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Aims While mexiletine has been used for over 40 years for prevention of (recurrent) ventricular arrhythmias and for myotonia, patient access has recently been critically endangered. Here we aim to demonstrate the effectiveness and safety of mexiletine in the treatment of patients with (recurrent) ventricular arrhythmias, emphasizing the absolute necessity of its accessibility. Methods and results Studies were included in this systematic review (PROSPERO, CRD42020213434) if the efficacy or safety of mexiletine in any dose was evaluated in patients at risk for (recurrent) ventricular arrhythmias with or without comparison with alternative treatments (e.g. placebo). A systematic search was performed in Ovid MEDLINE, Embase, and in the clinical trial registry databases ClinicalTrials.gov and ICTRP. Risk of bias were assessed and tailored to the different study designs. Large heterogeneity in study designs and outcome measures prompted a narrative synthesis approach. In total, 221 studies were included reporting on 8970 patients treated with mexiletine. Age ranged from 0 to 88 years. A decrease in ventricular arrhythmias of >50% was observed in 72% of the studies for pre-mature ventricular complexes, 64% for ventricular tachycardia, and 33% for ventricular fibrillation. Electrocardiographic effects of mexiletine were small; only in a subset of patients with primary arrhythmia syndromes, a relative (desired) QTc decrease was reproducibly observed. As for adverse events, gastrointestinal complaints were most frequently observed (33% of the patients). Conclusions In this systematic review, we present all the currently available knowledge of mexiletine in patients at risk for (recurrent) ventricular arrhythmias and show that mexiletine is both effective and safe.

Congenital long QT syndrome (LQTS) encompasses a group of heritable conditions that are associated with cardiac repolarization dysfunction. Since its initial description in 1957, our understanding of LQTS has increased dramatically. The prevalence of LQTS is estimated to be ∼1:2,000, with a slight female predominance. The diagnosis of LQTS is based on clinical, electrocardiogram, and genetic factors. Risk stratification of patients with LQTS aims to identify those who are at increased risk of cardiac arrest or sudden cardiac death. Factors including age, sex, QTc interval, and genetic background all contribute to current risk stratification paradigms. The management of LQTS involves conservative measures such as the avoidance of QT-prolonging drugs, pharmacologic measures with nonselective β-blockers, and interventional approaches such as device therapy or left cardiac sympathetic denervation. In general, most forms of exercise are considered safe in adequately treated patients, and implantable cardioverter-defibrillator therapy is reserved for those at the highest risk. This review summarizes our current understanding of LQTS and provides clinicians with a practical approach to diagnosis and management.

Aims In patients with Brugada syndrome (BrS) but without spontaneous Type-1 electrocardiogram, several electrocardiographic characteristics have been studied, including the β-angle. Previous studies suggested that the β-angle might be useful in distinguishing BrS-patients from patients with only suggestive repolarization patterns without performing sodium channel blocker provocation testing. In this study, we aimed to determine the diagnostic value of the β-angle in patients suspected of BrS. Methods and results A large cohort (n = 1430) of consecutive patients who underwent provocation testing was evaluated. β-angles were measured in leads V1, V2, and their corresponding positions over the second and third intercostal space. Receiver-operating characteristic curves were constructed and the diagnostic accuracy of previously reported β-angle cut-offs were calculated and evaluated. The importance of the β-angle for predicting the provocation test outcome was determined using a prediction model constructed with logistic regression. The optimum β-angle cut-off in our cohort for ruling out a positive provocation test was 15°; sensitivities were 80–98% and negative predictive values were 79–96% among the right precordial leads. Previously reported β-angle cut-offs performed less well, indicated by lower Youden indices. In the optimism-corrected prediction model [C-statistic: 0.78 (95% CI: 0.75–0.81)], the β-angle had large value (Z-score: 2.1–10.3) and aided construction of a nomogram to predict test outcome. Conclusion To predict the outcome of provocation testing for BrS, the β-angle alone does not demonstrate strong diagnostic characteristics. However, the β-angle is an important variable to predict provocation test outcome and thus has added value.

AIMS: Reflection magnitude (RM), the ratio of the amplitudes of the backward and forward central arterial pressure waves, has been shown to predict cardiovascular events. However, the association with blood pressure (BP) and hypertension is unclear. METHODS: We assessed RM in 10 195 individuals of Dutch, South-Asian Surinamese, African Surinamese, Ghanaian, Turkish and Moroccan origin aged between 18 and 70 years (54.2% female) participating in the Healthy Life in an Urban Setting study. To determine RM, central arterial pressure and flow were reconstructed from finger BP. Hypertension was defined based on office-BP and medication. Associations with BP, hypertension, and hypertensive organ damage were assessed using linear regression models with correction for relevant covariates. RESULTS: Mean RM was 62.5% (standard deviation [SD] 8.0) in men and 63.8% (SD 8.1) in women. RM was lowest in Dutch and highest in South-Asian and African participants. RM increased linearly with 1.35 (95% confidence interval [CI] 1.23-1.46) for every 10 mmHg increase in systolic BP from 120 mmHg onwards, while the relation with diastolic BP was nonlinear. RM was 2.40 (95% CI 2.04-2.76) higher in hypertensive men and 3.82 (95% CI 3.46-4.19) higher in hypertensive women compared to normotensive men and women. In hypertensive men and women with ECG-based left ventricular hypertrophy or albuminuria RM was 1.64 (95% CI 1.09-2.20) and 0.94 (95% CI 0.37-1.52) higher compared to hypertensive participants without hypertensive organ damage. CONCLUSION: RM is associated with BP, hypertension and hypertensive organ damage, and may in part explain disparities in hypertension associated cardiovascular risk.

Brugada syndrome (BrS) is an inherited cardiac disorder, characterised by a typical ECG pattern and an increased risk of arrhythmias and sudden cardiac death (SCD). BrS is a challenging entity, in regard to diagnosis as well as arrhythmia risk prediction and management. Nowadays, asymptomatic patients represent the majority of newly diagnosed patients with BrS, and its incidence is expected to rise due to (genetic) family screening. Progress in our understanding of the genetic and molecular pathophysiology is limited by the absence of a true gold standard, with consensus on its clinical definition changing over time. Nevertheless, novel insights continue to arise from detailed and in-depth studies, including the complex genetic and molecular basis. This includes the increasingly recognised relevance of an underlying structural substrate. Risk stratification in patients with BrS remains challenging, particularly in those who are asymptomatic, but recent studies have demonstrated the potential usefulness of risk scores to identify patients at high risk of arrhythmia and SCD. Development and validation of a model that incorporates clinical and genetic factors, comorbidities, age and gender, and environmental aspects may facilitate improved prediction of disease expressivity and arrhythmia/SCD risk, and potentially guide patient management and therapy. This review provides an update of the diagnosis, pathophysiology and management of BrS, and discusses its future perspectives.

Congenital long QT syndrome (LQTS) is characterised by heart rate corrected QT interval prolongation and life-threatening arrhythmias, leading to syncope and sudden death. Variations in genes encoding for cardiac ion channels, accessory ion channel subunits or proteins modulating the function of the ion channel have been identified as disease-causing mutations in up to 75% of all LQTS cases. Based on the underlying genetic defect, LQTS has been subdivided into different subtypes. Growing insights into the genetic background and pathophysiology of LQTS has led to the identification of genotype–phenotype relationships for the most common genetic subtypes, the recognition of genetic and non-genetic modifiers of phenotype, optimisation of risk stratification algorithms and the discovery of gene-specific therapies in LQTS. Nevertheless, despite these great advancements in the LQTS field, large gaps in knowledge still exist. For example, up to 25% of LQTS cases still remain genotype elusive, which hampers proper identification of family members at risk, and it is still largely unknown what determines the large variability in disease severity, where even within one family an identical mutation causes malignant arrhythmias in some carriers, while in other carriers, the disease is clinically silent. In this review, we summarise the current evidence available on the diagnosis, clinical management and therapeutic strategies in LQTS. We also discuss new scientific developments and areas of research, which are expected to increase our understanding of the complex genetic architecture in genotype-negative patients, lead to improved risk stratification in asymptomatic mutation carriers and more targeted (gene-specific and even mutation-specific) therapies.

OBJECTIVE: The reflection magnitude (RM), the ratio of the amplitudes of the backward and forward central arterial pressure waves, has been shown to be predictive for future cardiovascular events, but the association between blood pressure (BP) and RM remains unknown. We aimed to assess the association between RM, BP and hypertension in a large multi-ethnic population-based cohort study. DESIGN AND METHOD: We assessed RM in 10 195 individuals of Dutch, South-Asian Surinamese, African Surinamese, Ghanaian, Turkish and Moroccan origin aged between 18-70 years (54.2% female) participating in the HEalthy Life in an Urban Setting (HELIUS) study. To determine RM, central arterial pressure and flow were reconstructed from non-invasive finger BP measurements using a generalized transfer function and Windkessel model, whereafter wave separation was performed (Fig 1, panel A & B). Hypertension was defined based on office-BP and use of BP lowering medication. Associations between RM and systolic- and diastolic BP, hypertension, and hypertension mediated end-organ damage were assessed using regression models with correction for age, height, ethnicity and an interaction term for sex. RESULTS: Mean RM was 62.5% (SD 8.0) in men and 63.8% (SD 8.1) in women. For every 10 mmHg increase in systolic BP, RM increased linearly by 1.35 (95% CI 1.23-1.46) from 120 mmHg onwards, while for every 10 mmHg increase in diastolic BP above 80 mmHg RM increased by 1.99 (95% CI 1.61 - 2.38) (Fig 1, panel C & D). RM was 2.40 (95% CI 2.04-2.76) higher in hypertensive men and 3.82 (95% CI 3.46-4.19) higher in hypertensive women compared to normotensive men and women. RM was 1.64 (95% CI 1.09-2.20) and 0.94 (95% CI 0.37-1.52) higher in hypertensive men and women with ECG-based left ventricular hypertrophy or increased albuminuria compared to hypertensive men and women without hypertensive organ damage. Following correction for height ethnic and sex differences in RM were attenuated, however the relation with BP did not change. CONCLUSIONS: Hypertension is associated with a higher RM in men and women of different ethnic origins, and may, in part, explain disparities in hypertension associated cardiovascular risk.

Background: Adult long QT syndrome (LQTS) patients have inadequate corrected QT interval (QTc) shortening and an abnormal T-wave response to the sudden heart rate acceleration provoked by standing. In adults, this knowledge can be used to aid an LQTS diagnosis and, possibly, for risk stratification. However, data on the diagnostic value of the standing test in children are currently limited.Objective: To determine the potential value of the standing test to aid LQTS diagnostics in children.Methods: In a prospective cohort including children (≤18 years) who had a standing test, comprehensive analyses were performed including manual and automated QT interval assessments and determination of T-wave morphology changes.Results: We included 47 LQTS children and 86 control children. At baseline, the QTc that identified LQTS children with a 90% sensitivity was 435 ms, which yielded a 65% specificity. A QTc ≥ 490 ms after standing only slightly increased sensitivity (91%, 95% confidence interval [CI]: 80%-98%) and slightly decreased specificity (58%, 95% CI: 47%-70%). Sensitivity increased slightly more when T-wave abnormalities were present (94%, 95% CI: 82%-99%; specificity 53%, 95% CI: 42%-65%). When a baseline QTc ≥ 440 ms was accompanied by a QTc ≥ 490 ms and T-wave abnormalities after standing, sensitivity further increased (96%, 95% CI: 85%-99%) at the expense of a further specificity decrease (41%, 95% CI: 30%-52%). Beat-to-beat analysis showed that 30 seconds after standing, LQTS children had a greater increase in heart rate compared to controls, which was more evidently present in LQTS boys and LQTS type 1 children.Conclusion: In children, the standing test has limited additive diagnostic value for LQTS over a baseline electrocardiogram, while T-wave abnormalities after standing also have limited additional value. The standing test for LQTS should only be used with caution in children.

Failure of drugs and catheter ablation procedures for the treatment of ventricular arrhythmias is still extremely relevant. Recently, stereotactic body radiotherapy has been introduced to treat therapy refractory patients. In this systematic review (International Prospective Register of Systematic Reviews, CRD42019133212), we aimed to summarize electrophysiological and histopathological effects of radioablation in animals, patients, and extracted and perfused hearts. A systematic search was performed in OVID MEDLINE, OVID Embase, the Cochrane Central Register of Controlled Trials, Web of Science, Google Scholar, ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) from inception to September 2019. Identified records were independently screened for eligibility by 2 reviewers. Risk of bias and methodological quality were assessed using the SYRCLE, ROBINS-I, or Murad tool and tailored to the different study designs. We included 13 preclinical and 10 clinical publications. Large heterogeneity in study designs prompted a narrative synthesis approach. Baseline, (pre-)procedural details, outcome, target tissue analyses, and safety data were extracted and summarized. In animal studies evaluating electrophysiological parameters, radioablation induced a reduction in voltage/potential amplitude or bidirectional block in target areas in 93.2% of animals. Atrioventricular block (first to third degree) was induced in 78.3% of animals, and in studies evaluating ventricular arrhythmia inducibility, 75% reduction was achieved. In patients, predominantly ventricular tachycardias were targeted with >85% reduction in arrhythmia episodes during follow-up with an encouraging short-term safety profile. Preclinical and clinical evidence on the efficacy and safety of radioablation is limited in both quantity and quality. The results of radioablation for therapy refractory patients with ventricular tachycardia are promising, but further research is needed.

BACKGROUND Diagnosing long QT syndrome (LQTS) remains challenging because of a considerable overlap in QT interval between patients with LQTS and healthy subjects. Characterizing T-wave morphology might improve LQTS diagnosis.OBJECTIVE The purpose of this study was to improve LQTS diagnosis by combining new polynomial-based T-wave morphology parameters with the corrected QT interval (QTc), age, and sex in a model.METHODS A retrospective cohort consisting of 333 patients with LQTS and 345 genotype-negative family members was used in this study. For each patient, a linear combination of the first 2 Hermite-Gauss (HG) polynomials was fitted to the STT segments of an average complex of all precordial leads and limb leads I and II. The weight coefficients as well as the error of the best fit were used to characterize T-wave morphology. Subjects were classified as patients with LQTS or controls by clinical QTc cutoffs and 3 support vector machine models fed with different features. An external cohort consisting of 72 patients and 45 controls was finally used to check the robustness of the models.RESULTS Baseline QTc cutoffs were specific but had low sensitivity in diagnosing LQTS. The model with T-wave morphology features, QTc, age, and sex had the best overall accuracy (84%), followed by a model with QTc, age, and sex (79%). The model with T-wave morphology features especially performed better in LQTS type 3 patients (69%).CONCLUSION T-wave morphologies can be characterized by fitting a linear combination of the first 2 Hermite-Gauss polynomials. Adding T-wave morphology characterization to age, sex, and QTc in a support vector machine model improves LQTS diagnosis.

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Background: Brugada syndrome (BrS) is associated with mutations in the cardiac sodium channel gene, SCN5A. However, genetic studies of patients with BrS with arrhythmic events have been limited. We sought to compare various clinical, ECG, and electrophysiological parameters according to SCN5A genotype in a large cohort of BrS probands with first arrhythmic event. Methods: Survey on Arrhythmic Events in Brugada Syndrome is a survey of 10 Western and 4 Asian countries, gathering 678 patients with BrS with first arrhythmic event. Only probands were included, and SCN5A genotype adjudicated. Patients without appropriate genetic data were excluded. Associations of genotype with clinical features were analyzed. Results: The study group comprised 392 probands: 92 (23.5%) SCN5A+ (44 pathogenic/likely pathogenic [P/LP] and 48 variants of unknown significance) and 300 (76.5%) SCN5A−. SCN5A missense variants and the patients hosting them were similar regardless of adjudication. A higher proportion of patients with P/LP were pediatric (SCN5A− (11.4% versus 3%, P =0.023). The proportion of females was higher among patients with P/LP compared with SCN5A − (18.2% versus 6.3%, P =0.013). P/LP probands were more likely to have a family history of sudden cardiac death compared with SCN5A − (41.9% versus 16.8%, P SCN5A− (87.5% versus 47%, P P P =0.009) were independent variables associated with P/LP genotype following logistic regression. Conclusions: The genetic basis of BrS has a complex relationship with gender, ethnicity, and age. Probands hosting a P/LP variant tended to experience their first arrhythmic event at a younger age and to have events triggered by fever compared with patients with SCN5A− . In addition, they were more likely to be White and to have family history of sudden cardiac death. Among females, a P/LP variant suggests an increased risk of being symptomatic. This association should be further studied on an ethnically specific basis in large prospectively collected international cohorts.

Brugada syndrome (BrS) is associated with mutations in the cardiac sodium channel gene,Survey on Arrhythmic Events in Brugada Syndrome is a survey of 10 Western and 4 Asian countries, gathering 678 patients with BrS with first arrhythmic event. Only probands were included, andThe study group comprised 392 probands: 92 (23.5%)The genetic basis of BrS has a complex relationship with gender, ethnicity, and age. Probands hosting a P/LP variant tended to experience their first arrhythmic event at a younger age and to have events triggered by fever compared with patients with

Objectives Mexiletine is a long-known drug used for the treatment of arrhythmias and repurposed in the 1980s for patients with nondystrophic myotonia (NDM). Recently, the price of mexiletine in Europe increased significantly after registration as an orphan drug for NDM. This led to international discussions on affordability and willingness to reimburse mexiletine in the absence of background information that would justify such a price. Our objective was to calculate a cost-based price for mexiletine for adult patients with NDM based on detailed information on development costs. Methods We calculated a fair price based on a cost-based pricing model for commercial mexiletine to treat adults with NDM using a recent European drug-pricing model as a framework to include actual costs incurred. Three scenarios were applied: 1 with minimum estimated costs, 1 with maximum estimated costs, and 1 with costs as if mexiletine was innovative. Results The calculated fair price of mexiletine per patient per year (PPPY) is €452 for the minimum scenario and €1996 for the maximum scenario. By using hypothetical R&D costs used for innovative drugs, the price would be €6685 PPPY. In Europe, the list price of mexiletine ranges from €30 707-60 730 PPPY, based on 600 mg daily. Conclusions The current list price for mexiletine in Europe is manifold higher than any scenario of the cost-based models. Accounting for the reduced costs for clinical development in a repurposing scenario, the cost-based pricing model provides a fair commercial price range, which can be used as benchmark for pricing negotiations and/or reimbursement decisions.

Aims: Data on predictors of time-to-first appropriate implantable cardioverter-defibrillator (ICD) therapy in patients with Brugada Syndrome (BrS) and prophylactically implanted ICD's are scarce.Methods and results: SABRUS (Survey on Arrhythmic Events in BRUgada Syndrome) is an international survey on 678 BrS patients who experienced arrhythmic event (AE) including 252 patients in whom AE occurred after prophylactic ICD implantation. Analysis was performed on time-to-first appropriate ICD discharge regarding patients' characteristics. Multivariate logistic regression models were utilized to identify which parameters predicted time to arrhythmia ≤5 years. The median time-to-first appropriate ICD therapy was 24.8 ± 2.8 months. A shorter time was observed in patients from Asian ethnicity (P Conclusion: First appropriate therapy in BrS patients with prophylactic ICD's occurred during the first 5 years in 76.6% of patients. Syncope and spontaneous Type 1 Brugada ECG correlated with a shorter time to ICD therapy.

Background: Idiopathic ventricular fibrillation (IVF) is diagnosed in patients with sudden onset of ventricular fibrillation of unidentified origin. New diagnostic tools that can detect subtle abnormalities are needed to diagnose and treat patients with an underlying substrate. Objective: The purpose of this study was to explore echocardiographic deformation characteristics in IVF patients. Methods: Echocardiograms were analyzed with deformation imaging by 2-dimensional speckle tracking. Global and regional measurements of the left ventricle (LV) and right ventricle (RV) were performed. Regional LV deformation patterns were evaluated for the presence of postsystolic shortening. Regional RV deformation patterns were classified as type I (normal) or type II/III (abnormal). Results: In total, 47 IVF patients (mean age 45 years; left ventricular ejection fraction [LVEF] 56%) and 47 healthy controls (mean age 41 years; LVEF 60%) were included. IVF patients showed more global deformation abnormalities as indicated by lower LV global longitudinal strain (18.5% ± 2.6% vs 21.6% ± 1.8%; P

Funding Acknowledgements Type of funding sources: None. Introduction An aberrant DPP6 mutation haplotype on chromosome 7 is associated with familial idiopathic ventricular fibrillation in severely affected Dutch families with numerous cases of sudden cardiac death (SCD) So far, no clinical parameters could be linked to predict SCD risk other than this genetic predisposition. In various other cardiac disease, global longitudinal strain (GLS) and mechanical dispersion (MD), both markers of left ventricular (LV) dysfunction, are predictive tools for patients at risk for ventricular arrhythmias (VA) and SCD. The goal of the current study was to investigate whether LV dysfunction, detected by GLS and MD, is present in patients with DPP6 haplotype. Method DPP6 risk-haplotype carriers with sufficient echocardiographic images were included as cases (n = 31, 15 males mean age 41 ± 11 years) and individuals evaluated during cascade screening who were tested but appeared not to be affected as controls (n = 14, 7 males, mean age 39 ± 12 years). Echocardiographic bi-plane ejection fraction (LVEF), GLS and MD of the left ventricular were determined. Results LVEF was similar between DPP6 cases (57.3%) and controls (60.5%, p = 0.07). In contrast, the GLS of the LV (-18.0%) of DPP6 cases was significant lower compared to controls (-21.1%, p Conclusion DPP6 risk- haplotype carriers have similar LVEF, but significant lower LV-GLS and higher mechanical dispersion than controls. These findings can be used for clinical discrimination. Whether these markers can be used for prediction of clinical events has to be determined after a longer follow up. echocardiographic characteristics controls DPP6 p-value LVEF (%) 60.5 57.3 0.07 GLS LV (%) -21.2 -18.0 0.0001 MD ( ms) 26.7 43.4 0.0001

Background Medical castration, gonadotropin-releasing hormone agonists, and antiandrogens have been widely applied as a treatment for prostate cancer. Sex steroid hormones influence cardiac ion channels. However, few studies have examined the proarrhythmic properties of medical castration. Methods and Results This study included 149 patients who underwent medical castration using gonadotropin-releasing hormones with/without antiandrogen for prostate cancer. The changes in the ECG findings during the therapy and associations of the electrocardiographic findings with malignant arrhythmias were studied. The QT and corrected QT (QTc) intervals prolonged during the therapy compared with baseline (QT, 394±32 to 406±39 ms [