A Novel Mutation in the RYR2 Gene Leading to Catecholaminergic Polymorphic Ventricular Tachycardia and Paroxysmal Atrial Fibrillation: Dose-Dependent Arrhythmia-Event Suppression by β-Blocker Therapy

2011 ◽  
Vol 27 (6) ◽  
pp. 870.e7-870.e10 ◽  
Author(s):  
Pedram Kazemian ◽  
Michael H. Gollob ◽  
Alfredo Pantano ◽  
Gavin Y. Oudit
Keyword(s):  
Atrial Fibrillation ◽  
Ventricular Tachycardia ◽  
Paroxysmal Atrial Fibrillation ◽  
Novel Mutation ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Blocker Therapy ◽  
Β Blocker ◽  
Dose Dependent

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.

Abstract 15566: Induced Pluripotent Stem Cell-Derived Cardiomyocytes Recapitulate Clinically Observed Refractoriness to Therapeutic β-Blockade in a Patient-Specific Model of Catecholaminergic Polymorphic Ventricular Tachycardia

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Marcela K Preininger ◽  
Rajneesh Jha ◽  
Qingling Wu ◽  
Monalisa Singh ◽  
Joshua T Maxwell ◽  
...  
Keyword(s):  
Stem Cell ◽  
Ventricular Tachycardia ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Polymorphic Ventricular Tachycardia ◽  
Patient Specific ◽  
Blocker Therapy ◽  
Β Blocker ◽  
Induced Pluripotent

Introduction: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by diastolic store overload-induced Ca2+ waves during β-adrenergic receptor (β-AR) stimulation. Mysteriously, β-blockers are ineffective at abolishing stress-induced ventricular arrhythmias in ~25% of patients. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from these CPVT patients offer an attractive system for investigating the phenomenon, but it remains unknown whether iPSC-CMs can recapitulate clinically observed patient-specific drug responses. Hypothesis: This study assessed the hypothesis that patient-specific refractoriness to β-blocker therapy can be observed in vitro using CPVT iPSC-CMs. Methods: We generated iPSC-CMs from a control individual and a CPVT patient insensitive to the widely prescribed β-blocker nadolol, but responsive to flecainide, and compared the efficacy of the two drugs in vitro in diminishing diastolic Ca2+ waves and restoring Ca2+ spark parameters during β-AR stimulation. Results: In CPVT hiPSC-CMs (n = 34), β-AR agonism elicited intense diastolic Ca2+ waves and potentiated unduly frequent, large, and prolonged Ca2+ sparks compared to control iPSC-CMs (n = 12). Pursuant to the patient’s in vivo responses, nadolol-treated CPVT iPSC-CMs (n = 27) demonstrated inadequate improvement of Ca2+ handling defects during β-AR stimulation relative to flecainide-treated CPVT iPSC-CMs (n = 25). Nadolol showed no significant effect on the frequency of diastolic Ca2+ waves, but reduced mean amplitude by 50% (p < 0.0001). In contrast, flecainide reduced both frequency and amplitude by 83% (p < 0.001) and 72% (p < 0.0001), respectively. During nadolol treatment, Ca2+ spark frequency, width, and duration remained significantly altered, while flecainide restored all Ca2+ spark parameters to baseline levels. Conclusions: Clinically observed recalcitrance to β-blocker therapy in individuals with CPVT can be modeled in vitro using patient-derived iPSC-CMs. Furthermore, the efficacy of other drugs such as flecainide can be comparatively evaluated, supporting the use of patient-specific iPSC-CMs as a clinically-relevant implement of precision medicine.

scholarly journals Scared to death—A novel mutation in catecholaminergic polymorphic ventricular tachycardia

2020 ◽  
Vol 6 (5) ◽  
pp. 268-271
Author(s):  
Nikhil Jain ◽  
Jaime C. Holbert ◽  
William Black ◽  
Reem Hussein ◽  
Gayathri Baljepally ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Novel Mutation ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia
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