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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.

Objectives This study aimed to explore echocardiographic characteristics of phospholamban (PLN) p.Arg14del mutation carriers to investigate whether structural and/or functional abnormalities could be identified before onset of symptoms. Background Carriers of the genetic PLN p.Arg14del mutation may develop arrhythmogenic and/or dilated cardiomyopathy. Overt disease is preceded by a pre-symptomatic phase of variable length in which disease expression seems to be absent. Methods PLN p.Arg14del mutation carriers with an available echocardiogram were included. Mutation carriers were classified as pre-symptomatic if they had no history of ventricular arrhythmias (VAs), a premature ventricular complex count of Results The final study population consisted of 281 PLN p.Arg14del mutation carriers, 139 of whom were classified as pre-symptomatic. In comparison to control subjects, pre-symptomatic mutation carriers had lower global longitudinal strain and higher LV mechanical dispersion (both p Conclusions Global and regional LV mechanical alterations in PLN p.Arg14del mutation carriers precede arrhythmic symptoms and overt structural disease. Pre-symptomatic mutation carriers with normal deformation patterns in the apex are at low risk of developing VA within 3 years, whereas mutation carriers with apical PSS appear to be at higher risk.

IntroductionSudden cardiac death (SCD) is the leading cause of death in patients with myocardial infarction (MI) and can be prevented by the implantable cardioverter defibrillator (ICD). Currently, risk stratification for SCD and decision on ICD implantation are based solely on impaired left ventricular ejection fraction (LVEF). However, this strategy leads to over- and under-treatment of patients because LVEF alone is insufficient for accurate assessment of prognosis. Thus, there is a need for better risk stratification. This is the study protocol for developing and validating a prediction model for risk of SCD in patients with prior MI.Methods and AnalysisThe EU funded PROFID project will analyse 23 datasets from Europe, Israel and the US (∼225,000 observations). The datasets include patients with prior MI or ischemic cardiomyopathy with reduced LVEFEthics and disseminationLocal ethical approval was obtained. The final model will be disseminated through scientific publications and a web-calculator. Statistical code will be published through open-source repositories.

Aims This study was performed to develop and externally validate prediction models for appropriate implantable cardioverter-defibrillator (ICD) shock and mortality to identify subgroups with insufficient benefit from ICD implantation. Methods and results We recruited patients scheduled for primary prevention ICD implantation and reduced left ventricular function. Bootstrapping-based Cox proportional hazards and Fine and Gray competing risk models with likely candidate predictors were developed for all-cause mortality and appropriate ICD shock, respectively. Between 2014 and 2018, we included 1441 consecutive patients in the development and 1450 patients in the validation cohort. During a median follow-up of 2.4 (IQR 2.1–2.8) years, 109 (7.6%) patients received appropriate ICD shock and 193 (13.4%) died in the development cohort. During a median follow-up of 2.7 (IQR 2.0–3.4) years, 105 (7.2%) received appropriate ICD shock and 223 (15.4%) died in the validation cohort. Selected predictors of appropriate ICD shock were gender, NSVT, ACE/ARB use, atrial fibrillation history, Aldosterone-antagonist use, Digoxin use, eGFR, (N)OAC use, and peripheral vascular disease. Selected predictors of all-cause mortality were age, diuretic use, sodium, NT-pro-BNP, and ACE/ARB use. C-statistic was 0.61 and 0.60 at respectively internal and external validation for appropriate ICD shock and 0.74 at both internal and external validation for mortality. Conclusion Although this cohort study was specifically designed to develop prediction models, risk stratification still remains challenging and no large group with insufficient benefit of ICD implantation was found. However, the prediction models have some clinical utility as we present several scenarios where ICD implantation might be postponed.

Aims Phospholamban (PLN) p.Arg14del mutation carriers are at risk of developing malignant ventricular arrhythmias (VAs) and/or heart failure. Currently, left ventricular ejection fraction (LVEF) plays an important role in risk assessment for VA in these individuals. We aimed to study the incremental prognostic value of left ventricular mechanical dispersion (LVMD) by echocardiographic deformation imaging for prediction of sustained VA in PLN p.Arg14del mutation carriers. Methods and results We included 243 PLN p.Arg14del mutation carriers, which were classified into three groups according to the ‘45/45’ rule: (i) normal left ventricular (LV) function, defined as preserved LVEF ≥45% with normal LVMD ≤45 ms (n = 139), (ii) mechanical LV dysfunction, defined as preserved LVEF ≥45% with abnormal LVMD >45 ms (n = 63), and (iii) overt LV dysfunction, defined as reduced LVEF Conclusion LVMD has incremental prognostic value on top of LVEF in PLN p.Arg14del mutation carriers, particularly in those with preserved LVEF. The ‘45/45’ rule is a practical approach to echocardiographic risk stratification in this challenging group of patients. This approach may also have added value in other diseases where LVEF deterioration is a relative late marker of myocardial dysfunction.

Background One third of primary prevention implantable cardioverter‐defibrillator patients receive appropriate therapy, but all remain at risk of defibrillator complications. Information on these complications in contemporary cohorts is limited. This study assessed complications and their risk factors after defibrillator implantation in a Dutch nationwide prospective registry cohort and forecasts the potential reduction in complications under distinct scenarios of updated indication criteria. Methods and Results Complications in a prospective multicenter registry cohort of 1442 primary implantable cardioverter‐defibrillator implant patients were classified as major or minor. The potential for reducing complications was derived from a newly developed prediction model of appropriate therapy to identify patients with a low probability of benefitting from the implantable cardioverter‐defibrillator. During a follow‐up of 2.2 years (interquartile range, 2.0–2.6 years), 228 complications occurred in 195 patients (13.6%), with 113 patients (7.8%) experiencing at least one major complication. Most common ones were lead related (n=93) and infection (n=18). Minor complications occurred in 6.8% of patients, with lead‐related (n=47) and pocket‐related (n=40) complications as the most prevailing ones. A surgical reintervention or additional hospitalization was required in 53% or 61% of complications, respectively. Complications were strongly associated with device type. Application of stricter implant indication results in a comparable proportional reduction of (major) complications. Conclusions One in 13 patients experiences at least one major implantable cardioverter‐defibrillator–related complication, and many patients undergo a surgical reintervention. Complications are related to defibrillator implantations, and these should be discussed with the patient. Stricter implant indication criteria and careful selection of device type implanted may have significant clinical and financial benefits.

Background Phospholamban (PLN) p.Arg14del mutation carriers are known to develop dilated and/or arrhythmogenic cardiomyopathy, and typical electrocardiographic (ECG) features have been identified for diagnosis. Machine learning is a powerful tool used in ECG analysis and has shown to outperform cardiologists. Objectives We aimed to develop machine learning and deep learning models to diagnose PLN p.Arg14del cardiomyopathy using ECGs and evaluate their accuracy compared to an expert cardiologist. Methods We included 155 adult PLN mutation carriers and 155 age- and sex-matched control subjects. Twenty-one PLN mutation carriers (13.4%) were classified as symptomatic (symptoms of heart failure or malignant ventricular arrhythmias). The data set was split into training and testing sets using 4-fold cross-validation. Multiple models were developed to discriminate between PLN mutation carriers and control subjects. For comparison, expert cardiologists classified the same data set. The best performing models were validated using an external PLN p.Arg14del mutation carrier data set from Murcia, Spain (n = 50). We applied occlusion maps to visualize the most contributing ECG regions. Results In terms of specificity, expert cardiologists (0.99) outperformed all models (range 0.53–0.81). In terms of accuracy and sensitivity, experts (0.28 and 0.64) were outperformed by all models (sensitivity range 0.65–0.81). T-wave morphology was most important for classification of PLN p.Arg14del carriers. External validation showed comparable results, with the best model outperforming experts. Conclusion This study shows that machine learning can outperform experienced cardiologists in the diagnosis of PLN p.Arg14del cardiomyopathy and suggests that the shape of the T wave is of added importance to this diagnosis.

Introduction The p.Arg14del founder mutation in the gene encoding phospholamban (PLN) is associated with an increased risk of malignant ventricular arrhythmia and heart failure. Ejection fraction (EF) is the gold standard of systolic left ventricular (LV) function, however new technics using global longitudinal strain (GLS) are able to detect LV dysfunction early, e.g. in patients with chemotherapy. Moreover, strain analysis on post systolic shortening (PSS) can show distinct pattern in various diseases, e.g. patients with myocardial fibrosis and amyloid. The goal of this study was to investigate whether speckle tracking (GLS and PSS) of the LV can detect LV dysfunction in patients with PLN mutations and whether these patients have a specific PSS pattern. Method 72 Patients (49 female, mean age 32 years) diagnosed with the genetic PLN mutation p.Arg14del and 21 controls (10 female, mean age 27 years) underwent complete Echocardiographic exam including LVEF, GLS and PSI of all LV segments. LVEF Results Pearson correlation is in PLN patients between PSI apex and EF 0.677 (P PLN patients appeared to have a typical pattern with a high PSI in the apical segments. An apical PSI >20 was the strongest diagnostic parameter indicating LV dysfunction. Apical PSI >20 and LVEF Diagnostic characteristics PLN Controls P-value LVEF, % 55.2 59.3 0.033 GLS, % 15.5 17.3 0.163 PSI basal 8.5 10.1 0.326 PSI mid 5.6 2.9 0.070 PSI apical 15.6 2.1 0.01 LVEF, left ventricular ejection fraction; GLS, Global longitudinal strain; PSI, post systolic index. PSI Conclusion PLN patients have a typical pattern of high PSI in the apex of the left ventricular which can be used as a diagnostic test to detect LV dysfunction.

Background/Introduction The founder mutation p.Arg14del in the gene encoding phospholamban (PLN) is a known cause of arrhythmogenic cardiomyopathy (ACM) with distinct clinical features, such as microvoltages on the ECG and right or left ventricular dysfunction or both. At present, risk stratification for ICD implantation in carriers of this mutation is based on left ventricular ejection fraction and previous ventricular arrhythmia's, which are not specific risk factors for the PLN p.Arg14del cardiomyopathy. Purpose Our goal is to develop a mutation specific prediction model for incident malignant ventricular arrhythmia to guide ICD implantation. Methods Data were collected from p.Arg14del carriers with no history of malignant VA at baseline, identified between September 2009 and June 2018 in three Dutch university hospitals. Genetic analysis of PLN was performed in a clinical setting in index patients with clinical signs of DCM/ACM, or in family members of p.Arg14del carriers. We collected clinical data from the first cardiac evaluation and follow-ups. Malignant VAs were defined as sustained VA, appropriate ICD intervention or (aborted) sudden cardiac death. A prediction model was developed using Cox Proportional Hazard regression. Candidate baseline predictors were pre specified based on literature and clinical expertise. Age, sex, proband status, sudden cardiac death (SCD) in 1st degree relative, repolarization abnormalities, microvoltages, premature ventricular complexes (PVC) burden on 24hrs Holter monitoring, LVEF and non-sustained ventricular arrhythmias (NSVT) were considered. The multivariable model was fitted using stepwise backward selection based on Akaike's Information Criterion. Results We included 440 p.Arg14del carriers with a mean age of 41±18 years and 41% males. During a median follow-up of 4.7 years (IQR 1.7–7.3), 44 incident malignant VA occurred, 20 sustained VAs and 24 appropriate ICD therapies. The multivariable HR's of selected predictors were: 2.2 for minor and 4.5 for major repolarization abnormalities vs no abnormalities (p value respectively 0.06 and 0.01), 2.2 for LVEF 500PVC/24hrs (p value 0.003). Carriers with and without events could be accurately distinguished with this model, with an optimism corrected C-statistic of 0.81. The model calibrated well, with agreement of observed and predicted 5 year malignant VA risk. Risk groups were split into quintiles of predicted risk, figure 1 shows the Kaplan Meier curve of incident malignant VA per risk group. The 5 year risk of incident malignant VA in the lowest 3 quintiles was 0%, 9% in the 4th quintile and 25.2% in the highest quintile. Conclusion We created a PLN p.Arg14del mutation specific prediction model to estimate risk of incident malignant VA. With this model a clear distinction between high risk and low risk patients can be made and can be used to guide ICD implantation for primary prevention.

Background Gastrointestinal functional and motility disorders, like irritable bowel syndrome (IBS), have a high prevalence in the Western population and cause significant morbidity and loss of quality of life leading to considerable costs for health care. A decade ago, it has been demonstrated that interstitial cells of Cajal and intestinal smooth muscle cells, cells important for gastrointestinal motility, express the sodium channel alpha subunit Nav1.5. In the heart, aberrant variants in this sodium channel, encoded by SCN5A, are linked to inherited arrhythmia syndromes, like the long-QT syndrome type 3 and Brugada syndrome. Mounting data show a possible contribution of SCN5A mutants to gastrointestinal functional and motility disorders. Two percent of IBS patients harbor SCN5A mutations with electrophysiological evidence of loss- and gain-of-function. In addition, gastrointestinal symptoms are more prevalent in cardiac SCN5A-mutation positive patients. Purpose This review firstly describes the Nav1.5 channel and its physiological role in ventricular cardiomyocytes and gastrointestinal cells, then we focus on the involvement of mutant Nav1.5 in gastrointestinal functional and motility disorders. Future research might uncover novel mutation-specific treatment strategies for SCN5A-encoded gastrointestinal channelopathies.

Aims This study aims to improve risk stratification for primary prevention implantable cardioverter defibrillator (ICD) implantation by developing a new mutation-specific prediction model for malignant ventricular arrhythmia (VA) in phospholamban (PLN) p.Arg14del mutation carriers. The proposed model is compared to an existing PLN risk model. Methods and results Data were collected from PLN p.Arg14del mutation carriers with no history of malignant VA at baseline, identified between 2009 and 2020. Malignant VA was defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. A prediction model was developed using Cox regression. The study cohort consisted of 679 PLN p.Arg14del mutation carriers, with a minority of index patients (17%) and male sex (43%), and a median age of 42 years [interquartile range (IQR) 27–55]. During a median follow-up of 4.3 years (IQR 1.7–7.4), 72 (10.6%) carriers experienced malignant VA. Significant predictors were left ventricular ejection fraction, premature ventricular contraction count/24 h, amount of negative T waves, and presence of low-voltage electrocardiogram. The multivariable model had an excellent discriminative ability {C-statistic 0.83 [95% confidence interval (CI) 0.78–0.88]}. Applying the existing PLN risk model to the complete cohort yielded a C-statistic of 0.68 (95% CI 0.61–0.75). Conclusion This new mutation-specific prediction model for individual VA risk in PLN p.Arg14del mutation carriers is superior to the existing PLN risk model, suggesting that risk prediction using mutation-specific phenotypic features can improve accuracy compared to a more generic approach.