Purkinje cell calcium dysregulation is the cellular mechanism that underlies catecholaminergic polymorphic ventricular tachycardia

Herron, Todd J.; Milstein, Michelle L.; Anumonwo, Justus M.B.; Priori, Silvia G.; Jalife, José

doi:10.1016/j.hrthm.2010.06.010

Cited by 76 publications

(68 citation statements)

References 22 publications

(40 reference statements)

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“…Previous studies have demonstrated the mechanism of arrhythmia origination for BDVT and PMVT in CPVT to be abnormal calcium regulation and delayed after depolarizations (DADs). [18][19][20] Modeling studies suggest that origination and alternation of premature beats between the right and the left bundle branches of the purkinje system (the Ping-Pong mechanism) result in BDVT. When DADs arise from multiple purkinje sites, PMVT ensues.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Implantable Cardioverter Defibrillators in Young Patients With Catecholaminergic Polymorphic Ventricular Tachycardia

Miyake

Webster

Czosek

et al. 2013

Circ: Arrhythmia and Electrophysiology

129

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Background— The effectiveness of implantable cardioverter-defibrillator (ICD) therapy for the management of catecholaminergic polymorphic ventricular tachycardia (VT) in young patients is not known. ICD discharges are not always effective and inappropriate discharges are common, both resulting in morbidity and mortality. Methods and Results— This is a multicenter, retrospective review of young patients with catecholaminergic polymorphic VT and ICDs from 5 centers. ICD discharges were evaluated to determine arrhythmia mechanism, appropriateness, efficacy of therapy, and complications. A total of 24 patients were included. Median (interquartile range) ages at onset of catecholaminergic polymorphic VT symptoms and ICD implant were 10.6 (5.0–13.8) years and 13.7 (10.7–16.3) years, respectively. Fourteen patients received 140 shocks. Ten patients (42%) experienced 75 appropriate shocks and 11 patients (46%) received 65 inappropriate shocks. On actuarial analysis, freedom from appropriate shock at 1 year after ICD implant was 75%. Of appropriate shocks, only 43 (57%) demonstrated successful primary termination. All successful appropriate ICD discharges were for ventricular fibrillation. No episodes of polymorphic VT or bidirectional VT demonstrated successful primary termination. The adjusted mean (95% confidence interval) cycle length of successful discharges was significantly shorter than unsuccessful discharges (168 [152–184] ms versus 245 [229–262] ms; adjusted P =0.002). Electrical storm occurred in 29% (4/14) and induction of more malignant ventricular arrhythmias in 36% (5/14). There were no deaths. Conclusions— ICD efficacy in catecholaminergic polymorphic VT depends on arrhythmia mechanism. Episodes of ventricular fibrillation were uniformly successfully treated, whereas polymorphic and bidirectional VT did not demonstrate successful primary termination. Inappropriate shocks, electrical storm, and ICD complications were common.

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Section: Discussionmentioning

confidence: 99%

Efficacy of Implantable Cardioverter Defibrillators in Young Patients With Catecholaminergic Polymorphic Ventricular Tachycardia

Miyake

Webster

Czosek

et al. 2013

Circ: Arrhythmia and Electrophysiology

129

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“…2+ handling in cardiac Purkinje cells (P-cells) has been stimulated by growing evidence that spontaneous intracellular Ca 2+ activity accounts for abnormal Purkinje automaticity (Boyden & ter Keurs, 2001, 2005Boyden et al 2003;ter Keurs & Boyden, 2007;Hirose et al 2008b;Herron et al 2010;Kang et al 2010). Several studies re-examined normal P-cells using advanced imaging technology and highlighted unique features in the Ca 2+ mobilization of these cells (Boyden et al 2000;Cordeiro et al 2001a,b;Stuyvers et al 2005;Hirose et al 2008a).…”

Section: Recent Interest In Intracellular Camentioning

confidence: 99%

Evoked centripetal Ca²⁺ mobilization in cardiac Purkinje cells: insight from a model of three Ca²⁺ release regions

Haq

Daniels

Miller

et al. 2013

The Journal of Physiology

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Key points• Abnormal oscillations of calcium (Ca 2+ ) concentration in cardiac Purkinje cells (P-cells) have been associated with life-threatening arrhythmias, but the mechanism by which these cells control their Ca 2+ level in normal conditions remains unknown.• We modelled our previous hypothesis that the principal intracellular Ca 2+ compartment (endoplasmic reticulum; ER) which governs intracellular Ca 2+ concentration, formed, in P-cells, three concentric and adjacent layers, each including a distinct Ca 2+ release channel. We then tested the model against typical Ca 2+ variations observed in stimulated P-cells.• We found in swine P-cells, as in the rabbit and dog, that stimulation evokes an elevation of Ca 2+ concentration first under the membrane , which then propagates to the interior of the cell.• Our mathematical model could reproduce accurately this typical 'centripetal' Ca 2+ spread, hence supporting (1) the existence of the '3 layered' Ca 2+ compartment, and (2) its central role in the regulation of Ca 2+ concentration in P-cells.• To model the 'centripetal' Ca 2+ spread, local variations of Ca 2+ concentration were calculated for a virtual cell environment encompassing three different regions that mimicked the three layers of ER in P-cells. Various tests of the model revealed that the second intermediate layer was essential for 'forwarding' the Ca 2+ elevation from the periphery to the cell centre.• This novel finding suggests that a thin intermediate layer of specific ER Ca 2+ channels controls the entire Ca 2+ signalling of P-cells. Because Ca 2+ plays a role in the electric properties of P-cells, any abnormality affecting this intermediate region is likely to be pro-arrhythmic and could explain the origin of serious cardiac arrhythmias known to start in the Purkinje fibres.Abstract Despite strong suspicion that abnormal Ca 2+ handling in Purkinje cells (P-cells) is implicated in life-threatening forms of ventricular tachycardias, the mechanism underlying the Ca 2+ cycling of these cells under normal conditions is still unclear. There is mounting evidence that P-cells have a unique Ca 2+ handling system. Notably complex spontaneous Ca 2+ activity was previously recorded in canine P-cells and was explained by a mechanistic hypothesis involving a triple layered system of Ca 2+ release channels. Here we examined the validity of this hypothesis for the electrically evoked Ca 2+ transient which was shown, in the dog and rabbit, to occur progressively from the periphery to the interior of the cell. To do so, the hypothesis was incorporated in a model of intracellular Ca 2+ dynamics which was then used to reproduce numerically the Ca 2+ activity of P-cells under stimulated conditions. The modelling was thus performed through a 2D computational array that encompassed three distinct Ca 2+ release nodes arranged, respectively,

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“…58 In this setting, it has been shown that delayed afterdepolarizations caused by calcium overload are a more common occurrence in Purkinje cells than in ventricular myocytes, both at baseline and after β-adrenergic stimulation. 59 The Purkinje cells are probably critical contributors to arrhythmic triggers in animal models and humans with CPVT.…”

Section: Pathophysiological Backgroundmentioning

confidence: 99%

Catecholaminergic Polymorphic Ventricular Tachycardia

Leenhardt

Denjoy

Guicheney

2012

Circ: Arrhythmia and Electrophysiology

146

115

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Purkinje cell calcium dysregulation is the cellular mechanism that underlies catecholaminergic polymorphic ventricular tachycardia

Cited by 76 publications

References 22 publications

Efficacy of Implantable Cardioverter Defibrillators in Young Patients With Catecholaminergic Polymorphic Ventricular Tachycardia

Efficacy of Implantable Cardioverter Defibrillators in Young Patients With Catecholaminergic Polymorphic Ventricular Tachycardia

Evoked centripetal Ca²⁺ mobilization in cardiac Purkinje cells: insight from a model of three Ca²⁺ release regions

Catecholaminergic Polymorphic Ventricular Tachycardia

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Purkinje cell calcium dysregulation is the cellular mechanism that underlies catecholaminergic polymorphic ventricular tachycardia

Cited by 76 publications

References 22 publications

Efficacy of Implantable Cardioverter Defibrillators in Young Patients With Catecholaminergic Polymorphic Ventricular Tachycardia

Efficacy of Implantable Cardioverter Defibrillators in Young Patients With Catecholaminergic Polymorphic Ventricular Tachycardia

Evoked centripetal Ca2+ mobilization in cardiac Purkinje cells: insight from a model of three Ca2+ release regions

Catecholaminergic Polymorphic Ventricular Tachycardia

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Evoked centripetal Ca²⁺ mobilization in cardiac Purkinje cells: insight from a model of three Ca²⁺ release regions