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Nadolol decreases the incidence and severity of ventricular arrhythmias during exercise stress testing compared with β1-selective β-blockers in patients with catecholaminergic polymorphic ventricular tachycardia
Author's Accepted Manuscript
Nadolol Decreases Incidence and Severity of Ventricular Arrhythmias During Exercise Testing Compared to Beta-1 Selective Beta Blockers in Patients with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Ida S. Leren MD, Jørg Saberniak MD, Eman Majid, Trine F. Haland MD, Thor Edvardsen MD, PhD, Kristina H. Haugaa MD, PhD www.elsevier.com/locate/buildenv
PII: DOI: Reference:
S1547-5271(15)01237-0 http://dx.doi.org/10.1016/j.hrthm.2015.09.029 HRTHM6449
To appear in:
Heart Rhythm
Cite this article as: Ida S. Leren MD, Jørg Saberniak MD, Eman Majid, Trine F. Haland MD, Thor Edvardsen MD, PhD, Kristina H. Haugaa MD, PhD, Nadolol Decreases Incidence and Severity of Ventricular Arrhythmias During Exercise Testing Compared to Beta-1 Selective Beta Blockers in Patients with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), Heart Rhythm, http://dx.doi.org/10.1016/j. hrthm.2015.09.029 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Nadolol Decreases Incidence and Severity of Ventricular Arrhythmias During Exercise Testing Compared to Beta-1 Selective Beta Blockers in Patients with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Short title: Anti arrhythmic effects of beta blockers in CPVT
Ida S. Leren, MDa,b, Jørg Saberniak, MDa,b,c, Eman Majidb, Trine F. Haland, MDa,b,c, Thor Edvardsen, MD, PhDa,b,c, Kristina H. Haugaa, MD, PhDa,b,c
a
Dept. of Cardiology and Center for Cardiological Innovation, Oslo University Hospital,
Rikshospitalet, Sognsvannsveien 20, 0372 Oslo, Norway b
University of Oslo, PO Box 1072 Blindern, 0316 Oslo, Norway
c
Institute for Surgical Research, Oslo University Hospital, Rikshospitalet, Sognsvannsveien
20, 0372 Oslo, Norway
Disclosures: None of the authors have any disclosures to declare
Address for correspondence: Assoc Prof Kristina H. Haugaa, MD, PhD Department of Cardiology, Oslo University Hospital, Rikshospitalet PO Box 4950 Nydalen, NO-0424 Oslo, Norway Fax number +4723073530, Telephone number +4723071393 E-mail: [email protected]
1
Abstract Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inheritable cardiac disease predisposing to malignant ventricular arrhythmias. Objective We aimed to explore the incidence and severity of ventricular arrhythmias in CPVT patients untreated, on beta-1 selective beta blockers and on nadolol. Methods In this study, 34 CPVT patients were included (age 34±19 years, 44% female, 88% ryanodine receptor-2 variant positive). We performed 3 bicycle exercise stress tests in each patient;1) before start of beta blocker treatment (untreated), 2)>6 weeks on beta-1 selective beta blockers and 3)>6 weeks on nadolol. We recorded resting and maximum heart rate (HR) and the most severe ventricular arrhythmia occurring. Severity of arrhythmias was scored as: no arrhythmias or only single ventricular extrasystoles (VES)(1), >10 VES per minute or bigeminy (2), couplets (3) and NSVT or VT (4). Results Resting HR was similar on nadolol and beta-1 selective beta blockers (54±10 bpm vs. 56±14 bpm, p=0.50), while maximum heart rate was lower on nadolol (122±21 bpm vs. 139±24 bpm, p=0.001). Arrhythmias during exercise were less severe on nadolol compared to beta-1 selective beta blockers (score: 1.6±0.9 vs. 2.5±0.8, p<0.001) and compared to untreated (1.6±0.9 vs. 2.7±0.9, p=0.001) but not different on beta-1 selective beta blockers compared to untreated (2.5±0.8 vs. 2.7±0.9, p=0.46).
2
Conclusion Incidence and severity of ventricular arrhythmias decreased on nadolol compared to beta-1 selective beta blockers. Beta-1 selective beta blockers did not change occurrence or severity of arrhythmias compared to no medication.
Key words: Catecholaminergic polymorphic ventricular tachycardia, ventricular arrhythmias, beta blocker therapy, exercise test.
3
Abbreviations CPVT: Catecholaminergic polymorphic ventricular tachycardia ECG: Electrocardiography ICD: Implantable cardioverter defibrillator NSVT: Nonsustained ventricular tachycardia RyR2: Ryanodine receptor-2 SCA: Sudden cardiac arrest VES: Ventricular extrasystole VT: Ventricular tachycardia
4
Introduction Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inheritable, arrhythmogenic, cardiac disease with an estimated prevalence of 1:10 000.1 Despite the low prevalence, CPVT is an important cause of sudden cardiac arrest (SCA) in young individuals, and cardiac event rates as high as 80% before the age of 40, have been reported if left untreated.2 However, in the patient populations seen in the era of genetic screening, event rates may be considerably lower.3 Patients typically experience syncope or palpitations due to ventricular arrhythmias during physical activity or emotional stress, but SCA may also be the first manifestation of the disease.2,4 Exercise stress testing is considered the most sensitive clinical tool to detect CPVT and reveals frequent premature ventricular contractions,2,5-7 arrhythmias of increasing severity as workload increases and ultimately bidirectional or polymorphic ventricular tachycardia (VT) which might degenerate to ventricular fibrillation.1,5,8 In about 60% of cases,9 CPVT is caused by mutations in the ryanodine receptor-2 (RyR2) gene. Catecholaminergic stimulation of the beta receptor aggravates pathological, diastolic calcium release from an unstable RyR2 channel, causing malignant ventricular arrhythmias.4 The proarrhythmic mechanism described may not be entirely similar in CPVT patients with probable pathogenic variants in other genes or variant-negative patients. In the new guidelines, beta blocker therapy is a class IC recommendation in clinically diagnosed CPVT patients, and should also be considered in genotype positive, phenotype negative family members (class IIa C).10 Beta blockers are suggested to provide arrhythmia protection by reducing the influence of catecholamines11 by blocking the beta receptor induced intracellular signaling which leads to destabilization of RyR2. However, beta blockers differ in many aspects, including selectivity, half life, lipid solubility and bio availability, and 5
limited data exist on how anti arrhythmic effects differ in specific beta blockers.12-14 A previous report indicated that the unselective beta blocker nadolol might prevent cardiac events more effectively than other beta blockers in CPVT patients.3 Superior effects of unselective beta blockers as nadolol have also been reported in the long QT syndrome.12,15 In this study, we aimed to investigate the effect of different beta blockers on arrhythmias in CPVT patients. We serially investigated the frequency and severity of ventricular arrhythmias untreated, during treatment with a beta-1 selective beta blocker and during nadolol treatment. We hypothesized that nadolol is more effective compared to beta-1 selective beta blockers in suppressing ventricular arrhythmias in CPVT patients.
Methods Patient population and recruitment CPVT patients were included for repeated exercise tests during a visit to the Department of Cardiology, Oslo University Hospital, Rikshospitalet, Norway between 2008 and 2012. Outcome data were collected from patients’ history and were recorded during follow up. The CPVT diagnosis was reviewed in 2014 according to new Expert Consensus Recommendations16 to ensure an up to date CPVT diagnosis in all subjects. These recommendations include patients harbouring a probable pathogenic variant and patients with a structurally normal heart and a normal resting ECG with unexplained exercise induced bidirectional VT or polymorphic ventricular premature beats.16 All patients fulfilled these criteria. Collection of data on effects of different beta blockers was performed retrospectively. Index patients, defined as the first patient in a family to be diagnosed, were genetically tested and variant positive family members were included after family cascade screening. We performed serial investigations of the same patients untreated and on two 6
different beta blocking medications. All changes in medication were performed on clinical indication based on the paper by Hayashi et al. in 2009,3 indicating that patients on nadolol treatment had fewer cardiac events compared to other beta blockers in CPVT. Patients included after 2009 were considered for direct start of nadolol. However, due to legislation formalities regarding availability of nadolol, new patients were treated with a beta-1 selective beta blocker as a bridge to nadolol. All patients were intended to switch from our standard treatment with metoprolol SR to nadolol. Exceptions were patients with contra indications against unselective beta blockers or patients who did not agree to medication change. Compliance to beta blocker therapy was monitored by direct feedback from each patient at the clinical visits. CPVT related symptoms were defined as cardiac syncope, documented ventricular arrhythmia (including nonsustained ventricular tachycardia (NSVT)) from ICD recordings or Holter monitoring, appropriate ICD shocks, aborted cardiac arrest or sudden cardiac death. For calculation of annual event rates, only syncope, appropriate ICD shocks, aborted cardiac arrests and sudden cardiac deaths were included. NSVT was defined as previously reported.17 Significant arrhythmias at the exercise test were defined as >10 single ventricular extrasystoles (VES)/min, bigeminy, couplets, NSVT and VT. Use of medication was recorded. Beta blocker dosage was up-titrated until maximum tolerated dosage in each individual, considering side effects e.g. bradycardia and fatigue. In patients with implantable cardioverter defibrillators (ICDs), the numbers of appropriate and inappropriate shocks were recorded. Arrhythmic window, reflecting span of heart rate during which arrhythmias occurred, was assessed by exercise stress test. Electrocardiography and exercise stress test Twelve-lead resting electrocardiography (ECG) was obtained at time of the exercise stress test. We intended to perform 3 bicycle exercise stress tests in each patient; 1) before 7
start of beta blocker treatment, 2) after >6 weeks on maximum tolerated dosages of beta-1 selective beta blockers and 3) after >6 weeks on maximum tolerated dosages of nadolol. Bicycle exercise tests were performed starting at a workload of 50 W, and increased by 25 W every second minute until exhaustion, e.g. shortness of breath or fatigue or until sustained VT. When multiple exercise tests were performed on the same medication, we chose the test for analysis in the following order: the exercise test at highest beta blocker dosage, highest workload, and longest follow up time. All ECG tracings were analyzed by minimum two independent investigators. Twelve-lead ECG was obtained at the start, monitored continuously, and recorded throughout the examination. Resting and maximum heart rates and maximum workloads were recorded, as well as the heart rate at appearance of arrhythmias. In addition, the most severe arrhythmia during the exercise test was recorded. We defined the arrhythmic window as the range of heart rate between heart rate at first VES and maximum achieved heart rate. Severity of ventricular arrhythmias during exercise was scored as: no arrhythmias or only single VES: 1 point, >10 VES per minute or bigeminy: 2 points, couplets: 3 points and NSVT or VT: 4 points, reflecting severity of arrhythmias.18 Holter recordings Repeated 24-hour Holter recordings were performed before start of treatment and during treatment with maximum tolerated dosage of beta-1 selective beta blockers and nadolol. Holter recordings were analyzed for number of ventricular beats and severity of arrhythmias (scored similarly to the exercise test). Genetic analyses Genetic testing was performed as part of the diagnostic work-up for suspected CPVT. DNA sequencing of 29 of the 105 exons of the RyR2 gene was performed in all index 8
patients, using version 3.1 of BigDye-terminator cycle-sequencing kit and a GeneticAnalyzer3730 from Applied Biosystems. The Calsequestrin-2 gene was not analyzed. Cascade genetic screening was performed in family members of variant positive index patients according to clinical standards and Norwegian legislation. Family members of variant negative patients were not included. Decisions on pathogenicity were based on a total evaluation including previous reports, genomic databases,19,20 in silico programs (PolyPhen and SIFT) and family co segregation studies. Statistical Analyses Continuous data were presented as mean±standard deviation or as median (quartile 1, quartile 3). Comparisons between groups were performed by linear mixed models for dependent continuous variables or by Mc Nemar’s test for dependent nominal variables. Linear mixed models allowed for inclusion of patients with <3 exercise tests available for analyses. Two sided p-values ≤0.05 were considered statistically significant. All participants gave written informed consent. The study complied with the Declaration of Helsinki and was approved by the Regional Committees for Medical Research Ethics.
Results Clinical characteristics A total of 34 CPVT patients (age 34±19 years, 44% female) were included in the study (Table 1) and 30(88%) had a probable pathogenic variant in the RyR2 gene. Five different variants were identified in 5 families. Ten (29%) were index patients and 24(71%) were variant positive family members. Median follow up was 8 years (ranging from 2 to 15 years) including a median of 49 months on beta-1 selective beta blockers (Q1, Q3: 30, 81months) and a median of 35 months on nadolol (Q1, Q3: 19, 46 months). 9
Before initiation of treatment, 13(38%) patients had experienced syncope, 4(12%) had aborted cardiac arrest and 1(3%) had a documented ventricular arrhythmia. During treatment with beta-1 selective beta blockers, 3(11%) patients had syncope including 1(4%) that also had an appropriate ICD shock (non adherent to therapy). One (4%) patient survived a cardiac arrest and had several episodes of NSVT, and 3(11%) patients had documented ventricular arrhythmias (NSVT). One patient died due to stroke during follow up (Figure 1). When treated with nadolol, only 1(6%) patient had syncope. In case of non-adherence to beta blocker therapy (n=2), an individual approach with intensified follow up was applied and ICD implantation and left cardiac sympathetic denervation were considered. Annual event rates were 0.04 on beta-1 selective beta blockers and 0.02 on nadolol (p=0.64). An ICD was implanted in 9(26%) patients of whom 4 received no shock therapy from their ICD during follow up. On beta-1 selective beta blockers, 1 patient had appropriate shock, 1 patient had both appropriate and inappropriate shocks and 2 patients had only inappropriate shocks. On nadolol, 1 patient had both appropriate and inappropriate shocks (non adherent to therapy) and 1 had an inappropriate shock. Exercise tests Exercise test 1 was performed in beta blocker naïve patients. Exercise test 2 and 3 were performed with the beta blocker taken in the morning the same day. In 57 out of a total of 68 exercise tests (84%), the ventricular arrhythmias increased in severity during exercise test. During exercise test 2, the majority of patients was treated with metoprolol SR (dosage 1.4±0.7 mg/kg), while 2 patients were treated with the beta-1 selective beta blocker bisoprolol (dosage 0.14±0.01 mg/kg) due to side effects on metoprolol. Eleven patients remained on beta-1 selective beta blockers (Figure 1) either due to pulmonary disease, other contraindications to unselective beta blocker therapy or unwillingness of the patients to change their previous medication on which they had good arrhythmia control (Figure 1). The 10
11 patients remaining on beta-1 selective beta blockers did not differ in age at diagnosis, nor in total follow up time from those who changed medication. Three patients were treated with flecainide in addition to nadolol, and were consequently excluded from analyses of the effects of nadolol. Occurrence and severity of arrhythmias Resting heart rate was lower on beta blocker treatment compared to untreated regardless of beta blocker type (both p ≤0.01)(Table 2), but was similar during treatment with beta-1 selective beta blockers and nadolol (56±14 bpm vs. 54±10 bpm, p=0.50). Also maximum heart rate was lower during beta blocker treatment compared to untreated (both p<0.001) and lowest during nadolol treatment (p=0.001 vs. beta-1 selective beta blocker treatment). Blood pressure was similar on beta-1 selective beta blockers and nadolol treatment (systolic 115±19 mmHg vs. 121±24mmHg, p=0.21 and diastolic 70±16 mmHg vs. 72±12 mmHg, p=0.31, respectively). Maximum work load was similar at all 3 exercise tests (p>0.10 for all comparisons)(Table 2). Untreated, 23(92%) CPVT patients had ventricular arrhythmias during exercise (ranging from >10 VES/min to NSVT), including 6(25%) NSVT. The average arrhythmic score untreated was 2.7±0.9. Three (12%) patients had no significant arrhythmias (arrhythmic score =1, no arrhythmias or ≤10 single VES/min). Using a beta-1 selective beta blocker (Table 2), 27(96%) patients had ventricular arrhythmias, including 4(14%) with NSVT. The arrhythmic score was similar to untreated (p=0.46)(Table 2 and Figure 2). Two (7%) patients had no significant arrhythmias. During nadolol treatment, 10(59%) patients had no significant arrhythmias (p=0.02 vs. untreated and p=0.008 vs. beta-1 selective beta blocker treatment) and only 1(6%) patient had NSVT (p=0.38 vs. untreated). On nadolol the arrhythmic score was 1.6±0.9, which was lower compared to both beta-1 selective beta blockers (2.5±0.8, p<0.001) and untreated (2.7±0.9, p=0.001)(Figure 2 and Table 2). This result was unchanged 11
when including only patients who serially underwent all 3 exercise tests (Supplemental table). Arrhythmic window, reflecting range of heart rate from occurrence of arrhythmias to maximum heart rate, was smaller on nadolol treatment (17±10 bpm) compared to untreated (37±22 bpm, p<0.001)(Table 2 and Figure 3), and compared to beta-1 selective beta blockers (32±26 bpm, p=0.03)(Table 2 and Figure 3). The threshold for arrhythmias was lower during treatment with beta-1 selective beta blockers compared to untreated (113±19 bpm vs. 128±20 bpm, p<0.001), while no differences were observed during treatment with beta-1 selective beta blockers and nadolol (113±19 bpm and 113±21 bpm, p=1.0)(Table 2). Beta blocker dosages, heart rates and arrhythmias During exercise test 3, dosage of nadolol was 1.3±0.5 mg/kg compared to metoprolol 1.4±0.7 mg/kg during exercise test 2. A dosage of 0.8 mg/kg nadolol and 1 mg/kg metoprolol SR are considered equipotent21,22 and therefore, calculated as equivalents, the dosages of nadolol compared to metoprolol were similar (p=0.15). In intra-individual analyses, 7(50%) patients had equivalent dosages of nadolol and metoprolol SR. Among these, 6(86%) had lower maximal heart rate on nadolol, and 5(71%) had a less severe arrhythmia. This was similar to the 6(43%) patients who had higher dosages of nadolol; 5(83%) had lower maximal heart rate on nadolol, and 5(83%) had less severe arrhythmias on nadolol. One (7%) patient had higher dosages of metoprolol SR, but still had lower maximum heart rate and less severe arrhythmias on nadolol. In 3 patients maximum heart rate was similar (<5 bpm difference) during treatment with beta-1 selective beta blockers and nadolol. In 2 of these patients, severity of arrhythmias decreased (bigeminy to single VES and couplets to bigeminy) and in 1 patient severity was unchanged.
12
Holter monitoring Arrhythmic score calculated from Holter recordings was similar in untreated patients and during treatment with beta-1 selective beta blockers (p=0.42), but the score was lower during treatment with nadolol compared to untreated (p=0.05)(Table 2). Incidence of VES during 24-hour Holter monitoring did not differ between untreated (median 4(0, 17) VES), during treatment with a beta-1 selective beta blocker (2(0, 34) VES) and during nadolol treatment (0(0, 12) VES).
Discussion We present for the first time a study with serial investigations of CPVT patients untreated, treated with beta-1 selective beta blockers, and treated with the unselective beta blocker nadolol. Repeated exercise tests and Holter monitoring showed a reduced frequency and severity of arrhythmias in CPVT during nadolol treatment compared to both beta-1 selective beta blockers and untreated. Occurrence and severity of arrhythmias Untreated, almost every CPVT patient had exercise induced arrhythmias, highlighting the high sensitivity of the exercise test to diagnose patients with CPVT.23 Severity of arrhythmias increased as workload and heart rate increased in the majority of exercise tests performed, similar to previous studies.1,8 In a minority of exercise tests, arrhythmias decreased in severity or disappeared at maximal exercise, as also shown previously.24 The occurrence of arrhythmias was similar during treatment with beta-1 selective beta blockers and untreated, as also reported by others.25-27 However, on nadolol, the occurrence of arrhythmias was lower than untreated and than on beta-1 selective beta blockers and severity of arrhythmias, reflected as arrhythmic score, was lower.
13
Arrhythmias during exercise tests are only surrogate markers of arrhythmias in daily life. However, Hayashi et al. demonstrated that results from exercise tests were associated with future cardiac events, and that patients on nadolol had a lower daily life event rate compared to patients on other beta blockers.3 In our study, arrhythmic events during daily life were present in 7 patients on beta-1 selective beta blockers, but in only one patient on nadolol. However, follow up of patients on nadolol was shorter, thus limiting the interpretation of this finding. Effects of different beta blockers in CPVT Nadolol has been referred to as the beta blocker of choice in CPVT.28,29 This recommendation was based on one single observational study,3 reporting lower cardiac event rate in 63 CPVT patients on nadolol compared to 18 CPVT patients treated with other beta blockers. Our study strengthens this observation by serially investigating CPVT patients and supports nadolol as the beta blocker of choice in CPVT. Possible explanations for the observed effects of nadolol include: 1. Nadolol has a stronger effect on chronotropic response compared to metoprolol and bisoprolol, 2. Nadolol was better tolerated, and metoprolol and bisoprolol were not sufficiently up-titrated or 3. A combination of these and other unknown factors. In our patients, nadolol resulted in lower maximum heart rate compared to beta-1 selective beta blockers which might indicate a more pronounced chronotropic effect. Other parameters as blood pressures, resting heart rate and maximum workloads were similar on nadolol and on beta-1 selective beta blockers, indicating comparable beta blocking action. Heart rate at occurrence of first arrhythmias was similar on beta-1 selective beta blockers and nadolol, hence the arrhythmic window reflecting the range of heart rate during which arrhythmias occurred, was smaller on nadolol treatment. This significant effect of nadolol on chronotropy may reduce the opportunity for more severe arrhythmias to occur during nadolol treatment, although this mechanism is not proven by this 14
study. Other possible factors of different beta blocker action include that metoprolol SR and bisoprolol as beta-1 selective, and nadolol as an unselective beta blocker, differ in several pharmacological aspects. It has been speculated that the additional, small sodium blocking effect of nadolol has a membrane stabilizing effect, important for arrhythmia protection.12,13 Furthermore, nadolol has a long half-life (20-24 hours),30 which reduces the risk of breakthrough symptoms during potential beta blocker non-adherence. Beta blocker nonadherence is a concerning risk in CPVT patients.3,6,31 We carefully up-titrated the dosages of beta blocker in each individual patient over several visits to reach the maximum tolerated dosages of both metoprolol SR and nadolol and final dosages were considered equipotent. In an intra-individual comparison, both maximum heart rate and severity of arrhythmias were lower on nadolol compared to metoprolol SR in patients with equivalent dosages of the two beta blockers, and this was also observed in a patient on higher dosage of metoprolol SR than nadolol. Also in patients with similar maximum heart rate, arrhythmias were less severe on nadolol treatment than on beta-1 selective beta blockers. Therefore, we do not believe that the reduced occurrence and severity of arrhythmias on nadolol was attributed to higher dosage of medication only. On the other hand, the reduction in maximum heart rate on nadolol could also be interpreted as nadolol being better tolerated and more easily uptitrated. In combination, our results indicate that nadolol may be most beneficial in patients with CPVT although the mechanisms are not clear. Our study included a limited number of patients and larger studies are needed to further explore these effects.
Clinical implications Ventricular arrhythmias in CPVT patients are highly malignant and may cause SCA. Treatment to prevent occurrence of arrhythmias, including high dosages of beta blockers, 15
flecainide,18 and eventual left cardiac sympathetic denervation 32 are of vital importance, in particular since ICD therapy in CPVT is not straight forward.33 Our study showed by serial investigations of CPVT patients, that occurrence and severity of arrhythmias decreased during equipotent nadolol treatment compared to beta-1 selective beta blockers. Beta blocker side effects did not seem to increase on nadolol and equipotent dosages of nadolol were well tolerated compared to beta-1 selective beta blockers. However, our population included mainly CPVT1 patients (RyR2 probable pathogenic variant positive), and future studies should include more gene-elusive CPVT patients.
Limitations This study included a limited number of patients, thereby reducing the strength of the conclusions. However, CPVT is a rare condition and the serial investigation design of our study strengthens our results. A few patients were included in the study after start of beta-1 selective beta blockers and not all patients were switched to nadolol medication, making the dataset incomplete. However, the results did not differ when including only patients with all 3 exercise tests completed (supplemental table). It is a potential bias that the patients with most severe arrhythmias (and insufficient arrhythmic control during treatment with beta-1 selective beta blockers) were switched to nadolol, while some of those with less severe arrhythmias remained on beta-1 selective beta blockers. However, nadolol treatment still resulted in fewer and less severe arrhythmias despite the potential bias towards more severe arrhythmias in those switched to nadolol. We analyzed only one exercise test per patient per medication. Results may vary between two exercise tests25 although arrhythmic threshold in CPVT is surprisingly reproducible in our experience. The exercise tests were performed un-blinded to current medication. The tracings were subsequently analyzed by two independent investigators to assure accuracy of arrhythmia interpretation. 16
We did not sequence the entire exome of RyR2, hence variant negative patients may potentially have a probable pathogenic variant in a non-sequenced area.
Conclusion In this study, nadolol treatment was associated with a lower incidence and severity of ventricular arrhythmias compared to beta-1 selective beta blocker treatment in patients with CPVT. Beta-1 selective beta blockers did not seem to change occurrence or severity of arrhythmias compared to untreated. Our results indicate that nadolol may be superior to beta1 selective beta blockers in preventing arrhythmias in CPVT patients.
Acknowledgements We thank all the participants in the study. This work was supported by the Norwegian Health Association, Norway, the Center for Cardiological Innovation, funded by the Research Council of Norway and Simon Fougner Hartmann’s Family Foundation.
Disclosures None.
17
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Inama G, Durin O, Pedrinazzi C, Berisso MZ, Furlanello F. 'Orphan drugs' in cardiology: nadolol and quinidine. J Cardiovasc Med (Hagerstown) 2010;11:143-4.
31.
Roston TM, Vinocur JM, Maginot KR et al. Catecholaminergic polymorphic ventricular tachycardia in children: analysis of therapeutic strategies and outcomes from an international multicenter registry. Circ Arrhythm Electrophysiol 2015;8:63342.
32.
Wilde AA, Bhuiyan ZA, Crotti L, Facchini M, De Ferrari GM, Paul T, Ferrandi C, Koolbergen DR, Odero A, Schwartz PJ. Left cardiac sympathetic denervation for catecholaminergic polymorphic ventricular tachycardia. N Engl J Med 2008;358:2024-9.
33.
Roses-Noguer F, Jarman JW, Clague JR, Till J. Outcomes of defibrillator therapy in catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm 2014;11:5866.
21
Clinical Perspectives Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inheritable, arrhythmogenic disease predisposing to malignant ventricular arrhythmias during exercise or emotional stress, presenting as syncope or sudden cardiac death. Beta blocker therapy is mainstay of medical treatment, but differences in anti arrhythmic efficacy between different beta blockers may exist. We performed for the first time a study with serial exercise tests and Holter examinations in CPVT patients assessing presence and severity of ventricular arrhythmias while beta blocker naïve, treated with beta-1 beta blockers, and treated with the unselective beta blocker nadolol. Our study showed that occurrence and severity of arrhythmias decreased during equipotent dosages of nadolol compared to beta-1 selective beta blockers. Maximum heart rate during exercise test decreased on nadolol, while heart rate at occurrence of arrhythmias remained similar compared to beta-1 selective beta blockers. The reduction in maximum heart rate on nadolol could be a result of better tolerance and easier uptitration of nadolol. The study supports that nadolol seems to provide better anti arrhythmic effects compared to unselective beta blockers and that nadolol may be first choice beta blocker in CPVT patients. Further, favourable effects of nadolol in CPVT emphasize the importance of continued availability of this beta blocker, which has occasionally been limited. Optimal medical therapy is of vital importance in CPVT, in particular since ICD therapy is ambiguous with inherent risk of inappropriate shocks and potentially devastating electrical storms.
22
Tables Table 1: Baseline clinical characteristics of 34 CPVT patients CPVT patients (34) Index patients (n(%))
10(29)
Variant positive family members (n(%))
24(71)
Age at diagnosis (years)
34±19
Female (n(%))
15(44)
Variant positive (n(%))
30(88)
Symptomatic when untreated (n(%))
18(53)
Aborted cardiac arrest
4(12)
Syncope
13(38)
Documented ventricular arrhythmias with
1(3)
hemodynamic deterioration ICD (n(%))
9(26)
CPVT: Catecholaminergic polymorphic ventricular tachycardia, ICD: implantable cardioverter defibrillator, VT: ventricular tachycardia
23
Table 2: Results from exercise tests and Holter recordings untreated, during treatment with beta-1 selective beta blockers and during nadolol treatment in 34 CPVT patients Exercise test 1
Exercise test 2
Exercise test 3
Untreated
Beta-1 selective beta
Nadolol
n=25
blockers
n=17
p-value
n=28 Metoprolol SR: 1.4±0.7 Dosage beta blocker (mg/kg)
1.3±0.5
n.a
Bisoprolol: 0.14±0.01
Resting heart rate (bpm)
63±12
56±14†
54±10†
0.01
Heart rate at first VES (bpm)
128±20
113±19†
113±21
0.003
Maximum heart rate (bpm)
164±17
139±24†
122±21†‡
<0.001
Arrhythmic window (bpm)
37±22
32±26
17±10†‡
0.001
Arrhythmic score
2.7±0.9
2.5±0.8
1.6±0.9†‡
<0.001
Arrhythmic score (Holter)
1.5±0.7
1.4±0.8
1.2±0.6†
0.12
Maximum work load (W)
146±42
163±49
148±38
0.26
(exercise test)
Values given as mean±SD. P by linear mixed models. †: p ≤0.05 vs. untreated ‡: p ≤0.05 vs. beta-1 selective beta blockers. Bpm: beats per minute, CPVT: Catecholaminergic polymorphic ventricular tachycardia, VES: Ventricular extrasystole, W: watt.
24
Figure Legends Figure 1: Flow chart of inclusion and follow up of 34 CPVT patients. Flowchart showing CPVT patients during the 3 exercise tests. CPVT: Catecholaminergic polymorphic ventricular tachycardia.
Figure 2: Incidence and severity of arrhythmias during exercise stress tests in 34 CPVT patients untreated (left), during treatment with beta-1 selective beta blockers (middle) and during nadolol treatment (right). Arrhythmias were less frequent and less severe during nadolol treatment compared with both untreated and beta-1 selective beta blockers, whereas there was no difference between beta-1 selective beta blockers and untreated. CPVT: Catecholaminergic polymorphic ventricular tachycardia, NSVT: Nonsustained ventricular tachycardia, VES: Ventricular extra systole.
Figure 3: Arrhythmic window in patients with CPVT untreated, during treatment with beta-1 beta blockers and during treatment with nadolol. Green bars indicate arrhythmia free heart rates at exercise test and red bars indicate heart rates during which arrhythmias occurred. Green vertical arrows indicate resting heart rate, red vertical arrows indicate heart rate at start of arrhythmias and black vertical arrows indicate maximum heart rate. Red horizontal lines indicate arrhythmic window. The arrhythmic window was smaller during treatment with nadolol compared to both untreated and beta-1 selective beta blockers (*both p <0.05). AW: arrhythmic window, bpm: beats per minute, CPVT: Catecholaminergic polymorphic ventricular tachycardia.
25
Figure 1
26
Figure 2
27
Figure 3
28
Nadolol Decreases Incidence and Severity of Ventricular Arrhythmias During Exercise Testing Compared to Beta-1 Selective Beta Blockers in Patients with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Ida S. Leren MD, Jørg Saberniak MD, Eman Majid, Trine F. Haland MD, Thor Edvardsen MD, PhD, Kristina H. Haugaa MD, PhD www.elsevier.com/locate/buildenv
PII: DOI: Reference:
S1547-5271(15)01237-0 http://dx.doi.org/10.1016/j.hrthm.2015.09.029 HRTHM6449
To appear in:
Heart Rhythm
Cite this article as: Ida S. Leren MD, Jørg Saberniak MD, Eman Majid, Trine F. Haland MD, Thor Edvardsen MD, PhD, Kristina H. Haugaa MD, PhD, Nadolol Decreases Incidence and Severity of Ventricular Arrhythmias During Exercise Testing Compared to Beta-1 Selective Beta Blockers in Patients with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), Heart Rhythm, http://dx.doi.org/10.1016/j. hrthm.2015.09.029 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Nadolol Decreases Incidence and Severity of Ventricular Arrhythmias During Exercise Testing Compared to Beta-1 Selective Beta Blockers in Patients with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Short title: Anti arrhythmic effects of beta blockers in CPVT
Ida S. Leren, MDa,b, Jørg Saberniak, MDa,b,c, Eman Majidb, Trine F. Haland, MDa,b,c, Thor Edvardsen, MD, PhDa,b,c, Kristina H. Haugaa, MD, PhDa,b,c
a
Dept. of Cardiology and Center for Cardiological Innovation, Oslo University Hospital,
Rikshospitalet, Sognsvannsveien 20, 0372 Oslo, Norway b
University of Oslo, PO Box 1072 Blindern, 0316 Oslo, Norway
c
Institute for Surgical Research, Oslo University Hospital, Rikshospitalet, Sognsvannsveien
20, 0372 Oslo, Norway
Disclosures: None of the authors have any disclosures to declare
Address for correspondence: Assoc Prof Kristina H. Haugaa, MD, PhD Department of Cardiology, Oslo University Hospital, Rikshospitalet PO Box 4950 Nydalen, NO-0424 Oslo, Norway Fax number +4723073530, Telephone number +4723071393 E-mail: [email protected]
1
Abstract Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inheritable cardiac disease predisposing to malignant ventricular arrhythmias. Objective We aimed to explore the incidence and severity of ventricular arrhythmias in CPVT patients untreated, on beta-1 selective beta blockers and on nadolol. Methods In this study, 34 CPVT patients were included (age 34±19 years, 44% female, 88% ryanodine receptor-2 variant positive). We performed 3 bicycle exercise stress tests in each patient;1) before start of beta blocker treatment (untreated), 2)>6 weeks on beta-1 selective beta blockers and 3)>6 weeks on nadolol. We recorded resting and maximum heart rate (HR) and the most severe ventricular arrhythmia occurring. Severity of arrhythmias was scored as: no arrhythmias or only single ventricular extrasystoles (VES)(1), >10 VES per minute or bigeminy (2), couplets (3) and NSVT or VT (4). Results Resting HR was similar on nadolol and beta-1 selective beta blockers (54±10 bpm vs. 56±14 bpm, p=0.50), while maximum heart rate was lower on nadolol (122±21 bpm vs. 139±24 bpm, p=0.001). Arrhythmias during exercise were less severe on nadolol compared to beta-1 selective beta blockers (score: 1.6±0.9 vs. 2.5±0.8, p<0.001) and compared to untreated (1.6±0.9 vs. 2.7±0.9, p=0.001) but not different on beta-1 selective beta blockers compared to untreated (2.5±0.8 vs. 2.7±0.9, p=0.46).
2
Conclusion Incidence and severity of ventricular arrhythmias decreased on nadolol compared to beta-1 selective beta blockers. Beta-1 selective beta blockers did not change occurrence or severity of arrhythmias compared to no medication.
Key words: Catecholaminergic polymorphic ventricular tachycardia, ventricular arrhythmias, beta blocker therapy, exercise test.
3
Abbreviations CPVT: Catecholaminergic polymorphic ventricular tachycardia ECG: Electrocardiography ICD: Implantable cardioverter defibrillator NSVT: Nonsustained ventricular tachycardia RyR2: Ryanodine receptor-2 SCA: Sudden cardiac arrest VES: Ventricular extrasystole VT: Ventricular tachycardia
4
Introduction Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inheritable, arrhythmogenic, cardiac disease with an estimated prevalence of 1:10 000.1 Despite the low prevalence, CPVT is an important cause of sudden cardiac arrest (SCA) in young individuals, and cardiac event rates as high as 80% before the age of 40, have been reported if left untreated.2 However, in the patient populations seen in the era of genetic screening, event rates may be considerably lower.3 Patients typically experience syncope or palpitations due to ventricular arrhythmias during physical activity or emotional stress, but SCA may also be the first manifestation of the disease.2,4 Exercise stress testing is considered the most sensitive clinical tool to detect CPVT and reveals frequent premature ventricular contractions,2,5-7 arrhythmias of increasing severity as workload increases and ultimately bidirectional or polymorphic ventricular tachycardia (VT) which might degenerate to ventricular fibrillation.1,5,8 In about 60% of cases,9 CPVT is caused by mutations in the ryanodine receptor-2 (RyR2) gene. Catecholaminergic stimulation of the beta receptor aggravates pathological, diastolic calcium release from an unstable RyR2 channel, causing malignant ventricular arrhythmias.4 The proarrhythmic mechanism described may not be entirely similar in CPVT patients with probable pathogenic variants in other genes or variant-negative patients. In the new guidelines, beta blocker therapy is a class IC recommendation in clinically diagnosed CPVT patients, and should also be considered in genotype positive, phenotype negative family members (class IIa C).10 Beta blockers are suggested to provide arrhythmia protection by reducing the influence of catecholamines11 by blocking the beta receptor induced intracellular signaling which leads to destabilization of RyR2. However, beta blockers differ in many aspects, including selectivity, half life, lipid solubility and bio availability, and 5
limited data exist on how anti arrhythmic effects differ in specific beta blockers.12-14 A previous report indicated that the unselective beta blocker nadolol might prevent cardiac events more effectively than other beta blockers in CPVT patients.3 Superior effects of unselective beta blockers as nadolol have also been reported in the long QT syndrome.12,15 In this study, we aimed to investigate the effect of different beta blockers on arrhythmias in CPVT patients. We serially investigated the frequency and severity of ventricular arrhythmias untreated, during treatment with a beta-1 selective beta blocker and during nadolol treatment. We hypothesized that nadolol is more effective compared to beta-1 selective beta blockers in suppressing ventricular arrhythmias in CPVT patients.
Methods Patient population and recruitment CPVT patients were included for repeated exercise tests during a visit to the Department of Cardiology, Oslo University Hospital, Rikshospitalet, Norway between 2008 and 2012. Outcome data were collected from patients’ history and were recorded during follow up. The CPVT diagnosis was reviewed in 2014 according to new Expert Consensus Recommendations16 to ensure an up to date CPVT diagnosis in all subjects. These recommendations include patients harbouring a probable pathogenic variant and patients with a structurally normal heart and a normal resting ECG with unexplained exercise induced bidirectional VT or polymorphic ventricular premature beats.16 All patients fulfilled these criteria. Collection of data on effects of different beta blockers was performed retrospectively. Index patients, defined as the first patient in a family to be diagnosed, were genetically tested and variant positive family members were included after family cascade screening. We performed serial investigations of the same patients untreated and on two 6
different beta blocking medications. All changes in medication were performed on clinical indication based on the paper by Hayashi et al. in 2009,3 indicating that patients on nadolol treatment had fewer cardiac events compared to other beta blockers in CPVT. Patients included after 2009 were considered for direct start of nadolol. However, due to legislation formalities regarding availability of nadolol, new patients were treated with a beta-1 selective beta blocker as a bridge to nadolol. All patients were intended to switch from our standard treatment with metoprolol SR to nadolol. Exceptions were patients with contra indications against unselective beta blockers or patients who did not agree to medication change. Compliance to beta blocker therapy was monitored by direct feedback from each patient at the clinical visits. CPVT related symptoms were defined as cardiac syncope, documented ventricular arrhythmia (including nonsustained ventricular tachycardia (NSVT)) from ICD recordings or Holter monitoring, appropriate ICD shocks, aborted cardiac arrest or sudden cardiac death. For calculation of annual event rates, only syncope, appropriate ICD shocks, aborted cardiac arrests and sudden cardiac deaths were included. NSVT was defined as previously reported.17 Significant arrhythmias at the exercise test were defined as >10 single ventricular extrasystoles (VES)/min, bigeminy, couplets, NSVT and VT. Use of medication was recorded. Beta blocker dosage was up-titrated until maximum tolerated dosage in each individual, considering side effects e.g. bradycardia and fatigue. In patients with implantable cardioverter defibrillators (ICDs), the numbers of appropriate and inappropriate shocks were recorded. Arrhythmic window, reflecting span of heart rate during which arrhythmias occurred, was assessed by exercise stress test. Electrocardiography and exercise stress test Twelve-lead resting electrocardiography (ECG) was obtained at time of the exercise stress test. We intended to perform 3 bicycle exercise stress tests in each patient; 1) before 7
start of beta blocker treatment, 2) after >6 weeks on maximum tolerated dosages of beta-1 selective beta blockers and 3) after >6 weeks on maximum tolerated dosages of nadolol. Bicycle exercise tests were performed starting at a workload of 50 W, and increased by 25 W every second minute until exhaustion, e.g. shortness of breath or fatigue or until sustained VT. When multiple exercise tests were performed on the same medication, we chose the test for analysis in the following order: the exercise test at highest beta blocker dosage, highest workload, and longest follow up time. All ECG tracings were analyzed by minimum two independent investigators. Twelve-lead ECG was obtained at the start, monitored continuously, and recorded throughout the examination. Resting and maximum heart rates and maximum workloads were recorded, as well as the heart rate at appearance of arrhythmias. In addition, the most severe arrhythmia during the exercise test was recorded. We defined the arrhythmic window as the range of heart rate between heart rate at first VES and maximum achieved heart rate. Severity of ventricular arrhythmias during exercise was scored as: no arrhythmias or only single VES: 1 point, >10 VES per minute or bigeminy: 2 points, couplets: 3 points and NSVT or VT: 4 points, reflecting severity of arrhythmias.18 Holter recordings Repeated 24-hour Holter recordings were performed before start of treatment and during treatment with maximum tolerated dosage of beta-1 selective beta blockers and nadolol. Holter recordings were analyzed for number of ventricular beats and severity of arrhythmias (scored similarly to the exercise test). Genetic analyses Genetic testing was performed as part of the diagnostic work-up for suspected CPVT. DNA sequencing of 29 of the 105 exons of the RyR2 gene was performed in all index 8
patients, using version 3.1 of BigDye-terminator cycle-sequencing kit and a GeneticAnalyzer3730 from Applied Biosystems. The Calsequestrin-2 gene was not analyzed. Cascade genetic screening was performed in family members of variant positive index patients according to clinical standards and Norwegian legislation. Family members of variant negative patients were not included. Decisions on pathogenicity were based on a total evaluation including previous reports, genomic databases,19,20 in silico programs (PolyPhen and SIFT) and family co segregation studies. Statistical Analyses Continuous data were presented as mean±standard deviation or as median (quartile 1, quartile 3). Comparisons between groups were performed by linear mixed models for dependent continuous variables or by Mc Nemar’s test for dependent nominal variables. Linear mixed models allowed for inclusion of patients with <3 exercise tests available for analyses. Two sided p-values ≤0.05 were considered statistically significant. All participants gave written informed consent. The study complied with the Declaration of Helsinki and was approved by the Regional Committees for Medical Research Ethics.
Results Clinical characteristics A total of 34 CPVT patients (age 34±19 years, 44% female) were included in the study (Table 1) and 30(88%) had a probable pathogenic variant in the RyR2 gene. Five different variants were identified in 5 families. Ten (29%) were index patients and 24(71%) were variant positive family members. Median follow up was 8 years (ranging from 2 to 15 years) including a median of 49 months on beta-1 selective beta blockers (Q1, Q3: 30, 81months) and a median of 35 months on nadolol (Q1, Q3: 19, 46 months). 9
Before initiation of treatment, 13(38%) patients had experienced syncope, 4(12%) had aborted cardiac arrest and 1(3%) had a documented ventricular arrhythmia. During treatment with beta-1 selective beta blockers, 3(11%) patients had syncope including 1(4%) that also had an appropriate ICD shock (non adherent to therapy). One (4%) patient survived a cardiac arrest and had several episodes of NSVT, and 3(11%) patients had documented ventricular arrhythmias (NSVT). One patient died due to stroke during follow up (Figure 1). When treated with nadolol, only 1(6%) patient had syncope. In case of non-adherence to beta blocker therapy (n=2), an individual approach with intensified follow up was applied and ICD implantation and left cardiac sympathetic denervation were considered. Annual event rates were 0.04 on beta-1 selective beta blockers and 0.02 on nadolol (p=0.64). An ICD was implanted in 9(26%) patients of whom 4 received no shock therapy from their ICD during follow up. On beta-1 selective beta blockers, 1 patient had appropriate shock, 1 patient had both appropriate and inappropriate shocks and 2 patients had only inappropriate shocks. On nadolol, 1 patient had both appropriate and inappropriate shocks (non adherent to therapy) and 1 had an inappropriate shock. Exercise tests Exercise test 1 was performed in beta blocker naïve patients. Exercise test 2 and 3 were performed with the beta blocker taken in the morning the same day. In 57 out of a total of 68 exercise tests (84%), the ventricular arrhythmias increased in severity during exercise test. During exercise test 2, the majority of patients was treated with metoprolol SR (dosage 1.4±0.7 mg/kg), while 2 patients were treated with the beta-1 selective beta blocker bisoprolol (dosage 0.14±0.01 mg/kg) due to side effects on metoprolol. Eleven patients remained on beta-1 selective beta blockers (Figure 1) either due to pulmonary disease, other contraindications to unselective beta blocker therapy or unwillingness of the patients to change their previous medication on which they had good arrhythmia control (Figure 1). The 10
11 patients remaining on beta-1 selective beta blockers did not differ in age at diagnosis, nor in total follow up time from those who changed medication. Three patients were treated with flecainide in addition to nadolol, and were consequently excluded from analyses of the effects of nadolol. Occurrence and severity of arrhythmias Resting heart rate was lower on beta blocker treatment compared to untreated regardless of beta blocker type (both p ≤0.01)(Table 2), but was similar during treatment with beta-1 selective beta blockers and nadolol (56±14 bpm vs. 54±10 bpm, p=0.50). Also maximum heart rate was lower during beta blocker treatment compared to untreated (both p<0.001) and lowest during nadolol treatment (p=0.001 vs. beta-1 selective beta blocker treatment). Blood pressure was similar on beta-1 selective beta blockers and nadolol treatment (systolic 115±19 mmHg vs. 121±24mmHg, p=0.21 and diastolic 70±16 mmHg vs. 72±12 mmHg, p=0.31, respectively). Maximum work load was similar at all 3 exercise tests (p>0.10 for all comparisons)(Table 2). Untreated, 23(92%) CPVT patients had ventricular arrhythmias during exercise (ranging from >10 VES/min to NSVT), including 6(25%) NSVT. The average arrhythmic score untreated was 2.7±0.9. Three (12%) patients had no significant arrhythmias (arrhythmic score =1, no arrhythmias or ≤10 single VES/min). Using a beta-1 selective beta blocker (Table 2), 27(96%) patients had ventricular arrhythmias, including 4(14%) with NSVT. The arrhythmic score was similar to untreated (p=0.46)(Table 2 and Figure 2). Two (7%) patients had no significant arrhythmias. During nadolol treatment, 10(59%) patients had no significant arrhythmias (p=0.02 vs. untreated and p=0.008 vs. beta-1 selective beta blocker treatment) and only 1(6%) patient had NSVT (p=0.38 vs. untreated). On nadolol the arrhythmic score was 1.6±0.9, which was lower compared to both beta-1 selective beta blockers (2.5±0.8, p<0.001) and untreated (2.7±0.9, p=0.001)(Figure 2 and Table 2). This result was unchanged 11
when including only patients who serially underwent all 3 exercise tests (Supplemental table). Arrhythmic window, reflecting range of heart rate from occurrence of arrhythmias to maximum heart rate, was smaller on nadolol treatment (17±10 bpm) compared to untreated (37±22 bpm, p<0.001)(Table 2 and Figure 3), and compared to beta-1 selective beta blockers (32±26 bpm, p=0.03)(Table 2 and Figure 3). The threshold for arrhythmias was lower during treatment with beta-1 selective beta blockers compared to untreated (113±19 bpm vs. 128±20 bpm, p<0.001), while no differences were observed during treatment with beta-1 selective beta blockers and nadolol (113±19 bpm and 113±21 bpm, p=1.0)(Table 2). Beta blocker dosages, heart rates and arrhythmias During exercise test 3, dosage of nadolol was 1.3±0.5 mg/kg compared to metoprolol 1.4±0.7 mg/kg during exercise test 2. A dosage of 0.8 mg/kg nadolol and 1 mg/kg metoprolol SR are considered equipotent21,22 and therefore, calculated as equivalents, the dosages of nadolol compared to metoprolol were similar (p=0.15). In intra-individual analyses, 7(50%) patients had equivalent dosages of nadolol and metoprolol SR. Among these, 6(86%) had lower maximal heart rate on nadolol, and 5(71%) had a less severe arrhythmia. This was similar to the 6(43%) patients who had higher dosages of nadolol; 5(83%) had lower maximal heart rate on nadolol, and 5(83%) had less severe arrhythmias on nadolol. One (7%) patient had higher dosages of metoprolol SR, but still had lower maximum heart rate and less severe arrhythmias on nadolol. In 3 patients maximum heart rate was similar (<5 bpm difference) during treatment with beta-1 selective beta blockers and nadolol. In 2 of these patients, severity of arrhythmias decreased (bigeminy to single VES and couplets to bigeminy) and in 1 patient severity was unchanged.
12
Holter monitoring Arrhythmic score calculated from Holter recordings was similar in untreated patients and during treatment with beta-1 selective beta blockers (p=0.42), but the score was lower during treatment with nadolol compared to untreated (p=0.05)(Table 2). Incidence of VES during 24-hour Holter monitoring did not differ between untreated (median 4(0, 17) VES), during treatment with a beta-1 selective beta blocker (2(0, 34) VES) and during nadolol treatment (0(0, 12) VES).
Discussion We present for the first time a study with serial investigations of CPVT patients untreated, treated with beta-1 selective beta blockers, and treated with the unselective beta blocker nadolol. Repeated exercise tests and Holter monitoring showed a reduced frequency and severity of arrhythmias in CPVT during nadolol treatment compared to both beta-1 selective beta blockers and untreated. Occurrence and severity of arrhythmias Untreated, almost every CPVT patient had exercise induced arrhythmias, highlighting the high sensitivity of the exercise test to diagnose patients with CPVT.23 Severity of arrhythmias increased as workload and heart rate increased in the majority of exercise tests performed, similar to previous studies.1,8 In a minority of exercise tests, arrhythmias decreased in severity or disappeared at maximal exercise, as also shown previously.24 The occurrence of arrhythmias was similar during treatment with beta-1 selective beta blockers and untreated, as also reported by others.25-27 However, on nadolol, the occurrence of arrhythmias was lower than untreated and than on beta-1 selective beta blockers and severity of arrhythmias, reflected as arrhythmic score, was lower.
13
Arrhythmias during exercise tests are only surrogate markers of arrhythmias in daily life. However, Hayashi et al. demonstrated that results from exercise tests were associated with future cardiac events, and that patients on nadolol had a lower daily life event rate compared to patients on other beta blockers.3 In our study, arrhythmic events during daily life were present in 7 patients on beta-1 selective beta blockers, but in only one patient on nadolol. However, follow up of patients on nadolol was shorter, thus limiting the interpretation of this finding. Effects of different beta blockers in CPVT Nadolol has been referred to as the beta blocker of choice in CPVT.28,29 This recommendation was based on one single observational study,3 reporting lower cardiac event rate in 63 CPVT patients on nadolol compared to 18 CPVT patients treated with other beta blockers. Our study strengthens this observation by serially investigating CPVT patients and supports nadolol as the beta blocker of choice in CPVT. Possible explanations for the observed effects of nadolol include: 1. Nadolol has a stronger effect on chronotropic response compared to metoprolol and bisoprolol, 2. Nadolol was better tolerated, and metoprolol and bisoprolol were not sufficiently up-titrated or 3. A combination of these and other unknown factors. In our patients, nadolol resulted in lower maximum heart rate compared to beta-1 selective beta blockers which might indicate a more pronounced chronotropic effect. Other parameters as blood pressures, resting heart rate and maximum workloads were similar on nadolol and on beta-1 selective beta blockers, indicating comparable beta blocking action. Heart rate at occurrence of first arrhythmias was similar on beta-1 selective beta blockers and nadolol, hence the arrhythmic window reflecting the range of heart rate during which arrhythmias occurred, was smaller on nadolol treatment. This significant effect of nadolol on chronotropy may reduce the opportunity for more severe arrhythmias to occur during nadolol treatment, although this mechanism is not proven by this 14
study. Other possible factors of different beta blocker action include that metoprolol SR and bisoprolol as beta-1 selective, and nadolol as an unselective beta blocker, differ in several pharmacological aspects. It has been speculated that the additional, small sodium blocking effect of nadolol has a membrane stabilizing effect, important for arrhythmia protection.12,13 Furthermore, nadolol has a long half-life (20-24 hours),30 which reduces the risk of breakthrough symptoms during potential beta blocker non-adherence. Beta blocker nonadherence is a concerning risk in CPVT patients.3,6,31 We carefully up-titrated the dosages of beta blocker in each individual patient over several visits to reach the maximum tolerated dosages of both metoprolol SR and nadolol and final dosages were considered equipotent. In an intra-individual comparison, both maximum heart rate and severity of arrhythmias were lower on nadolol compared to metoprolol SR in patients with equivalent dosages of the two beta blockers, and this was also observed in a patient on higher dosage of metoprolol SR than nadolol. Also in patients with similar maximum heart rate, arrhythmias were less severe on nadolol treatment than on beta-1 selective beta blockers. Therefore, we do not believe that the reduced occurrence and severity of arrhythmias on nadolol was attributed to higher dosage of medication only. On the other hand, the reduction in maximum heart rate on nadolol could also be interpreted as nadolol being better tolerated and more easily uptitrated. In combination, our results indicate that nadolol may be most beneficial in patients with CPVT although the mechanisms are not clear. Our study included a limited number of patients and larger studies are needed to further explore these effects.
Clinical implications Ventricular arrhythmias in CPVT patients are highly malignant and may cause SCA. Treatment to prevent occurrence of arrhythmias, including high dosages of beta blockers, 15
flecainide,18 and eventual left cardiac sympathetic denervation 32 are of vital importance, in particular since ICD therapy in CPVT is not straight forward.33 Our study showed by serial investigations of CPVT patients, that occurrence and severity of arrhythmias decreased during equipotent nadolol treatment compared to beta-1 selective beta blockers. Beta blocker side effects did not seem to increase on nadolol and equipotent dosages of nadolol were well tolerated compared to beta-1 selective beta blockers. However, our population included mainly CPVT1 patients (RyR2 probable pathogenic variant positive), and future studies should include more gene-elusive CPVT patients.
Limitations This study included a limited number of patients, thereby reducing the strength of the conclusions. However, CPVT is a rare condition and the serial investigation design of our study strengthens our results. A few patients were included in the study after start of beta-1 selective beta blockers and not all patients were switched to nadolol medication, making the dataset incomplete. However, the results did not differ when including only patients with all 3 exercise tests completed (supplemental table). It is a potential bias that the patients with most severe arrhythmias (and insufficient arrhythmic control during treatment with beta-1 selective beta blockers) were switched to nadolol, while some of those with less severe arrhythmias remained on beta-1 selective beta blockers. However, nadolol treatment still resulted in fewer and less severe arrhythmias despite the potential bias towards more severe arrhythmias in those switched to nadolol. We analyzed only one exercise test per patient per medication. Results may vary between two exercise tests25 although arrhythmic threshold in CPVT is surprisingly reproducible in our experience. The exercise tests were performed un-blinded to current medication. The tracings were subsequently analyzed by two independent investigators to assure accuracy of arrhythmia interpretation. 16
We did not sequence the entire exome of RyR2, hence variant negative patients may potentially have a probable pathogenic variant in a non-sequenced area.
Conclusion In this study, nadolol treatment was associated with a lower incidence and severity of ventricular arrhythmias compared to beta-1 selective beta blocker treatment in patients with CPVT. Beta-1 selective beta blockers did not seem to change occurrence or severity of arrhythmias compared to untreated. Our results indicate that nadolol may be superior to beta1 selective beta blockers in preventing arrhythmias in CPVT patients.
Acknowledgements We thank all the participants in the study. This work was supported by the Norwegian Health Association, Norway, the Center for Cardiological Innovation, funded by the Research Council of Norway and Simon Fougner Hartmann’s Family Foundation.
Disclosures None.
17
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Clinical Perspectives Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inheritable, arrhythmogenic disease predisposing to malignant ventricular arrhythmias during exercise or emotional stress, presenting as syncope or sudden cardiac death. Beta blocker therapy is mainstay of medical treatment, but differences in anti arrhythmic efficacy between different beta blockers may exist. We performed for the first time a study with serial exercise tests and Holter examinations in CPVT patients assessing presence and severity of ventricular arrhythmias while beta blocker naïve, treated with beta-1 beta blockers, and treated with the unselective beta blocker nadolol. Our study showed that occurrence and severity of arrhythmias decreased during equipotent dosages of nadolol compared to beta-1 selective beta blockers. Maximum heart rate during exercise test decreased on nadolol, while heart rate at occurrence of arrhythmias remained similar compared to beta-1 selective beta blockers. The reduction in maximum heart rate on nadolol could be a result of better tolerance and easier uptitration of nadolol. The study supports that nadolol seems to provide better anti arrhythmic effects compared to unselective beta blockers and that nadolol may be first choice beta blocker in CPVT patients. Further, favourable effects of nadolol in CPVT emphasize the importance of continued availability of this beta blocker, which has occasionally been limited. Optimal medical therapy is of vital importance in CPVT, in particular since ICD therapy is ambiguous with inherent risk of inappropriate shocks and potentially devastating electrical storms.
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Tables Table 1: Baseline clinical characteristics of 34 CPVT patients CPVT patients (34) Index patients (n(%))
10(29)
Variant positive family members (n(%))
24(71)
Age at diagnosis (years)
34±19
Female (n(%))
15(44)
Variant positive (n(%))
30(88)
Symptomatic when untreated (n(%))
18(53)
Aborted cardiac arrest
4(12)
Syncope
13(38)
Documented ventricular arrhythmias with
1(3)
hemodynamic deterioration ICD (n(%))
9(26)
CPVT: Catecholaminergic polymorphic ventricular tachycardia, ICD: implantable cardioverter defibrillator, VT: ventricular tachycardia
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Table 2: Results from exercise tests and Holter recordings untreated, during treatment with beta-1 selective beta blockers and during nadolol treatment in 34 CPVT patients Exercise test 1
Exercise test 2
Exercise test 3
Untreated
Beta-1 selective beta
Nadolol
n=25
blockers
n=17
p-value
n=28 Metoprolol SR: 1.4±0.7 Dosage beta blocker (mg/kg)
1.3±0.5
n.a
Bisoprolol: 0.14±0.01
Resting heart rate (bpm)
63±12
56±14†
54±10†
0.01
Heart rate at first VES (bpm)
128±20
113±19†
113±21
0.003
Maximum heart rate (bpm)
164±17
139±24†
122±21†‡
<0.001
Arrhythmic window (bpm)
37±22
32±26
17±10†‡
0.001
Arrhythmic score
2.7±0.9
2.5±0.8
1.6±0.9†‡
<0.001
Arrhythmic score (Holter)
1.5±0.7
1.4±0.8
1.2±0.6†
0.12
Maximum work load (W)
146±42
163±49
148±38
0.26
(exercise test)
Values given as mean±SD. P by linear mixed models. †: p ≤0.05 vs. untreated ‡: p ≤0.05 vs. beta-1 selective beta blockers. Bpm: beats per minute, CPVT: Catecholaminergic polymorphic ventricular tachycardia, VES: Ventricular extrasystole, W: watt.
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Figure Legends Figure 1: Flow chart of inclusion and follow up of 34 CPVT patients. Flowchart showing CPVT patients during the 3 exercise tests. CPVT: Catecholaminergic polymorphic ventricular tachycardia.
Figure 2: Incidence and severity of arrhythmias during exercise stress tests in 34 CPVT patients untreated (left), during treatment with beta-1 selective beta blockers (middle) and during nadolol treatment (right). Arrhythmias were less frequent and less severe during nadolol treatment compared with both untreated and beta-1 selective beta blockers, whereas there was no difference between beta-1 selective beta blockers and untreated. CPVT: Catecholaminergic polymorphic ventricular tachycardia, NSVT: Nonsustained ventricular tachycardia, VES: Ventricular extra systole.
Figure 3: Arrhythmic window in patients with CPVT untreated, during treatment with beta-1 beta blockers and during treatment with nadolol. Green bars indicate arrhythmia free heart rates at exercise test and red bars indicate heart rates during which arrhythmias occurred. Green vertical arrows indicate resting heart rate, red vertical arrows indicate heart rate at start of arrhythmias and black vertical arrows indicate maximum heart rate. Red horizontal lines indicate arrhythmic window. The arrhythmic window was smaller during treatment with nadolol compared to both untreated and beta-1 selective beta blockers (*both p <0.05). AW: arrhythmic window, bpm: beats per minute, CPVT: Catecholaminergic polymorphic ventricular tachycardia.
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Figure 1
26
Figure 2
27
Figure 3
28