scholarly journals 769 Differential pharmacological modulation of arrhythmic phenotype in catecholaminergic polymorphic ventricular tachycardia: not all betablockers are the same

2021 ◽  
Vol 23 (Supplement_G) ◽  
Author(s):  
Deni Kukavica ◽  
Andrea Mazzanti ◽  
Alessandro Trancuccio ◽  
Gala Giannini ◽  
Maira Marino ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Ventricular Arrhythmias ◽  
Stress Test ◽  
Response To Therapy ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Exercise Stress ◽  
Polymorphic Ventricular Tachycardia ◽  
Maximal Heart Rate ◽  
Dose Increase ◽  
Exercise Time

Abstract Aims Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder that predisposes patients to develop catecholamine-mediated ventricular arrhythmias (VA), manifesting as exercise- or emotion-induced syncope or cardiac arrest. Due to the catecholaminergic nature of CPVT, exercise stress test (EST) represents the most important diagnostic test. Although widely used in clinical practice to monitor response to therapy, how BBs modulate the occurrence of ventricular arrhythmias during EST in CPVT patients is unclear. To compare the relative efficacy of different classes of betablockers (BBs, β1-selective BBs vs. nadolol) on the arrhythmic manifestations during ESTs performed off-therapy and on-therapy in patients with CPVT. Methods and results We selected 72 patients (45 females) with pathogenic or likely pathogenic variants on RYR2 or CASQ2 from our cohort of 246 genotype-positive CPVT patients, who had at least one EST off-therapy and at least one EST during BB therapy. Overall, 507 ESTs (77 ESTs off-therapy, 29 ESTs during β1-selective BBs, and 401 during nadolol) were prospectively collected over 11.1 ± 6.8 years of follow-up and analysed, with a median of 5 ESTs per patient [interquartile range (IQR): 3–10 ESTs, range: 2–27 ESTs]. In the absence of therapy, VT was documented in 46/77 (60%) cases. BB therapy with nadolol significantly reduced VT at EST to 10% (41/398; P < 0.001). Conversely, β1-selective BBs did not significantly decrease VT incidence at EST (13/29, 45%, P = 0.289) as compared to baseline. Importantly, nadolol was superior in preventing VT both when compared to off-therapy [odds ratio (OR): 33.9, 95% confidence interval (CI): 15.6–73.5, P < 0.001] but also when compared to β1-selective BBs [OR: 18.0, 95% CI: 6.0–53.5, P < 0.001]. Although β1-selective BBs significantly increased the total exercise time free of arrhythmias (median 248 s, IQR: 212–315 s) as compared to baseline (median 83 s, IQR: 12–207 s; P < 0.001), arrhythmia-free exercise time during nadolol (median 381 s, IQR: 251–543 s) was significantly longer as compared to both off-therapy (P < 0.001) and β1-selective BBs (P = 0.020). Multivariate mixed effects logistic regression confirmed that at parity of time of occurrence of first arrhythmia and percentage of maximal heart rate reached, both of which were significantly associated to VT occurrence (P = 0.001 for both), the use of nadolol (OR: 0.23; 95% CI: 0.09–0.60; P = 0.011) was independently associated with decreased incidence of VT. Focusing on the 14 patients (overall 133 ESTs) who had at least one ESTs after the occurrence of VT in nadolol, we dissected the effect of dose increase on the probability of VT reoccurrence. Following the documentation of breakthrough VT, increasing the dose of nadolol by 0.5 mg/kg reduced by 2.5 times the probability of having a recurrence of VT (OR: −2.49, 95% CI: −3.96 to − 1.0; P < 0.001). Conclusions Once CPVT is diagnosed, nadolol at 1 mg/kg/day should be used as preferred therapy as it has been shown to suppress VT in most patients. In rare instances in which VA persist despite an adequate nadolol dose, dose increase to 1.5 mg/kg/day may represent an efficacious antiarrhythmic strategy.

Monogenic and oligogenic cardiovascular diseases: genetics of arrhythmias—catecholaminergic polymorphic ventricular tachycardia

ESC CardioMed ◽  
2018 ◽  
pp. 683-685
Author(s):  
Peter J. Schwartz ◽  
Lia Crotti
Keyword(s):  
Ventricular Tachycardia ◽  
Beta Blockers ◽  
Stress Test ◽  
Exercise Stress Test ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Exercise Stress ◽  
Polymorphic Ventricular Tachycardia ◽  
Cascade Screening ◽  
Icd Implantation ◽  
Symptomatic Diagnosis

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited disorder associated with syncope and sudden death manifesting in the young during sympathetic activation. The electrocardiogram is normal and the heart is structurally normal. The diagnosis is usually made with an exercise stress test that shows a typical pattern of onset and offset of adrenergically induced ventricular arrhythmias. Molecular screening of RyR2, the major CPVT gene, is recommended whenever the suspicion of CPVT is high. If a disease-causing mutation is identified, cascade screening allows pre-symptomatic diagnosis among family members. All affected subjects should be treated with beta blockers (nadolol or propranolol). Preliminary data support the association of beta blockers with flecainide. After a cardiac arrest, an implantable cardioverter defibrillator (ICD) should be implanted, but it is accompanied by a disquietingly high incidence of adverse effects. After syncope on beta blocker therapy, left cardiac sympathetic denervation is most effective, preserves quality of life, and does not preclude a subsequent ICD implantation.

Monogenic and oligogenic cardiovascular diseases: genetics of arrhythmias—catecholaminergic polymorphic ventricular tachycardia

2018 ◽  
Author(s):  
Peter J. Schwartz ◽  
Lia Crotti
Keyword(s):  
Ventricular Tachycardia ◽  
Beta Blockers ◽  
Stress Test ◽  
Exercise Stress Test ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Exercise Stress ◽  
Polymorphic Ventricular Tachycardia ◽  
Cascade Screening ◽  
Icd Implantation ◽  
Symptomatic Diagnosis

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited disorder associated with syncope and sudden death manifesting in the young during sympathetic activation. The electrocardiogram is normal and the heart is structurally normal. The diagnosis is usually made with an exercise stress test that shows a typical pattern of onset and offset of adrenergically induced ventricular arrhythmias. Molecular screening of RyR2, the major CPVT gene, is recommended whenever the suspicion of CPVT is high. If a disease-causing mutation is identified, cascade screening allows pre-symptomatic diagnosis among family members. All affected subjects should be treated with beta blockers (nadolol or propranolol). Preliminary data support the association of beta blockers with flecainide. After a cardiac arrest, an implantable cardioverter defibrillator (ICD) should be implanted, but it is accompanied by a disquietingly high incidence of adverse effects. After syncope on beta blocker therapy, left cardiac sympathetic denervation is most effective, preserves quality of life, and does not preclude a subsequent ICD implantation.

Atenolol is not effective in reducing ventricular arrhythmia severity on exercise stress test in patients with catecholaminergic polymorphic ventricular tachycardia

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
P Peltenburg ◽  
K.V.V Lieve ◽  
C Van Der Werf ◽  
A.A.M Wilde ◽  
R Brugada ◽  
...  
Keyword(s):  
Heart Rate ◽  
Ventricular Tachycardia ◽  
Beta Blockers ◽  
Stress Test ◽  
Exercise Stress Test ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Exercise Stress ◽  
Polymorphic Ventricular Tachycardia ◽  
Funding Source ◽  
Different Types

Abstract   Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for malignant ventricular arrhythmias during exercise and emotions which may lead to sudden cardiac death. Beta-blockers (BB) are the mainstay of therapy in patients with CPVT, but studies comparing the efficacy of different types of BB are scarce. Our objective was to determine the efficacy of different types of BB in reducing the ventricular arrhythmia (VA) severity on exercise stress test (EST) in patients with CPVT. Data was derived from the International CPVT Registry, a large retrospective cohort study. We included patients who had an EST before (pre-EST) and after start of BB (post-EST). We divided the cohort into five groups based on the first prescribed BB and compared pre-EST and post-EST. We included 428 patients (median age 18.5 [11.7–39.6] years, 240 (56.%) female), 155 (36.2%) probands) of whom 38 (8.9%) used atenolol, 131 (30.6%) bisoprolol, 82 (19.2%) metoprolol, 124 (29.0%) nadolol and 53 (12.4%) propranolol. Sex and history of aborted cardiac arrest were similar in all groups. The age at start of BB differed (p<0,001): patients using bisoprolol were oldest (35.0 [15.7–35.3]) while patients using propranolol were youngest (12.3 [8.8–24.9]). Median daily BB dose in mg/kg was: 1.0 [0.8–2.3] for atenolol, 0.06 [0.05–0.10] for bisoprolol, 0.9 [0.6–1.5] for metoprolol, 1.1 [0.9–1.6] for nadolol and 1.5 [1.1–2.8] for propranolol. Resting heart rate on pre-EST and post-EST was similar in all groups. Patients using metoprolol had a significantly higher maximum heart rate post-EST compared to nadolol and propranolol (161±18 vs 136±19 and 130±22 bpm, p=0,002 and p=0,001, respectively). The VA severity decreased significantly after BB (147 (37.9%) (non-sustained) ventricular tachycardia ((NS)VT) and 120 (30.9%) no or isolated ventricular premature beat (iVPB) pre-EST vs 46 (11.4%) (NS)VT and 184 (45.7%) iVPB post-EST, p<0,001). Examining the different groups, the VA severity decreased significantly after BB in all but atenolol (13 (40.6%) (NS)VT and 8 (25.0%) iVPB pre-EST vs 9 (25.0%) (NS)VT and 15 (41.7%) iVPB post-EST, p=0,103). Based on these results we conclude that all beta-blockers except atenolol are effective in reducing the VA severity on EST in patients with CPVT. Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): E-Rare Joint Transnational Call for Proposals 2015 “Improving Diagnosis and Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia: Integrating Clinical and Basic Science”

scholarly journals Genealogy and clinical course of catecholaminergic polymorphic ventricular tachycardia caused by the ryanodine receptor type 2 P2328S mutation

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0243649
Author(s):  
Mikael Koponen ◽  
Annukka Marjamaa ◽  
Annukka M. Tuiskula ◽  
Matti Viitasalo ◽  
Terhi Nallinmaa-Luoto ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Cox Regression ◽  
Clinical Course ◽  
Stress Test ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Exercise Stress ◽  
Polymorphic Ventricular Tachycardia ◽  
Rank Test ◽  
Premature Ventricular Contractions ◽  
Mutation Carriers

Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inherited arrhythmic disease associated with a risk of syncope and sudden cardiac death (SCD). Aims We aimed at identifying RYR2 P2328S founder mutation carriers and describing the clinical course associated with the mutation. Methods The study population was drawn from the Finnish Inherited Cardiac Disorder Research Registry, and from the present genealogical study. Kaplan-Meier graphs, log-rank test and Cox regression model were used to evaluate the clinical course. Results Genealogical study revealed a common ancestor couple living in the late 17th century. A total of 1837 living descendants were tested for RYR2 P2328S mutation unveiling 62 mutation carriers aged mean 39±23 years old. No arrhythmic deaths were documented among genotyped subjects, but 11 SCDs were detected in non-genotyped family members since 1970. Three genotyped patients (5%) suffered an aborted cardiac arrest (ACA), and 15 (25%) had a syncope triggered by exercise or stress. Rate of cardiac events was higher among patients who in exercise stress test showed a maximum rate of premature ventricular contractions >30/min (68% vs 17%, p<0.01; hazard ratio = 7.1, p = 0.02), in comparison to patients without the respective finding. A cardioverter-defibrillator (ICD) was implanted to 13 (22%) patients, with an appropriate ICD shock in four (31%) subjects. All ICD shocks, one ACA, and one syncope occurred during β-blocker medication. Conclusions Previously undiagnosed CPVT patients may be identified by well-conducted genealogical studies. The RYR2 P2328S mutation causes a potentially severe phenotype, but its expression is variable, thus calling for additional studies on modifying factors.

scholarly journals A Homozygous CASQ2 Mutation in a Japanese Patient with Catecholaminergic Polymorphic Ventricular Tachycardia

2019 ◽  
Vol 2019 ◽  
pp. 1-3
Author(s):  
Taishi Fujisawa ◽  
Yoshiyasu Aizawa ◽  
Yoshinori Katsumata ◽  
Akihiro Udo ◽  
Shogo Ito ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Japanese Patient ◽  
Stress Testing ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Exercise Stress ◽  
Polymorphic Ventricular Tachycardia ◽  
Ventricular Ectopy ◽  
Recessive Form ◽  
History Of ◽  
Structural Disease

A 62-year-old female had suffered from recurrent syncopal episodes triggered by physical and emotional stress since childhood. She had no family history of sudden death. An intensive examination could not detect any structural disease, and exercise stress testing provoked polymorphic ventricular ectopy followed by polymorphic ventricular tachycardia accompanied with syncope leading to a diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT). A genetic analysis with a next generation sequencer identified a homozygous W361X mutation in the CASQ2 gene. Careful history taking disclosed that her parents had a consanguineous marriage. Here we present a Japanese patient with a recessive form of CPVT.

scholarly journals Incidence and Clinical Management of Atrial Arrhythmias in Patients with Catecholaminergic Polymorphic Ventricular Tachycardia

2021 ◽  
Author(s):  
Gurukripa Kowlgi ◽  
John Giudicessi ◽  
Walid Barake ◽  
Konstantinos Siontis ◽  
Johan Bos ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Ventricular Arrhythmias ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Atrial Arrhythmias ◽  
Single Center ◽  
Ablation Therapy ◽  
Inappropriate Shocks ◽  
Drug Intolerance

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic arrhythmia syndrome characterized by adrenergically-triggered ventricular arrhythmias, syncope, and sudden cardiac death. Several small studies suggest that atrial arrhythmias (AAs) are common in patients with CPVT. Objective: To determine the incidence and type of AAs observed within a large, single-center cohort of CPVT cases as well as the efficacy and durability of AA-directed management. Methods: In this retrospective study, the electronic medical record of 129 patients (52% female; average age at diagnosis 20.8  15.3 years) with CPVT (95% with a putative CPVT1-causative RYR2 variant) between 01/2000 and 09/2019 were reviewed for electrocardiographic evidence of AAs. Clinical features and efficacy of pharmacologic and ablation therapy were assessed. Results: Overall, 10/129 (7.8%) CPVT patients, all RYR2 variant-positive, had evidence of an AA (atrial fibrillation/flutter in 6, atrial tachycardia in 3, and supraventricular tachycardia in 1). The median age at AA diagnosis was 23 (14.2-35.5) years. 8/10 of patients experienced symptoms attributed to their AA, including inappropriate shocks. All patients were trialed on anti-arrhythmics, including -blockers, and/or flecainide. Owing to drug failure (1/10), drug intolerance (1/10), or patient preference (2/10); 4/10 patients received an ablation. Over a median follow-up of 23.5 (4.5-63) months, no AA recurrences were observed. Conclusion: Compared to prior studies, the incidence of AAs in this large, single-center referral cohort of CPVT patients was substantially lower (7.8% vs. 26%-35%). Although larger multi-center studies are needed to confirm, this study suggests that ablation is efficacious and durable in CPVT-associated AAs.

scholarly journals Human RyR2 (Ryanodine Receptor 2) Loss-of-Function Mutations

2021 ◽  
Vol 14 (9) ◽  
Author(s):  
Yanhui Li ◽  
Jinhong Wei ◽  
Wenting Guo ◽  
Bo Sun ◽  
John Paul Estillore ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Sudden Cardiac Death ◽  
Cardiac Death ◽  
Stress Testing ◽  
Functional Characterization ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Exercise Stress ◽  
Polymorphic Ventricular Tachycardia ◽  
Loss Of Function

Background: The overall objective of the present study is to extend our understanding of the clinical phenotype and underlying mechanism of a newly discovered cardiac arrhythmia syndrome through a multicenter study. Gain-of-function mutations in the cardiac Ca 2+ release channel (RyR2 [ryanodine receptor 2]) cause catecholaminergic polymorphic ventricular tachycardia, whereas loss-of-function RyR2 mutations are linked to a new cardiac arrhythmia disorder termed Ca 2+ -release deficiency syndrome (CRDS). Catecholaminergic polymorphic ventricular tachycardia is an inherited arrhythmia disorder characterized by stress-induced bidirectional and polymorphic ventricular tachyarrhythmias and is routinely diagnosed by using exercise stress testing. Conversely, RyR2-CRDS is characterized by ventricular arrhythmias and sudden cardiac death but a negative exercise stress testing for catecholaminergic polymorphic ventricular tachycardia. There are currently no clinical diagnostic tests for CRDS and affected patients may manifest with sudden cardiac death as their first symptom. In the absence of effective clinical diagnostic tools, in vitro functional characterization of associated RyR2 mutations provides an alternative means to identify potential cases of CRDS. Methods: We searched for patients presenting with phenotypes compatible with CRDS that have RyR2 mutations and performed in vitro functional characterization. Results: We found that 3 novel (G570D, R4147K, and A4203V) and 2 previously reported (M4109R and A4204V) RyR2 mutations associated with CRDS phenotypes markedly reduced caffeine-induced Ca 2+ release and store overload-induced Ca 2+ release. We also characterized 2 additional loss-of-function RyR2 mutations previously reported (Q3925E and L4769S) that are located in the central and channel pore-forming domains critical for Ca 2+ activation and channel gating. Q3925E was identified through postmortem genetic testing in an individual who died suddenly, while L4769S is a variant of uncertain significance reported in ClinVar, suggesting that RyR2 CRDS may be under detected. Conclusions: These findings provide further support for the existence of an emerging RyR2 loss-of-function associated arrhythmia syndrome (CRDS) and shed new insights into the disease mechanism.

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