Advances in the diagnosis and treatment of catecholaminergic polymorphic ventricular tachycardia

2017 ◽  
Vol 27 (S1) ◽  
pp. S49-S56 ◽  
Author(s):  
Thomas M. Roston ◽  
Taylor C. Cunningham ◽  
Shubhayan Sanatani
Keyword(s):  
Cardiac Arrest ◽  
Ventricular Tachycardia ◽  
Ryanodine Receptor ◽  
Calcium Release ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Electrical Storm ◽  
Implantable Cardioverter Defibrillators ◽  
Cardiac Events ◽  
Β Blockers

AbstractSince the sentinel description of exercise-triggered ventricular arrhythmias in 21 children, our recognition and understanding of catecholaminergic polymorphic ventricular tachycardia has improved substantially. A variety of treatments are now available, but reaching a diagnosis before cardiac arrest remains a challenge. Most cases are related to variants in the gene encoding for ryanodine receptor-2 (RyR2), which mediates calcium-induced calcium release. Up to half of cases remain genetically elusive. The condition is presently incurable, but one basic intervention, the universal administration of β-blockers, has improved survival. In the past, implantable cardioverter-defibrillators (ICDs) were frequently implanted, especially in those with a history of cardiac arrest. Treatment limitations include under-dosing and poor compliance with β-blockers, and potentially lethal ICD-related electrical storm. Newer therapies include flecainide and sympathetic ganglionectomy. Limited data have suggested that genotype may predict phenotype in catecholaminergic polymorphic ventricular tachycardia, including a higher risk of life-threatening cardiac events in subjects with variants in the C-terminus of ryanodine receptor-2 (RyR2). At present, international efforts are underway to better understand this condition through large prospective registries. The recent publication of gene therapy in an animal model of the recessive form of the disease highlights the importance of improving our understanding of the genetic underpinnings of the disease.

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.

scholarly journals Implantable cardioverter-defibrillators in previously undiagnosed patients with catecholaminergic polymorphic ventricular tachycardia resuscitated from sudden cardiac arrest

2019 ◽  
Vol 40 (35) ◽  
pp. 2953-2961 ◽  
Author(s):  
Christian van der Werf ◽  
Krystien V Lieve ◽  
J Martijn Bos ◽  
Conor M Lane ◽  
Isabelle Denjoy ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Ventricular Tachycardia ◽  
Sudden Cardiac Arrest ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
High Rate ◽  
Polymorphic Ventricular Tachycardia ◽  
Implantable Cardioverter Defibrillators ◽  
Strict Adherence ◽  
Sentinel Event ◽  
Left Cardiac Sympathetic Denervation

Abstract Aims In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), implantable cardioverter-defibrillator (ICD) shocks are sometimes ineffective and may even trigger fatal electrical storms. We assessed the efficacy and complications of ICDs placed in patients with CPVT who presented with a sentinel event of sudden cardiac arrest (SCA) while undiagnosed and therefore untreated. Methods and results We analysed 136 patients who presented with SCA and in whom CPVT was diagnosed subsequently, leading to the initiation of guideline-directed therapy, including β-blockers, flecainide, and/or left cardiac sympathetic denervation. An ICD was implanted in 79 patients (58.1%). The primary outcome of the study was sudden cardiac death (SCD). The secondary outcomes were composite outcomes of SCD, SCA, appropriate ICD shocks, and syncope. After a median follow-up of 4.8 years, SCD had occurred in three patients (3.8%) with an ICD and none of the patients without an ICD (P = 0.1). SCD, SCA, or appropriate ICD shocks occurred in 37 patients (46.8%) with an ICD and 9 patients (15.8%) without an ICD (P < 0.0001). Inappropriate ICD shocks occurred in 19 patients (24.7%) and other device-related complications in 22 patients (28.9%). Conclusion In previously undiagnosed patients with CPVT who presented with SCA, an ICD was not associated with improved survival. Instead, the ICD was associated with both a high rate of appropriate ICD shocks and inappropriate ICD shocks along with other device-related complications. Strict adherence to guideline-directed therapy without an ICD may provide adequate protection in these patients without all the potential disadvantages of an ICD.

Nebivolol suppresses cardiac ryanodine receptor-mediated spontaneous Ca2+ release and catecholaminergic polymorphic ventricular tachycardia

2016 ◽  
Vol 473 (22) ◽  
pp. 4159-4172 ◽  
Author(s):  
Zhen Tan ◽  
Zhichao Xiao ◽  
Jinhong Wei ◽  
Jingqun Zhang ◽  
Qiang Zhou ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Ryanodine Receptor ◽  
Critical Role ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Hek293 Cells ◽  
Polymorphic Ventricular Tachycardia ◽  
Triggered Arrhythmias ◽  
Β Blockers ◽  
Pleiotropic Properties ◽  
Cardiac Ryanodine Receptor

β-Blockers are a standard treatment for heart failure and cardiac arrhythmias. There are ∼30 commonly used β-blockers, representing a diverse class of drugs with different receptor affinities and pleiotropic properties. We reported that among 14 β-blockers tested previously, only carvedilol effectively suppressed cardiac ryanodine receptor (RyR2)-mediated spontaneous Ca2+ waves during store Ca2+ overload, also known as store overload-induced Ca2+ release (SOICR). Given the critical role of SOICR in arrhythmogenesis, it is of importance to determine whether there are other β-blockers that suppress SOICR. Here, we assessed the effect of other commonly used β-blockers on RyR2-mediated SOICR in HEK293 cells, using single-cell Ca2+ imaging. Of the 13 β-blockers tested, only nebivolol, a β-1-selective β-blocker with nitric oxide synthase (NOS)-stimulating action, effectively suppressed SOICR. The NOS inhibitor (N-nitro-l-arginine methyl ester) had no effect on nebivolol's SOICR inhibition, and the NOS activator (histamine or prostaglandin E2) alone did not inhibit SOICR. Hence, nebivolol's SOICR inhibition was independent of NOS stimulation. Like carvedilol, nebivolol reduced the opening of single RyR2 channels and suppressed spontaneous Ca2+ waves in intact hearts and catecholaminergic polymorphic ventricular tachycardia (CPVT) in the mice harboring a RyR2 mutation (R4496C). Interestingly, a non-β-blocking nebivolol enantiomer, (l)-nebivolol, also suppressed SOICR and CPVT without lowering heart rate. These data indicate that nebivolol, like carvedilol, possesses a RyR2-targeted action that suppresses SOICR and SOICR-evoked VTs. Thus, nebivolol represents a promising agent for Ca2+-triggered arrhythmias.

Abstract 910: Catecholaminergic Polymorphic Ventricular Tachycardia: Genetics, Natural History and Response to Therapy

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Tom Rossenbacker ◽  
Raffaela Bloise ◽  
Luciana De Giuli ◽  
Emilia V Raytcheva-Buono ◽  
Juliane Theilade ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Ventricular Tachycardia ◽  
Age At Onset ◽  
Response To Therapy ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Compound Heterozygous ◽  
Mutation Carriers ◽  
History Of ◽  
Β Blockers

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmo-genic cardiac disease predisposing affected individuals to sudden cardiac death (SCD). Methods and Results: Here we provide data on the largest CPVT population thus far described. The study population consisted of 177 patients (64% female) of 93 families. All 93 probands (pbs) were screened for RYR2 mutations: 54 (58%) pbs carried a heterozygous RYR2 mutation, 1 pb a compound heterozygous RYR2 mutation and 3 pbs a homozygous (1), compound heterozygous (1) or heterozygous (1) CASQ2 mutation. One KCNJ2 mutation (T305I) was detected in a total of 15 pbs. In family members, another 40 RYR2 mutation carriers were identified. Only 29 of 95 gene carriers were phenotypically silent, therefore the penetrance of a RYR2 mutation was 69%. Of note, female sex was predominant among CPVT probands without a RYR2 mutation. Before the initiation of any treatment related to CPVT, 77 of 93 (83%) pbs experienced a cardiac e vent. Mean age of first event was 12±9 years. Neither sex nor the presence/absence of a RYR2 mutation was associated with a higher risk of developing events or with a younger age at onset of symptoms. Before therapy, 70% and 40% of 177 patients remained free of cardiac arrest and SCD before therapy by age 20 and 40 years, respectively. A history of juvenile SCD (<40 yrs) was present in 36% of families: the mean age of the lethal event was 18±9 yrs. One-hundred CPVT patients were initiated on β-blockers. On top, 41 patients were implanted with an ICD. During a mean follow-up time of 4.5±3 years, 28% of patients experienced a syncope (n=11), cardiac arrest (n=5) or appropriate ICD shock (n=12). Neither sex nor genotype was associated with a worse response to therapy. Conclusions: In this largest CPVT population reported so far, the presence/absence of a RYR2 mutation wasn’t associated with different clinical characteristics or response to therapy as compared to non-mutation carriers. CPVT remains a highly malignant disease with only a moderate response to β-blockers.

P6581Association of neuro-psycho-behavioral troubles to catecholaminergic polymorphic ventricular tachycardia: a more severe arrhythmic phenotype?

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
L Placide ◽  
F Sacher ◽  
P Maury ◽  
V Probst ◽  
J L Pasquie
Keyword(s):  
Cardiac Arrest ◽  
Ventricular Tachycardia ◽  
Symptom Onset ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Cardiac Events ◽  
Icd Implantation ◽  
Familial History ◽  
Time To Diagnosis ◽  
History Of

Abstract Catecholaminergic polymorphic ventricular tachycardia (CPVT) is defined by bidirectional or polymorphic ventricular tachycardia during adrenergic situations and is associated to a poor long-term prognosis. Clinical cases suggest an association between epilepsy and/or neuro-psycho-behavioral troubles (NPBT) to cardiac channelopathies. Methods This is a retrospective observational study based on case analysis from the INTEGRALIS database of the referral center for inherited cardiac arrythmias in Nantes. Epidemiological and clinical-biological features of the population have been studied. Patients with Presence or Absence of NPBT were compared. Results:From 8306 pts in the whole database, 533 presented with VT and 71 pts were diagnosed with CPVT and genotyped. Symptom onset occurred at a medium age of 17.1±13.5 years. Median LVEF was 65% (IQR 9,8%) and median corrected QT interval (QTc) was 399 ms (IQR 27 ms). 77.5% of pts had fainting and/or syncopes, and there were 28.2% patients with a history of cardiac arrest. Time to diagnosis was below1 year for 44.2% of symptomatic pts. Symptoms occurred during exertion for 42.3% of pts including swimming. The prevalence of NPBT was 23,9%. 74% of NPBT were convulsive seizures, 21% psycho-behavioral troubles and 5% epilepsy proved by EEG. Median age of symptom onset was younger in the group “NPBT” (12.2±4 yo vs 19.2±15.5 yo). The rate of patients with symptoms during exertion was higher in the group “NPBT” (29.4 vs 7.4% P=0.031). A mutation in the gene of Ryanodine receptor-2 was found in 64.8% of pts. Comparisons patients w/wo NPBT NPBT (N=17) Without NPBT (N=54) Familial history of Sudden death 7/17 (41.2%) 24/54 (44.4%) NS Familial history of CPVT 5/17 (29.4%) 29/54 (53.7%) NS Medium age of symptom onset (yo) 12.1±4 19.2±15.5 P=0.021 Time to diagnosis <1 year 4/17 (23.5%) 16/54 (27.8%) NS Malaises and/or syncopes 17/17 (100%) 38/54 (70.4%) P=0.035 Cardiac arrest 9/17 (52.9%) 11/54 (20.4%) P=0.025 ICD Implantation 6/17 (35.3%) 12/54 (22.2%) NS Supraventricular arrhythmias 3/17 (17.7%) 6/54 (11.1%) NS Antiepileptic treatment 5/17 (29.4%) 2/54 (3.7%) P=0.009 Conclusion NPBT appears to be associated to a younger age of symptom onset and a higher rate of serious cardiac events particularly during swimming. This study will serve as preliminary data for further clinical and experimental protocols.

scholarly journals The arrhythmogenic N53I variant subtly changes the structure and dynamics in the calmodulin N-terminal domain, altering its interaction with the cardiac ryanodine receptor

2020 ◽  
Vol 295 (22) ◽  
pp. 7620-7634
Author(s):  
Christian Holt ◽  
Louise Hamborg ◽  
Kelvin Lau ◽  
Malene Brohus ◽  
Anders Bundgaard Sørensen ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Ryanodine Receptor ◽  
Hydrophobic Surface ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Open Probability ◽  
Calmodulin Binding ◽  
Terminal Domain ◽  
Genes Encoding ◽  
Cardiac Ryanodine Receptor

Mutations in the genes encoding the highly conserved Ca2+-sensing protein calmodulin (CaM) cause severe cardiac arrhythmias, including catecholaminergic polymorphic ventricular tachycardia or long QT syndrome and sudden cardiac death. Most of the identified arrhythmogenic mutations reside in the C-terminal domain of CaM and mostly affect Ca2+-coordinating residues. One exception is the catecholaminergic polymorphic ventricular tachycardia–causing N53I substitution, which resides in the N-terminal domain (N-domain). It does not affect Ca2+ coordination and has only a minor impact on binding affinity toward Ca2+ and on other biophysical properties. Nevertheless, the N53I substitution dramatically affects CaM's ability to reduce the open probability of the cardiac ryanodine receptor (RyR2) while having no effect on the regulation of the plasmalemmal voltage-gated Ca2+ channel, Cav1.2. To gain more insight into the molecular disease mechanism of this mutant, we used NMR to investigate the structures and dynamics of both apo- and Ca2+-bound CaM-N53I in solution. We also solved the crystal structures of WT and N53I CaM in complex with the primary calmodulin-binding domain (CaMBD2) from RyR2 at 1.84–2.13 Å resolutions. We found that all structures of the arrhythmogenic CaM-N53I variant are highly similar to those of WT CaM. However, we noted that the N53I substitution exposes an additional hydrophobic surface and that the intramolecular dynamics of the protein are significantly altered such that they destabilize the CaM N-domain. We conclude that the N53I-induced changes alter the interaction of the CaM N-domain with RyR2 and thereby likely cause the arrhythmogenic phenotype of this mutation.

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