scholarly journals Dantrolene rescues arrhythmogenic RYR2 defect in a patient‐specific stem cell model of catecholaminergic polymorphic ventricular tachycardia

2012 ◽  
Vol 4 (3) ◽  
pp. 180-191 ◽  
Author(s):  
Christian B. Jung ◽  
Alessandra Moretti ◽  
Michael Mederos y Schnitzler ◽  
Laura Iop ◽  
Ursula Storch ◽  
...  
Keyword(s):  
Stem Cell ◽  
Ventricular Tachycardia ◽  
Cell Model ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Patient Specific ◽  
Stem Cell Model

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.

A Patient-Specific Stem Cell Model to Investigate the Neurological Phenotype Observed in Ataxia-Telangiectasia

2017 ◽  
pp. 391-400
Author(s):  
Romal Stewart ◽  
Gautam Wali ◽  
Chris Perry ◽  
Martin F. Lavin ◽  
Francois Féron ◽  
...  
Keyword(s):  
Stem Cell ◽  
Ataxia Telangiectasia ◽  
Cell Model ◽  
Patient Specific ◽  
Neurological Phenotype ◽  
Stem Cell Model
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