergic polymorphic ventricular tachycardia is a rare life-threatening arrhythmogenic disorder. An association with paroxysmal atrial fibrillation and other atrial arrhythmias has been described, but in all published cases the initial manifestation of the disease was ventricular arrhythmia. This is the first report about a patient who presented with complex atrial tachycardia and sinus node dysfunction about 1 year before the typical ventricular arrhythmias were observed, leading to the diagnosis of catecholaminergic polymorphic ventricular tachycardia. In this girl, a mutation of the ryanodine receptor type 2 gene, which has not been described so far, was discovered.

scholarly journals The arrhythmogenic N53I variant subtly changes the structure and dynamics in the calmodulin N-terminal domain, altering its interaction with the cardiac ryanodine receptor

2020 ◽  
Vol 295 (22) ◽  
pp. 7620-7634
Author(s):  
Christian Holt ◽  
Louise Hamborg ◽  
Kelvin Lau ◽  
Malene Brohus ◽  
Anders Bundgaard Sørensen ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Ryanodine Receptor ◽  
Hydrophobic Surface ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Open Probability ◽  
Calmodulin Binding ◽  
Terminal Domain ◽  
Genes Encoding ◽  
Cardiac Ryanodine Receptor

Mutations in the genes encoding the highly conserved Ca2+-sensing protein calmodulin (CaM) cause severe cardiac arrhythmias, including catecholaminergic polymorphic ventricular tachycardia or long QT syndrome and sudden cardiac death. Most of the identified arrhythmogenic mutations reside in the C-terminal domain of CaM and mostly affect Ca2+-coordinating residues. One exception is the catecholaminergic polymorphic ventricular tachycardia–causing N53I substitution, which resides in the N-terminal domain (N-domain). It does not affect Ca2+ coordination and has only a minor impact on binding affinity toward Ca2+ and on other biophysical properties. Nevertheless, the N53I substitution dramatically affects CaM's ability to reduce the open probability of the cardiac ryanodine receptor (RyR2) while having no effect on the regulation of the plasmalemmal voltage-gated Ca2+ channel, Cav1.2. To gain more insight into the molecular disease mechanism of this mutant, we used NMR to investigate the structures and dynamics of both apo- and Ca2+-bound CaM-N53I in solution. We also solved the crystal structures of WT and N53I CaM in complex with the primary calmodulin-binding domain (CaMBD2) from RyR2 at 1.84–2.13 Å resolutions. We found that all structures of the arrhythmogenic CaM-N53I variant are highly similar to those of WT CaM. However, we noted that the N53I substitution exposes an additional hydrophobic surface and that the intramolecular dynamics of the protein are significantly altered such that they destabilize the CaM N-domain. We conclude that the N53I-induced changes alter the interaction of the CaM N-domain with RyR2 and thereby likely cause the arrhythmogenic phenotype of this mutation.

scholarly journals Tetrodotoxin‐Sensitive Neuronal‐Type Na + Channels: A Novel and Druggable Target for Prevention of Atrial Fibrillation

2020 ◽  
Vol 9 (11) ◽  
Author(s):  
Mark A. Munger ◽  
Yusuf Olğar ◽  
Megan L. Koleske ◽  
Heather L. Struckman ◽  
Jessica Mandrioli ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Ventricular Tachycardia ◽  
Medical Center ◽  
Close Association ◽  
Academic Medical Center ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Atrial Arrhythmias ◽  
Neuronal Type

Background Atrial fibrillation (AF) is a comorbidity associated with heart failure and catecholaminergic polymorphic ventricular tachycardia. Despite the Ca 2+ ‐dependent nature of both of these pathologies, AF often responds to Na + channel blockers. We investigated how targeting interdependent Na + /Ca 2+ dysregulation might prevent focal activity and control AF. Methods and Results We studied AF in 2 models of Ca 2+ ‐dependent disorders, a murine model of catecholaminergic polymorphic ventricular tachycardia and a canine model of chronic tachypacing‐induced heart failure. Imaging studies revealed close association of neuronal‐type Na + channels (nNa v ) with ryanodine receptors and Na + /Ca 2+ exchanger. Catecholamine stimulation induced cellular and in vivo atrial arrhythmias in wild‐type mice only during pharmacological augmentation of nNa v activity. In contrast, catecholamine stimulation alone was sufficient to elicit atrial arrhythmias in catecholaminergic polymorphic ventricular tachycardia mice and failing canine atria. Importantly, these were abolished by acute nNa v inhibition (tetrodotoxin or riluzole) implicating Na + /Ca 2+ dysregulation in AF. These findings were then tested in 2 nonrandomized retrospective cohorts: an amyotrophic lateral sclerosis clinic and an academic medical center. Riluzole‐treated patients adjusted for baseline characteristics evidenced significantly lower incidence of arrhythmias including new‐onset AF, supporting the preclinical results. Conclusions These data suggest that nNa V s mediate Na + ‐Ca 2+ crosstalk within nanodomains containing Ca 2+ release machinery and, thereby, contribute to AF triggers. Disruption of this mechanism by nNa v inhibition can effectively prevent AF arising from diverse causes.

scholarly journals Incidence and Clinical Management of Atrial Arrhythmias in Patients with Catecholaminergic Polymorphic Ventricular Tachycardia

2021 ◽  
Author(s):  
Gurukripa Kowlgi ◽  
John Giudicessi ◽  
Walid Barake ◽  
Konstantinos Siontis ◽  
Johan Bos ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Ventricular Arrhythmias ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Atrial Arrhythmias ◽  
Single Center ◽  
Ablation Therapy ◽  
Inappropriate Shocks ◽  
Drug Intolerance

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic arrhythmia syndrome characterized by adrenergically-triggered ventricular arrhythmias, syncope, and sudden cardiac death. Several small studies suggest that atrial arrhythmias (AAs) are common in patients with CPVT. Objective: To determine the incidence and type of AAs observed within a large, single-center cohort of CPVT cases as well as the efficacy and durability of AA-directed management. Methods: In this retrospective study, the electronic medical record of 129 patients (52% female; average age at diagnosis 20.8  15.3 years) with CPVT (95% with a putative CPVT1-causative RYR2 variant) between 01/2000 and 09/2019 were reviewed for electrocardiographic evidence of AAs. Clinical features and efficacy of pharmacologic and ablation therapy were assessed. Results: Overall, 10/129 (7.8%) CPVT patients, all RYR2 variant-positive, had evidence of an AA (atrial fibrillation/flutter in 6, atrial tachycardia in 3, and supraventricular tachycardia in 1). The median age at AA diagnosis was 23 (14.2-35.5) years. 8/10 of patients experienced symptoms attributed to their AA, including inappropriate shocks. All patients were trialed on anti-arrhythmics, including -blockers, and/or flecainide. Owing to drug failure (1/10), drug intolerance (1/10), or patient preference (2/10); 4/10 patients received an ablation. Over a median follow-up of 23.5 (4.5-63) months, no AA recurrences were observed. Conclusion: Compared to prior studies, the incidence of AAs in this large, single-center referral cohort of CPVT patients was substantially lower (7.8% vs. 26%-35%). Although larger multi-center studies are needed to confirm, this study suggests that ablation is efficacious and durable in CPVT-associated AAs.

Abstract 17874: Aerobic Exercise Training Improves Exercise Capacity, Reduces Arrhythmia Susceptibility but Does Not Normalize Ryanodine Receptor Mediated Aberrant Calcium Release in Catecholaminergic Polymorphic Ventricular Tachycardia

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Zoe Swain ◽  
Hsiang-Ting Ho ◽  
Minori Minagawa ◽  
Bjorn C Knollmann ◽  
Sandor Gyorke ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Exercise Training ◽  
Aerobic Exercise ◽  
Exercise Capacity ◽  
Ryanodine Receptor ◽  
Calcium Release ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Treadmill Running ◽  
Aerobic Exercise Training ◽  
Polymorphic Ventricular Tachycardia

Introduction: Loss of Calsequestrin (CASQ2) promotes abnormal calcium (Ca2+) release events via the cardiac Ryanodine receptor (RyR2) during adrenergic stimulation, which trigger Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). Rationale: Since aerobic exercise training (AET) has been shown to normalize Sarcoplasmic reticulum (SR) Ca2+ cycling parameters in diseased hearts, we explored if AET impacts RyR2 dysfunction and CPVT susceptibility in CASQ2-/- mice. Methods and Results: Age matched wildtype (WT) and CASQ2-/- male mice (n=8) were subjected to treadmill running for 6 weeks (16mts/min for 1hr, 5 days/week at 10% incline). Subsequently, a graded exercise test showed that sedentary (Sed) CASQ2-/- mice have a significantly lower exercise capacity relative to SedWT. Compared to trained (Ex) WT mice, AET moderately increased maximal running speed, time, and RER values in ExCASQ2-/- mice, indicating improved aerobic capacity. Electrocardiographic analyses showed that ExCASQ2-/- mice were resistant to triggered arrhythmias compared to their Sed controls. Spectral analyses of heart rate variability indicated that the high frequency band power increased significantly in ExCASQ2-/- mice, especially during Isoproterenol (Iso) challenge compared to ExWT. Despite fewer arrhythmias, confocal Ca2+ imaging revealed that ExCASQ2-/- ventricular cardiomyocytes are prone to spontaneous Ca2+ sparks and waves even at baseline (compared to ExWT) along with a concomitant decrease in Ca2+ transient amplitude and SR Ca2+ load, both at baseline and during Iso challenge. Conclusions: Our results thus far indicate that AET partially improves exercise capacity and aerobic fitness in the CASQ2-/- mouse model of CPVT. Paradoxically, although arrhythmia incidence is reduced, RyR2 mediated dysfunctions in SR Ca2+ cycling are not normalized after 6 weeks of AET. Importantly, the parasympathetic tone is significantly enhanced in the ExCASQ2-/- mice particularly during Iso challenge. Ongoing studies will address mechanisms (SR protein expression, post translational modifications and pharmacological interventions to investigate the observed autonomic imbalance) that could underlie the intriguing effects of exercise in this model of CPVT.

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