Abnormal Propagation of Calcium Waves and Ultrastructural Remodeling in Recessive Catecholaminergic Polymorphic Ventricular Tachycardia

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.

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Faculty Opinions recommendation of Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1159184.621742 ◽

2009 ◽

Author(s):

Rafael Beyar ◽

Doron Aronson

Keyword(s):

Ventricular Tachycardia ◽

Catecholaminergic Polymorphic Ventricular Tachycardia ◽

Polymorphic Ventricular Tachycardia

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Faculty Opinions recommendation of Accelerated sinus rhythm prevents catecholaminergic polymorphic ventricular tachycardia in mice and in patients.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717982896.793472089 ◽

2013 ◽

Author(s):

Dirk van Helden ◽

Mohammad Imtiaz

Keyword(s):

Ventricular Tachycardia ◽

Sinus Rhythm ◽

Catecholaminergic Polymorphic Ventricular Tachycardia ◽

Polymorphic Ventricular Tachycardia

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A novel heterozygous mutation in cardiac calsequestrin causes autosomal dominant catecholaminergic polymorphic ventricular tachycardia

Heart Rhythm ◽

10.1016/j.hrthm.2016.05.004 ◽

2016 ◽

Vol 13 (8) ◽

pp. 1652-1660 ◽

Cited By ~ 31

Author(s):

Belinda Gray ◽

Richard D. Bagnall ◽

Lien Lam ◽

Jodie Ingles ◽

Christian Turner ◽

...

Keyword(s):

Ventricular Tachycardia ◽

Autosomal Dominant ◽

Catecholaminergic Polymorphic Ventricular Tachycardia ◽

Polymorphic Ventricular Tachycardia ◽

Heterozygous Mutation

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Catecholaminergic polymorphic ventricular tachycardia complicated by dilated cardiomyopathy: a case report

European Heart Journal - Case Reports ◽

10.1093/ehjcr/ytaa299 ◽

2020 ◽

Author(s):

Granitz Christina ◽

Jirak Peter ◽

Strohmer Bernhard ◽

Pölzl Gerhard

Keyword(s):

Heart Failure ◽

Ventricular Tachycardia ◽

Dilated Cardiomyopathy ◽

Sinus Bradycardia ◽

Clinical Care ◽

Structural Heart Disease ◽

Catecholaminergic Polymorphic Ventricular Tachycardia ◽

Polymorphic Ventricular Tachycardia ◽

Myocardial Inflammation ◽

As Stress

Abstract Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe genetic arrhythmogenic disorder characterized by adrenergically induced ventricular tachycardia manifesting as stress-induced syncope and sudden cardiac death. While CPVT is not associated with dilated cardiomyopathy (DCM) in most cases, the combination of both disease entities poses a major diagnostic and therapeutic challenge. Case summary We present the case of a young woman with CPVT. The clinical course since childhood was characterized by repetitive episodes of exercise-induced ventricular arrhythmias and a brady-tachy syndrome due to rapid paroxysmal atrial fibrillation and sinus bradycardia. Medical treatment included propranolol and flecainide until echocardiography showed a dilated left ventricle with severely depressed ejection fraction when the patient was 32 years old. Cardiac magnetic resonance imaging revealed non-specific late gadolinium enhancement. Myocardial inflammation, however, was excluded by subsequent endomyocardial biopsy. Genetic analysis confirmed a mutation in the cardiac ryanodine receptor but no pathogenetic variant associated with DCM. Guideline-directed medical therapy for HFrEF was limited due to symptomatic hypotension. Over the next months, the patient developed progressive heart failure symptoms that were finally managed by heart transplantation. Discussion Management in patients with CPVT and DCM is challenging, as Class I antiarrhythmic drugs are not recommended in structural heart disease and prophylactic internal cardioverter-defibrillator implantation without adjuvant antiarrhythmic therapy can be detrimental. Regular echocardiographic screening for DCM is recommendable in patients with CPVT. A multidisciplinary team of heart failure specialists, electrophysiologists, geneticists, and imaging specialists is needed to collaborate in the delivery of clinical care.

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Burst Exercise Testing Can Unmask Arrhythmias in Patients With Incompletely Penetrant Catecholaminergic Polymorphic Ventricular Tachycardia

JACC: Clinical Electrophysiology ◽

10.1016/j.jacep.2021.02.013 ◽

2021 ◽

Vol 7 (4) ◽

pp. 437-441

Author(s):

Thomas M. Roston ◽

Dania Kallas ◽

Brianna Davies ◽

Sonia Franciosi ◽

Astrid M. De Souza ◽

...

Keyword(s):

Ventricular Tachycardia ◽

Exercise Testing ◽

Catecholaminergic Polymorphic Ventricular Tachycardia ◽

Polymorphic Ventricular Tachycardia

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B-PO05-021 REPEATABILITY OF VENTRICULAR ARRHYTHMIA CHARACTERISTICS DURING EXERCISE STRESS TESTING IN PATIENTS WITH CATECHOLAMINERGIC POLYMORPHIC VENTRICULAR TACHYCARDIA

Heart Rhythm ◽

10.1016/j.hrthm.2021.06.941 ◽

2021 ◽

Vol 18 (8) ◽

pp. S379-S380

Author(s):

Puck Peltenburg ◽

Sanjeev NJ. Pultoo ◽

Krystien V.V. Lieve ◽

Sally-Ann Barker Clur ◽

Nico A. Blom ◽

...

Keyword(s):

Ventricular Tachycardia ◽

Ventricular Arrhythmia ◽

Stress Testing ◽

Catecholaminergic Polymorphic Ventricular Tachycardia ◽

Exercise Stress ◽

Polymorphic Ventricular Tachycardia ◽

Exercise Stress Testing

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

Journal of Clinical Medicine ◽

10.3390/jcm10132821 ◽

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.

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