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.

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.

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.

CaMKII as a therapeutic target in catecholaminergic polymorphic ventricular tachycardia type 1

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
M Sadredini ◽  
R Manotheepan ◽  
M Haugsten Hansen ◽  
M Frisk ◽  
WE Louch ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Therapeutic Target ◽  
Calcium Release ◽  
Left Ventricular ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Calcium Waves ◽  
Calcium Sparks ◽  
Acetyl Cysteine

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): South-Eastern Norway Regional Health Authority Background In catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) adrenergic activation of the cardiac ryanodine receptor (RyR2) causes spontaneous calcium release and triggers arrhythmias. Calcium/calmodulin-dependent protein kinase II (CaMKII) can contribute to such arrhythmogenic calcium release and has been proposed as a therapeutic target in CPVT1. To predict the efficacy and safety of this strategy, it is necessary to know whether the mechanism for CaMKII activation is important for its arrhythmogenic effects, and if inhibition has proarrhythmic effects. We tested (1) if oxidation of CaMKII contributes to spontaneous calcium release in CPVT1 and (2) if inhibition of CaMKII in this condition can induce calcium alternans. Methods Mice with the CPVT1-causative mutation RyR2-R2474S (RyR2-RS) were crossed with mice with the CaMKII M281/282V (MMVV) mutation that prevents CaMKII M281/282 oxidation, to create double mutants (RyR2-RSxMMVV). Telemetric ECG surveillance was used to study in vivo arrhythmias following an adrenergic challenge by i.p. administration of the beta-adrenoceptor agonist isoprenaline. Confocal line-scan imaging and whole-cell calcium imaging were used to study arrhythmogenic calcium release in isolated left ventricular cardiomyocytes during stimulation with isoprenaline. Results As expected, RyR2-RS mice exhibited more arrhythmic events and spontaneous calcium release (i.e. calcium sparks and calcium waves) compared to wild-type mice. Treatment of RyR2-RS cardiomyocytes with either the CaMKII inhibitor KN-93 or the antioxidant n-acetyl-cysteine reduced spontaneous calcium release (i.e. calcium sparks and calcium waves, for KN-93 and n-acetyl-cysteine, respectively). Interestingly, CaMKII inhibition by KN-93 also increased both incidence and degree of arrhythmogenic calcium alternans in RyR2-RS cardiomyocytes. This adverse effect was a result of prolonged refractoriness of calcium release. Furthermore, to test whether the protective effect of antioxidant treatment in RyR2-RS was mediated via CaMKII oxidation, we compared arrhythmias and spontaneous calcium release (i.e. calcium waves) in RyR2-RSxMMVV with RyR2-RS. However, these two genotypes did not differ in either incidence or severity of arrhythmias, and showed similar degree of spontaneous calcium release. Conclusions Inhibition of CaMKII protects against spontaneous calcium release in CPVT1, and is a promising therapeutic strategy. However, the fact that such inhibition also induces calcium alternans needs further exploration. Antioxidative agents also attenuate arrhythmogenic calcium release in CPVT1 cardiomyocytes, but this effect does not seem to involve the M281/282 CaMKII oxidation site. Future studies should explore other oxidation sites.

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 Sudden Death in Familial Polymorphic Ventricular Tachycardia Associated With Calcium Release Channel (Ryanodine Receptor) Leak

Circulation ◽  
2004 ◽  
Vol 109 (25) ◽  
pp. 3208-3214 ◽  
Author(s):  
Stephan E. Lehnart ◽  
Xander H.T. Wehrens ◽  
Päivi J. Laitinen ◽  
Steven R. Reiken ◽  
Shi-Xiang Deng ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Sudden Death ◽  
Ryanodine Receptor ◽  
Calcium Release ◽  
Polymorphic Ventricular Tachycardia ◽  
Calcium Release Channel ◽  
Release Channel
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