scholarly journals Multiphoton Imaging of Ca2+ Instability in Acute Myocardial Slices from a RyR2R2474S Murine Model of Catecholaminergic Polymorphic Ventricular Tachycardia

2021 ◽  
Vol 10 (13) ◽  
pp. 2821
Author(s):  
Giulia Borile ◽  
Tania Zaglia ◽  
Stephan E. Lehnart ◽  
Marco Mongillo
Keyword(s):  
Ventricular Tachycardia ◽  
Single Cells ◽  
Tissue Level ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Adrenergic Stimulation ◽  
Release Channel ◽  
Multiphoton Imaging ◽  
Delayed Afterdepolarizations ◽  
Multiple Cells

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a familial stress-induced arrhythmia syndrome, mostly caused by mutations in Ryanodine receptor 2 (RyR2), the sarcoplasmic reticulum (SR) Ca2+ release channel in cardiomyocytes. Pathogenetic mutations lead to gain of function in the channel, causing arrhythmias by promoting diastolic spontaneous Ca2+ release (SCR) from the SR and delayed afterdepolarizations. While the study of Ca2+ dynamics in single cells from murine CPVT models has increased our understanding of the disease pathogenesis, questions remain on the mechanisms triggering the lethal arrhythmias at tissue level. Here, we combined subcellular analysis of Ca2+ signals in isolated cardiomyocytes and in acute thick ventricular slices of RyR2R2474S knock-in mice, electrically paced at different rates (1–5 Hz), to identify arrhythmogenic Ca2+ dynamics, from the sub- to the multicellular perspective. In both models, RyR2R2474S cardiomyocytes had increased propensity to develop SCR upon adrenergic stimulation, which manifested, in the slices, with Ca2+ alternans and synchronous Ca2+ release events in neighboring cardiomyocytes. Analysis of Ca2+ dynamics in multiple cells in the tissue suggests that SCRs beget SCRs in contiguous cells, overcoming the protective electrotonic myocardial coupling, and potentially generating arrhythmia triggering foci. We suggest that intercellular interactions may underscore arrhythmic propensity in CPVT hearts with ‘leaky’ RyR2.

Targeting intracellular calcium cycling in catecholaminergic polymorphic ventricular tachycardia: a theoretical investigation

2011 ◽  
Vol 301 (4) ◽  
pp. H1625-H1638 ◽  
Author(s):  
Ruey J. Sung ◽  
Chu-Pin Lo ◽  
Pi Yin Hsiao ◽  
Hui-Chun Tien
Keyword(s):  
Ventricular Tachycardia ◽  
Intracellular Calcium ◽  
Markov Models ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Ventricular Tachyarrhythmias ◽  
Adrenergic Stimulation ◽  
Calcium Cycling ◽  
M Cell ◽  
Release Channel

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a malignant arrhythmogenic disorder linked to mutations in the cardiac ryanodine receptor (RyR2) and calsequestrin, predisposing the young to syncope and cardiac arrest. To define the role of β-adrenergic stimulation (BAS) and to identify potential therapeutic targeted sites relating to intracellular calcium cycling, we used a Luo-Rudy dynamic ventricular myocyte model incorporated with interacting Markov models of the L-type Ca2+ channel ( ICa,L) and RyR2 to simulate the heterozygous state of mouse RyR2 R4496C mutation (RyR2R4496C+/−) comparable with CPVT patients with RyR2 R4497C mutation. Characteristically, in simulated cells, pacing at 4 Hz or faster or pacing at 2 Hz under BAS with effects equivalent to those of isoproterenol at ≥0.1 μM could readily induce delayed afterdepolarizations (DADs) and DAD-mediated triggered activity (TA) in RyR2R4496C+/− but not in the wild-type via enhancing both ICa,L and sarcoplasmic reticulum (SR) Ca2+ ATPase ( IUP). Moreover, with the use of steady state values of isolated endocardial (Endo), mid-myocardial (M), and epicardial (Epi) cells as initial data for conducting single cell and one-dimensional strand studies, the M cell was more vulnerable for developing DADs and DAD-mediated TA than Endo and Epi cells, and the gap junction coupling represented by diffusion coefficient ( D) of ≤0.000766*98 cm2/ms was required for generating DAD-mediated TA in RyR2R4496C+/−. Whereas individual reduction of Ca2+ release channel of SR and Na-Ca exchanger up to 50% was ineffective, 30% or more reduction of either ICa,L or IUP could totally suppress the inducibility of arrhythmia under BAS. Of note, 15% reduction of both ICa,L and IUP exerted a synergistic antiarrhythmic efficacy. Findings of this model study confirm that BAS facilitates induction of ventricular tachyarrhythmias via its action on intracellular Ca2+ cycling and a pharmacological regimen capable of reducing ICa,L could be an effective adjunctive to β-adrenergic blockers for suppressing ventricular tachyarrhythmias during CPVT.

scholarly journals Molecular Mechanism and Current Therapies for Catecholaminergic Polymorphic Ventricular Tachycardia

2021 ◽  
Author(s):  
Bin Liu ◽  
Brian D. Tow ◽  
Ingrid M. Bonilla
Keyword(s):  
Ventricular Tachycardia ◽  
Molecular Mechanisms ◽  
Calcium Release ◽  
Heart Diseases ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Release Channel ◽  
Current Therapies ◽  
Cardiac Disorders

The rhythmic contraction of the heart relies on tightly regulated calcium (Ca) release from the sarcoplasmic reticulum (SR) Ca release channel, Ryanodine receptor (RyR2). Genetic mutations in components of the calcium release unit such as RyR2, cardiac calsequestrin and other proteins have been shown to cause a genetic arrhythmic syndrome known as catecholaminergic polymorphic ventricular tachycardia (CPVT). This book chapter will focus on the following: (1) to describing CPVT as a stress-induced cardiac arrhythmia syndrome and its genetic causes. (2) Discussing the regulation of SR Ca release, and how dysregulation of Ca release contributes to arrhythmogenesis. (3) Discussing molecular mechanisms of CPVT with a focus on impaired Ca signaling refractoriness as a unifying mechanism underlying different genetic forms of CPVT. (4) Discussing pharmacological approaches as CPVT treatments as well as other potential future therapies. Since dysregulated SR Ca release has been implicated in multiple cardiac disorders including heart failure and metabolic heart diseases, knowledge obtained from CPVT studies will also shed light on the development of therapeutic approaches for these devastating cardiac dysfunctions as a whole.

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