Heart Rate Recovery After Exercise Is Associated With Arrhythmic Events in Patients With Catecholaminergic Polymorphic Ventricular Tachycardia

BACKGROUND: Risk stratification in catecholaminergic polymorphic ventricular tachycardia remains ill defined. Heart rate recovery (HRR) immediately after exercise is regulated by autonomic reflexes, particularly vagal tone, and may be associated with symptoms and ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. Our objective was to evaluate whether HRR after maximal exercise on the exercise stress test (EST) is associated with symptoms and ventricular arrhythmias. METHODS: In this retrospective observational study, we included patients ≤65 years of age with an EST without antiarrhythmic drugs who attained at least 80% of their age- and sex-predicted maximal HR. HRR in the recovery phase was calculated as the difference in heart rate (HR) at maximal exercise and at 1 minute in the recovery phase (ΔHRR1'). RESULTS: We included 187 patients (median age, 36 years; 68 [36%] symptomatic before diagnosis). Pre-EST HR and maximal HR were equal among symptomatic and asymptomatic patients. Patients who were symptomatic before diagnosis had a greater ΔHRR1' after maximal exercise (43 [interquartile range, 25-58] versus 25 [interquartile range, 19-34] beats/min; P<0.001). Corrected for age, sex, and relatedness, patients in the upper tertile for ΔHRR1' had an odds ratio of 3.4 (95% CI, 1.6-7.4) of being symptomatic before diagnosis (P<0.001). In addition, ΔHRR1' was higher in patients with complex ventricular arrhythmias at EST off antiarrhythmic drugs (33 [interquartile range, 22-48] versus 27 [interquartile range, 20-36] beats/min; P=0.01). After diagnosis, patients with a ΔHRR1' in the upper tertile of its distribution had significantly more arrhythmic events as compared with patients in the other tertiles (P=0.045). CONCLUSIONS: Catecholaminergic polymorphic ventricular tachycardia patients with a larger HRR following exercise are more likely to be symptomatic and have complex ventricular arrhythmias during the first EST off antiarrhythmic drug

An International Multicenter Cohort Study on beta-Blockers for the Treatment of Symptomatic Children With Catecholaminergic Polymorphic Ventricular Tachycardia

Background: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. β-Blockers decrease this risk, but studies comparing individual β-blockers in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of β-blocker in a large cohort of symptomatic children with CPVT.Methods: From 2 international registries of patients with CPVT, RYR2 variant–carrying symptomatic children (defined as syncope or sudden cardiac arrest before β-blocker initiation and age at start of β-blocker therapy &lt;18 years), treated with a β-blocker were included. Cox regression analyses with time-dependent covariates for β-blockers and potential confounders were used to assess the hazard ratio (HR). The primary outcome was the first occurrence of sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter-defibrillator shock, or syncope. The secondary outcome was the first occurrence of any of the primary outcomes except syncope.Results: We included 329 patients (median age at diagnosis, 12 [interquartile range, 7–15] years, 35% females). Ninety-nine (30.1%) patients experienced the primary outcome and 74 (22.5%) experienced the secondary outcome during a median follow-up of 6.7 (interquartile range, 2.8–12.5) years. Two-hundred sixteen patients (66.0%) used a nonselective β-blocker (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a β1-selective β-blocker (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial β-blocker. Baseline characteristics did not differ. The HRs for both the primary and secondary outcomes were higher for β1-selective compared with nonselective β-blockers (HR, 2.04 [95% CI, 1.31–3.17]; and HR, 1.99 [95% CI, 1.20–3.30], respectively). When assessed separately, the HR for the primary outcome was higher for atenolol (HR, 2.68 [95% CI, 1.44–4.99]), bisoprolol (HR, 3.24 [95% CI, 1.47–7.18]), and metoprolol (HR, 2.18 [95% CI, 1.08–4.40]) compared with nadolol, but did not differ from propranolol. The HR of the secondary outcome was only higher in atenolol compared with nadolol (HR, 2.68 [95% CI, 1.30–5.55]).Conclusions: β1-selective β-blockers were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with nonselective β-blockers, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred β-blocker for treating symptomatic children with CPVT.</p

Inherited ion channel diseases: a brief review

Ion channelopathies are diseases caused by dysfunctional ion channels that may lead to sudden death. These diseases can be either acquired or inherited. The main phenotypes observed in patients carrying these heritable arrhythmia syndromes are congenital long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome. In the recent years, tremendous progress has been made in the recognition, mechanisms, and treatment of these diseases. The goal of this review is to provide an overview of the main phenotypes, genetic underpinnings, risk stratification, and treatment options for these so-called cardiac ion channelopathie

Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac arrhythmia disorder that is characterized by emotion- and exercise-induced polymorphic ventricular arrhythmias and may lead to sudden cardiac death (SCD). CPVT plays an important role in SCD in the young and therefore recognition and adequate treatment of the disease are of vital importance. In the past years tremendous improvements have been made in the diagnostic methods and treatment of the disease. In this review, we summarize the clinical characteristics, genetics, and diagnostic and therapeutic strategies of CPVT and describe the most recent advances and some of the current challenges. (Circ J 2016; 80: 1285-1291

Plotse dood en wegrakingen door een erfelijke hartritmestoornis; mogelijke diagnose bij wegrakingen en plots overlijden van familieleden

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited cardiac arrhythmia syndrome. CPVT is characterised by polymorphic ventricular arrhythmias induced by exercise or emotion. These arrhythmias may lead to sudden death. We describe 2 patients with CPVT: a 38-year-old asymptomatic male with a family history of sudden death at a young age, and a 28-year-old woman who suffered from recurrent syncopal episodes triggered by exercise or emotion. In both of these cases the diagnosis CPVT was missed initially, even though the typical arrhythmias were present during exercise tests. CPVT should be considered in young patients who present with syncopal episodes during exercise or emotions, or who display polymorphic ventricular arrhythmias. Family history can also be indicative, particularly if family members have died suddenly at a young age under similar circumstance

Cardiorenal axis and arrhythmias: Will renal sympathetic denervation provide additive value to the therapeutic arsenal?

Disruption of sympathetic tone may result in the occurrence or maintenance of cardiac arrhythmias. Multiple arrhythmic therapies that intervene by influencing cardiac sympathetic tone are common in clinical practice. These vary from pharmaceutical (β-blockers, angiotensin-converting enzyme inhibitors, and calcium antagonists) to percutaneous/surgical (cardiac sympathetic denervation) interventions. In some patients, however, these therapies have insufficient prophylactic and therapeutic capabilities. A safe and effective additional therapy wherein sympathetic drive is further attenuated would be expedient. Recently, renal sympathetic denervation (RSD) has been subject of research for various sympathetic nervous system-related diseases. By its presumed afferent and efferent sympatholytic effects, RSD might indirectly attenuate sympathetic outflow via the brain to the heart but might also reduce systemic catecholamine excretion and might therefore reduce catecholamine-sensitive arrhythmias. RSD is subject of research for various sympathetically driven arrhythmias, both supraventricular and ventricular. In this review, we give an overview of the rationale behind RSD as potential therapy in mediating arrhythmias that are triggered by a disrupted sympathetic nervous system and discuss the presently available results from animal and human studie

Results of Genetic Testing in 855 Consecutive Unrelated Patients Referred for Long QT Syndrome in a Clinical Laboratory

Aim: Our aim was to examine the diagnostic yield of genetic testing in 855 consecutive unrelated cases referred for Long QT syndrome (LQTS). Results: Eight hundred fifty five consecutive patients with a mean age at testing of 27.5±18.6 years, were referred for LQTS genetic testing and had accompanying clinical information. KCNQ1, KCNH2, SCN5A, ANK2, KCNE1, KCNE2, CACNA1C, KCNJ2, CAV3, and SCN4B were analyzed using Next-Generation sequencing in all patients, and 395 patients were also tested for an additional two genes, AKAP9 and SNTA1. We retrospectively analyzed the diagnostic yield of this genetic test and factors that predicted the likelihood of a disease causing mutation using ANOVA, χ2, t-test, and receiver operator curves. At least one mutation was identified in 30.3% of the patients (n=259), and 18 patients (2.1%) had two mutations. Patients with two mutations had a longer QTc interval (p <0.01) than patients with one mutation. A longer QTc duration and family history of LQTS were each associated with a higher yield of positive results on genetic testing (p <0.01 for each). Using a QTc cutoff of 476 msec or greater, the genetic testing had a sensitivity of 72% and a specificity of 49%. Mutations within the transmembrane domain of KCNQ1 were associated with a greater risk of cardiac arrest and syncope relative to mutations in other domains of the gene. Mutations in SCN5A were associated with a higher frequency of cardiac arrest (52.6%). Conclusion: Sequencing-based genetic testing has a sensitivity of 72% and has clinical utilit

Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Missense Variants of Uncertain Significance

Background Many rare, potentially pathogenic, RYR2 variants identified in individuals with clinically definite catecholaminergic polymorphic ventricular tachycardia are classified ambiguously as variants of uncertain significance (VUS). We aimed to determine if a phenotype-enhanced variant classification approach could reduce the burden of RYR2 VUS encountered during clinical genetic testing. Methods This retrospective study was conducted in 84 RYR2-positive individuals from the Mayo Clinic (Rochester, MN) and validated in 149 RYR2-positive individuals from Amsterdam University Medical Center (Amsterdam, NL). Using a newly developed diagnostic scorecard, the pretest clinical probability of catecholaminergic polymorphic ventricular tachycardia was determined for all RYR2-positive individuals. Each RYR2 variant was then readjudicated using a phenotype-enhanced American College of Medical Genetics approach that incorporates new criteria that reflect the phenotypic strength associated with each individual RYR2 variant. Results Overall, 72 distinct RYR2 variants were identified among the 84 Mayo Clinic (39 unique) and 149 Amsterdam University Medical Center (30 unique) cases. Three variants were present in both cohorts. American College of Medical Genetics guidelines classified 47% of all RYR2 variants as VUS. In the Mayo Clinic cohort, readjudication using amended phenotype-enhanced American College of Medical Genetics standards dropped the VUS rate significantly (20/42 [48%] versus 3/42 [7%]; P<0.001) with 13/20 (65%) RYR2 VUS promoted to likely pathogenic and 4/20 (20%) demoted to likely benign. A similar drop in VUS rate (14/33 [42%] versus 3/33 [9%]; P=0.001) was observed in the Amsterdam University Medical Center validation cohort with 10/14 (71%) RYR2 VUS promoted to likely pathogenic and 1/14 (7%) demoted to likely benign. Conclusions This multicenter study illustrates the potential utility of phenotype-enhanced variant classification in catecholaminergic polymorphic ventricular tachycardia

Determination and Interpretation of the QT Interval. Comprehensive Analysis of a Large Cohort of Long QT Syndrome Patients and Controls

Background: Long QT syndrome (LQTS) is associated with potentially fatal arrhythmias. Treatment is very effective, but its diagnosis may be challenging. Importantly, different methods are used to assess the QT interval, which makes its recognition difficult. QT experts advocate manual measurements with the tangent or threshold method. However, differences between these methods and their performance in LQTS diagnosis have not been established. We aimed to assess similarities and differences between these 2 methods for QT interval analysis to aid in accurate QT assessment for LQTS. Methods: Patients with a confirmed pathogenic variant in KCNQ1(LQT1), KCNH2(LQT2), or SCN5A(LQT3) genes and their family members were included. Genotype-positive patients were identified as LQTS cases and genotype-negative family members as controls. ECGs were analyzed with both methods, providing inter- and intrareader validity and diagnostic accuracy. Cutoff values based on control population's 95th and 99th percentiles, and LQTS-patients' 1st and 5th percentiles were established based on the method to correct for heart rate, age, and sex. Results: We included 1484 individuals from 265 families, aged 3321 years and 55% females. In the total cohort, QT(Tangent) was 10.4 ms shorter compared with QT(Threshold) (95% limits of agreement +/- 20.5 ms, P0.96), and a high diagnostic accuracy (area under the curve >0.84). Using the current guideline cutoff (QTc interval 480 ms), both methods had similar specificity but yielded a different sensitivity. QTc interval cutoff values of QT(Tangent) were lower compared with QT(Threshold) and different depending on the correction for heart rate, age, and sex. Conclusion: The QT interval varies depending on the method used for its assessment, yet both methods have a high validity and can both be used in diagnosing LQTS. However, for diagnostic purposes current guideline cutoff values yield different results for these 2 methods and could result in inappropriate reassurance or treatment. Adjusted cutoff values are therefore specified for method, correction formula, age, and sex. In addition, a freely accessible online probability calculator for LQTS (www.QTcalculator.org) has been made available as an aid in the interpretation of the QT interval