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Objectives\udThe aim of this study was to define the variability of maximal wall thickness (MWT) measurements across modalities and predict its impact on care in patients with hypertrophic cardiomyopathy (HCM).\ud\udBackground\udLeft ventricular MWT measured by echocardiography or cardiovascular magnetic resonance (CMR) contributes to the diagnosis of HCM, stratifies risk, and guides key decisions, including whether to place an implantable cardioverter-defibrillator (ICD).\ud\udMethods\udA 20-center global network provided paired echocardiographic and CMR data sets from patients with HCM, from which 17 paired data sets of the highest quality were selected. These were presented as 7 randomly ordered pairs (at 6 cardiac conferences) to experienced readers who report HCM imaging in their daily practice, and their MWT caliper measurements were captured. The impact of measurement variability on ICD insertion decisions was estimated in 769 separately recruited multicenter patients with HCM using the European Society of Cardiology algorithm for 5-year risk for sudden cardiac death.\ud\udResults\udMWT analysis was completed by 70 readers (from 6 continents; 91% with >5 years’ experience). Seventy-nine percent and 68% scored echocardiographic and CMR image quality as excellent. For both modalities (echocardiographic and then CMR results), intramodality inter-reader MWT percentage variability was large (range –59% to 117% [SD ±20%] and –61% to 52% [SD ±11%], respectively). Agreement between modalities was low (SE of measurement 4.8 mm; 95% CI 4.3 mm-5.2 mm; r = 0.56 [modest correlation]). In the multicenter HCM cohort, this estimated echocardiographic MWT percentage variability (±20%) applied to the European Society of Cardiology algorithm reclassified risk in 19.5% of patients, which would have led to inappropriate ICD decision making in 1 in 7 patients with HCM (8.7% would have had ICD placement recommended despite potential low risk, and 6.8% would not have had ICD placement recommended despite intermediate or high risk).\ud\udConclusions\udUsing the best available images and experienced readers, MWT as a biomarker in HCM has a high degree of inter-reader variability and should be applied with caution as part of decision making for ICD insertion. Better standardization efforts in HCM recommendations by current governing societies are needed to improve clinical decision making in patients with HCM.

This study aimed to identify electrocardiographic (ECG) predictors of a prolonged His-ventricular (HV) interval in patients with type 1 myotonic dystrophy (DM1).Patients with DM1 have an increased risk of sudden cardiac death. The presence of His-Purkinje system disease/prolonged HV interval (≥70 ms) is associated with a higher risk of potentially life-threatening bradyarrhythmic events.Electrophysiology studies (EPSs) were performed in all DM1 patients referred to 2 tertiary centers for routine cardiac assessment. In a subgroup of patients, the EPS was repeated at varying intervals.A total of 154 patients (mean age: 43.7 ± 13.3; 58.1% male) underwent 202 diagnostic EPSs. HV ≥70 ms was found on 58 EPSs (28.7%); 9 of 59 patients (15.2%) with PR 200 ms and QRS interval 110 ms on baseline ECG had an HV ≥70 ms on EPS. Among those with PR ≥200 ms and/or QRS interval ≥100 ms, only 33.9% had an HV ≥70 ms on EPS. There were 38 patients who underwent repeated EPS, in which 28.8% demonstrated a prolongation of the HV interval overall compared with baseline. QRS duration demonstrated the most powerful discriminative capacity for HV ≥70 ms (area under the receiver operating characteristic curve: 0.76; 95% confidence interval [CI]: 0.68 to 0.84; p 0.001). On multivariate analysis, QRS interval ≥112 ms had the highest predictive value for HV ≥70 ms (odds ratio: 7.94; 95% CI: 3.85 to 16.37.ECG parameters have a poor predictive value for infra-Hisian conduction block in DM1 patients. QRS and PR intervals are normal in up to 15.2% of DM1 patients with prolonged HV, and 66.1% of those with PR ≥200 ms and/or QRS ≥100 ms do not have advanced His-Purkinje conduction system disease on EPS. Electrophysiology testing should be a mandatory part of screening for all patients to guide prophylactic pacemaker implantation.

Aims: Dilated cardiomyopathy (DCM) associated with dystrophin gene (DMD) mutations in individuals with mild or absent skeletal myopathy is often indistinguishable from other DCM forms. We sought to describe the phenotype and prognosis of DMD associated DCM in DMD mutation carriers without severe skeletal myopathy. Methods and results: At 26 European centres, we retrospectively collected clinical characteristics and outcomes of 223 DMD mutation carriers (83% male, 33 ± 15 years). A total of 112 individuals (52%) had DCM at first evaluation [n = 85; left ventricular ejection fraction (LVEF) 34 ± 11.2%] or developed DCM (n = 27; LVEF 41.3 ± 7.5%) after a median follow-up of 96 months (interquartile range 5–311 months). DCM penetrance was 45% in carriers older than 40 years. DCM appeared earlier in males and was independent of the type of mutation, presence of skeletal myopathy, or elevated serum creatine kinase levels. Major adverse cardiac events (MACE) occurred in 22% individuals with DCM, 18% developed end-stage heart failure and 9% sudden cardiac death or equivalent. Skeletal myopathy was not associated with survival free of MACE in patients with DCM. Decreased LVEF and increased left ventricular end-diastolic diameter at baseline were associated with MACE. Individuals without DCM had favourable prognosis without MACE or death during follow-up. Conclusions: DMD-associated DCM without severe skeletal myopathy is characterized by incomplete penetrance but high risk of MACE, including progression to end-stage heart failure and ventricular arrhythmias. DCM onset is the major determinant of prognosis with similar survival regardless of the presence of skeletal myopathy.

Aims Atrial fibrillation (AF) is common in hypertrophic cardiomyopathy (HCM). Data on the efficacy of catheter ablation of AF in HCM patients are sparse. Methods and results Observational multicentre study in 137 HCM patients (mean age 55.0 ± 13.4, 29.1% female; 225 ablation procedures). We investigated (i) the efficacy of catheter ablation for AF beyond the initial 12 months; (ii) the available risk scores, stratification schemes and genotype as potential predictors of arrhythmia relapse, and (iii) the impact of cryoballoon vs. radiofrequency in procedural outcomes. Mean follow-up was 43.8 ± 37.0 months. Recurrences after the initial 12-month period post-ablation were frequent, and 24 months after the index procedure, nearly all patients with persistent AF had relapsed, and only 40% of those with paroxysmal AF remained free from arrhythmia recurrence. The APPLE score demonstrated a modest discriminative capacity for AF relapse post-ablation (c-statistic 0.63, 95% CI 0.52–0.75; P = 0.022), while the risk stratification schemes for sudden death did not. On multivariable analysis, left atrium diameter and LV apical aneurysm were independent predictors of recurrence. Fifty-eight patients were genotyped; arrhythmia-free survival was similar among subjects with different gene mutations. Rate of procedural complications was high (9.3%), although reducing over time. Outcome for cryoballoon and radiofrequency ablation was comparable. Conclusion Very late AF relapses post-ablation is common in HCM patients, especially in those with persistent AF. Left atrium size, LV apical aneurysm, and the APPLE score might contribute to identify subjects at higher risk of arrhythmia recurrence. First-time cryoballoon is comparable with radiofrequency ablation.

Fabry disease (FD) is a rare X-linked inherited lysosomal storage disorder caused by deficient α-galactosidase A activity that leads to an accumulation of globotriasylceramide (Gb3) in affected tissues, including the heart. Cardiovascular involvement usually manifests as left ventricular hypertrophy, myocardial fibrosis, heart failure, and arrhythmias, which limit quality of life and represent the most common causes of death. Following the introduction of enzyme replacement therapy, early diagnosis and treatment have become essential to slow disease progression and prevent major cardiac complications. Recent advances in the understanding of FD pathophysiology suggest that in addition to Gb3 accumulation, other mechanisms contribute to the development of Fabry cardiomyopathy. Progress in imaging techniques have improved diagnosis and staging of FD-related cardiac disease, suggesting a central role for myocardial inflammation and setting the stage for further research. In addition, with the recent approval of oral chaperone therapy and new treatment developments, the FD-specific treatment landscape is rapidly evolving.

Heart failure (HF), defined in its broadest sense as a syndromecharacterized by symptoms and signs of ventricular dysfunction inthe presence of structural and or functional abnormalities of heartfunction, affects millions of people worldwide; in addition, a substantialnumber of individuals have asymptomatic abnormalitiesof heart function that predispose them to symptomatic HF in laterlife. Coronary artery disease and hypertension are by far the most common causes of HF, but a substantial minority of cases arecaused by a heterogeneous group of heart muscle diseases, the cardiomyopathies.These disorders differ in several important respectsfrom other causes of HF in that they are often familial and presentthroughout life. With recent advances in the understanding of themolecular genetics of cardiomyopathies, cardiologists are havingto adapt diagnostic and treatment protocols in order to optimizemanagement of individual patients and their families. In thischapter we review the clinical presentation and pathophysiology ofthe most common monogenic cardiomyopathies and the cardiovascularmanifestations of mutations in the genes controlling therespiratory chain (mitochondrial diseases).

Aims Sudden cardiac death (SCD) is the most common mode of death in childhood hypertrophic cardiomyopathy (HCM). The newly developed HCM Risk-Kids model provides clinicians with individualized estimates of risk. The aim of this study was to externally validate the model in a large independent, multi-centre patient cohort. Methods and results A retrospective, longitudinal cohort of 421 patients diagnosed with HCM aged 1–16 years independent of the HCM Risk-Kids development and internal validation cohort was studied. Data on HCM Risk-Kids predictor variables (unexplained syncope, non-sustained ventricular tachycardia, maximal left ventricular wall thickness, left atrial diameter, and left ventricular outflow tract gradient) were collected from the time of baseline clinical evaluation. The performance of the HCM Risk-Kids model in predicting risk at 5 years was assessed. Twenty-three patients (5.4%) met the SCD end-point within 5 years, with an overall incidence rate of 2.03 per 100 patient-years [95% confidence interval (CI) 1.48–2.78]. Model validation showed a Harrell’s C-index of 0.745 (95% CI 0.52–0.97) and Uno’s C-index 0.714 (95% 0.58–0.85) with a calibration slope of 1.15 (95% 0.51–1.80). A 5-year predicted risk threshold of ≥6% identified 17 (73.9%) SCD events with a corresponding C-statistic of 0.702 (95% CI 0.60–0.81). Conclusions This study reports the first external validation of the HCM Risk-Kids model in a large and geographically diverse patient population. A 5-year predicted risk of ≥6% identified over 70% of events, confirming that HCM Risk-Kids provides a method for individualized risk predictions and shared decision-making in children with HCM.

Background Myocardial fibrosis is a common feature of hypertrophic cardiomyopathy (HCM) but its pathophysiology has yet to be elucidated. Purpose In this study, we used a multiplex approach to examine the genetic regulation of pathways associated with fibrosis in patients undergoing septal myectomy. Methods Myocardial tissue was collected at time of surgical intervention. Control biopsy samples were obtained from the left ventricular free wall from structurally normal hearts during autopsy following non-cardiac related death. Tissue was either snap frozen in liquid nitrogen and subsequently stored at −80 degrees or collected in RNA laterTM and frozen 24 hours later at −80 degrees. Total RNA was extracted from HCM tissue samples using the Qiagen RNeasy fibrous tissues mini kit and from control samples using mirVana isolation kit (Ambion), according to the manufacturer's protocol. Quantitative PCR (qPCR) was performed on the extracted RNA using a RT. Profiler™ Human finrosis PCR Array. Results The study cohort comprised 22 HCM samples and 5 controls. The relative regulation of genes involved in myocardial fibrosis in patients with HCM compared to controls is shown in figure 1. In patients with HCM, there was increased expression of genes involved in collagen synthesis. A significant two-fold upregulation in type III procollagen mRNA was observed relative to controls (p=0.013) with a similar trend identified for type I procollagen (1.5 fold up-regulation, p=0.081). The gene expression of MMP3 (−1.5 fold, p=0.029) and MMP8 (−1.8, p=0.002) which are involved in collaged degradation were downregulated in the HCM group. The gene expression of pro-fibrotic mediators TGF-β2 (4.8 fold, p=0.008) and CCN2 (2.9 fold, p=0.021) was also significantly elevated. Within the HCM group, there was a correlation between the fold regulation of TGF-β1 (r=0.570, p=0.006; r=0.528, p=0.012), TGF-β2 (r=0.569, p=0.006; r=0.514, p=0.014) and TGF-β3 (r=0.738, p The expression of BMP-7 which has been shown to reduce myocardial fibrosis by antagonising TGF- β mediated endothelial – mesothelial transformation of fibroblasts was also down-regulated in HCM (−3.8, p=0.015). Conclusions Genetic expression of procollagen is significantly upregulated in patients with HCM relative to controls. TGF-β and CCN2 mediated signalling appear to be key mediators in promoting collagen expression. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Heart Hospital Charitable Grant, UK Figure 1. Gene expression in HCM

Background Impaired myocardial blood flow (MBF) in the absence of epicardial coronary disease is a feature of hypertrophic cardiomyopathy (HCM). Although most evident in hypertrophied or scarred segments, reduced MBF can occur in apparently normal segments. We hypothesized that impaired MBF and myocardial perfusion reserve, quantified using perfusion mapping cardiac magnetic resonance, might occur in the absence of overt left ventricular hypertrophy (LVH) and late gadolinium enhancement, in mutation carriers without LVH criteria for HCM (genotype‐positive, left ventricular hypertrophy‐negative). Methods and Results A single center, case‐control study investigated MBF and myocardial perfusion reserve (the ratio of MBF at stress:rest), along with other pre‐phenotypic features of HCM. Individuals with genotype‐positive, left ventricular hypertrophy‐negative (n=50) with likely pathogenic/pathogenic variants and no evidence of LVH, and matched controls (n=28) underwent cardiac magnetic resonance. Cardiac magnetic resonance identified LVH‐fulfilling criteria for HCM in 5 patients who were excluded. Individuals with genotype‐positive, left ventricular hypertrophy‐negative had longer indexed anterior mitral valve leaflet length (12.52±2.1 versus 11.55±1.6 mm/m 2 , P =0.03), lower left ventricular end‐systolic volume (21.0±6.9 versus 26.7±6.2 mm/m 2 , P ≤0.005) and higher left ventricular ejection fraction (71.9±5.5 versus 65.8±4.4%, P≤ 0.005). Maximum wall thickness was not significantly different (9.03±1.95 versus 8.37±1.2 mm, P =0.075), and no subject had significant late gadolinium enhancement (minor right ventricle‒insertion point late gadolinium enhancement only). Perfusion mapping demonstrated visual perfusion defects in 9 (20%) carriers versus 0 controls ( P =0.011). These were almost all septal or near right ventricle insertion points. Globally, myocardial perfusion reserve was lower in carriers (2.77±0.83 versus 3.24±0.63, P =0.009), with a subendocardial:subepicardial myocardial perfusion reserve gradient (2.55±0.75 versus 3.2±0.65, P =P =0.026) but equivalent MBF (2.75±0.82 versus 2.65±0.69 mL/g per min, P =0.826). Conclusions Regional and global impaired myocardial perfusion can occur in HCM mutation carriers, in the absence of significant hypertrophy or scarring.

Background Recognizing the etiology of sudden cardiac arrest (SCA) has an enormous impact on the management of victims and their immediate families. A significant proportion of SCA survivors with a structurally normal heart are not offered a diagnosis and there is no clear consensus on the type and duration of follow‐up. We aimed to assess the utility of a multidisciplinary approach in optimizing diagnosis of cardiac arrest etiology during follow‐up. Methods and Results We retrospectively assessed 327 consecutive SCA survivors (mean age 61.9±16.2 years, 80% men) who underwent secondary prevention implantable cardioverter defibrillators between May 2015 and November 2018. The initial diagnosis was recorded at the time of admission and follow‐up diagnosis was deduced from subsequent clinic records, investigations, and outcomes of multidisciplinary team meetings. Structural heart disease accounted for 282 (86%) of SCAs. Forty‐five (14%) patients had a structurally normal heart and underwent comprehensive testing and follow‐up (mean duration 93±52 weeks). On initial evaluation, 14/45 (31%) of these received a diagnosis, rising to 29/45 (64%) with serial reviews during follow‐up. Discussion in multidisciplinary team meetings and imaging reassessment accounted for 47% of new diagnoses. No additional diagnoses were made beyond 96 weeks. Nineteen (5.8%) fatalities occurred in the entire cohort, exclusively in patients with structural heart disease. Conclusions Systematic comprehensive testing combined with multidisciplinary expert team review of SCA survivors without structural heart disease improves the yield and time to diagnosis compared with previously published studies. This approach has positive implications in the management of SCA survivors and their families.

Introduction Sudden cardiac death is the most common cause of mortality in childhood onset hypertrophic cardiomyopathy. Identifying individuals at highest risk is therefore an essential part of clinical care but remains challenging. The 12 lead electrocardiogram (ECG) has been proposed as a useful tool for risk stratification and an ECG risk score has been proposed. However, this has not been independently validated and the ECG phenotype of childhood HCM has not been previously described. The aim of this study was to describe the ECG phenotype of childhood HCM in a large, international, multi-centre cohort and investigate its role in risk prediction for arrhythmic events. Methods Participants with an available baseline resting 12-lead ECG were identified from a large, international, multi-centre, retrospective cohort of patients aged less than 16 years fulfilling the diagnostic criteria for HCM (n=1029). Resting baseline ECG was evaluated and ECG variables were extracted. In addition, the ECG risk score based on 8 parameters (deviation in QRS axis, pathological T-wave inversion in limb or precordial leads, ST-segment depression, dominant S-wave in V4, limb-lead amplitude sum, 12-lead amplitude duration product and QTc) was calculated as previously described. The primary study endpoint was a composite outcome of major cardiac events (MACE) defined as SCD, resuscitated cardiac arrest, appropriate implantable cardioverter defibrillator therapy, or sustained ventricular tachycardia (VT) with haemodynamic compromise. The discriminatory performance of using an ECG risk score >5 to identify patients at increased risk of MACE at 5 years was determined using Harrell’s C-index. Results Of 356 patients with childhood HCM (68.9% male, mean age at presentation 10.1 ± 4.5 years), 347 (97.5%) had baseline ECG abnormalities such as: repolarization abnormalities (n=277, 77.8%), left ventricular hypertrophy (n=240. 67.6%), abnormal QRS axis (n=126, 35.4%) or QT prolongation (n=131, 36.8%). Over a median follow up of 3.9 years (IQR 2.0-7.7), 25 (7%) had an arrhythmic event, with an overall annual event rate of 1.38 (95% CI 0.93-2.04). No ECG variables were associated with 5-year MACE on univariable or multivariable Cox regression analysis. Of the 164 participants with an ECG score >5, 153 (93.3%) did not have a MACE within 5 years. Harrell’s C-index (the probability of correctly distinguishing between high and low risk patients using an ECG risk score threshold of >5) was 0.60 (95% CI 0.484-0.715) at 5 years. The corresponding positive and negative predictive values were 6.7% (95% CI 4.7 – 9.4%) and 96.9% (95% CI 94.2 – 98.4%). Conclusions In a large, international, multi-centre cohort of children with HCM, ECG abnormalities are common. No ECG characteristic, either in isolation or combined in the ECG risk score, was associated with 5-year MACE risk. This suggests that the role of the baseline ECG phenotype in improving risk stratification in childhood HCM is limited. Conflict of Interest None

Background: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation. Methods: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator–treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range]. Results: We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0–7.2] and 5.1 [2.0–9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711–0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642–0.959), and the calibration slope was 1.082 (95% CI, 0.643–1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach. Conclusions: In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03058185.

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable heart muscle disease that causes sudden cardiac death in the young. Inflammatory myocardial infiltrates have been described at autopsy and on biopsy, but there are few data on the presence of myocarditis in living patients with ARVC using non-invasive imaging techniques. FDG-PET is a validated technique for detecting myocardial inflammation in clinically suspected myocarditis. We aimed to determine the prevalence of myocardial inflammation in patients with ARVC using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). Methods and results We performed a retrospective analysis of a single centre cohort of patients with ARVC referred for FDG-PET scans between 2012 and 2017 for investigation of symptoms or suspected device infection. Sixteen patients (12 male; age 42 ± 13 years) with a definite diagnosis of ARVC were identified. Seven had positive FDG-PET scans, two of whom had cardiac sarcoidosis on endomyocardial biopsy. Of the remaining five, two carried pathogenic desmoplakin mutations. FDG uptake was found in the left ventricular myocardium in all cases. One patient also had right ventricular uptake. Conclusion In this exploratory study, we show that some patients with ARVC have evidence for myocardial inflammation on FDG-PET, suggesting that myocarditis plays a role in disease pathogenesis.

Learning objectives Phenotype is defined as a set of observable characteristics of an individual resulting from the interaction of their genotype with the environment. It differs from ‘disease’ in that it does not reflect the mechanism by which it is produced. In 1982, the term arrhythmogenic right ventricular dysplasia was first used to describe a clinical phenotype characterised by ventricular arrhythmias of left bundle branch block (LBBB) configuration accompanied by right ventricular dilatation, wall motion abnormalities and fibrofatty replacement of the myocardium.1 Arrhythmogenic right ventricular cardiomyopathy (ARVC) became the preferred descriptor when subsequent histopathological analysis revealed that myocyte atrophy as a consequence of progressive cell death occurred after birth.2 3 Initial clinical diagnostic criteria for ARVC were based on descriptions of patients with advanced disease,4 but discovery of its genetic basis, and the phenotyping of large patient cohorts including relatives, revealed a broader disease spectrum in which right ventricle (RV) and left ventricle (LV) can be involved.5 The disease paradigm has expanded further with the recognition of new disease genes causing similar phenotypes. Hence, terms such as left-dominant arrhythmogenic cardiomyopathy , arrhythmic dilated cardiomyopathy or simply arrhythmogenic cardiomyopathy (AC) are increasingly used to describe the clinical phenotype observed in a family of disorders in which frequent ventricular arrhythmia and dysfunction of one or both ventricles are the defining features. In this article, we review this emerging concept with a focus on the …

Background:Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibrofatty replacement of the right and left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants in the nondesmosomal cadherin 2 (CDH2), a novel genetic substrate of ACM.Methods:A cohort of 500 unrelated patients with a definite diagnosis of ACM and no disease-causing variants in the main ACM genes was assembled. Genetic screening ofCDH2was performed through next-generation or Sanger sequencing. Whenever possible, cascade screening was initiated in the families ofCDH2-positive probands, and clinical evaluation was performed.Results:Genetic screening ofCDH2led to the identification of 7 rare variants: 5, identified in 6 probands, were classified as pathogenic or likely pathogenic. The previously established p.D407N pathogenic variant was detected in 2 additional probands. Probands and family members with pathogenic/likely pathogenic variants inCDH2were clinically evaluated, and along with previously published cases, altogether contributed to the identification of gene-specific features (13 cases from this cohort and 11 previously published, for a total of 9 probands and 15 family members). Ventricular arrhythmic events occurred in mostCDH2-positive subjects (20/24, 83%), while the occurrence of heart failure was rare (2/24, 8.3%). Among probands, sustained ventricular tachycardia and sudden cardiac death occurred in 5/9 (56%).Conclusions:In this worldwide cohort of previously genotype-negative ACM patients, the prevalence of probands withCDH2pathogenic/likely pathogenic variants was 1.2% (6/500). Our data show that this cohort ofCDH2-ACM patients has a high incidence of ventricular arrhythmias, while evolution toward heart failure is rare.

Aims The 12-lead electrocardiogram (ECG) is routinely performed in children with hypertrophic cardiomyopathy (HCM). An ECG risk score has been suggested as a useful tool for risk stratification, but this has not been independently validated. This aim of this study was to describe the ECG phenotype of childhood HCM in a large, international, multi-centre cohort and investigate its role in risk prediction for arrhythmic events. Methods and results Data from 356 childhood HCM patients with a mean age of 10.1 years (±4.5) were collected from a retrospective, multi-centre international cohort. Three hundred and forty-seven (97.5%) patients had ECG abnormalities at baseline, most commonly repolarization abnormalities (n = 277, 77.8%); left ventricular hypertrophy (n = 240, 67.7%); abnormal QRS axis (n = 126, 35.4%); or QT prolongation (n = 131, 36.8%). Over a median follow-up of 3.9 years (interquartile range 2.0–7.7), 25 (7%) had an arrhythmic event, with an overall annual event rate of 1.38 (95% CI 0.93–2.04). No ECG variables were associated with 5-year arrhythmic event on univariable or multivariable analysis. The ECG risk score threshold of >5 had modest discriminatory ability [C-index 0.60 (95% CI 0.484–0.715)], with corresponding negative and positive predictive values of 96.7% and 6.7% Conclusion In a large, international, multi-centre cohort of childhood HCM, ECG abnormalities were common and varied. No ECG characteristic, either in isolation or combined in the previously described ECG risk score, was associated with 5-year sudden cardiac death risk. This suggests that the role of baseline ECG phenotype in improving risk stratification in childhood HCM is limited.

Aim This executive summary of the hypertrophic cardiomyopathy clinical practice guideline provides recommendations and algorithms for clinicians to diagnose and manage hypertrophic cardiomyopathy in adult and pediatric patients as well as supporting documentation to encourage their use. Methods A comprehensive literature search was conducted from January 1, 2010, to April 30, 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Collaboration, Agency for Healthcare Research and Quality reports, and other relevant databases. Structure Many recommendations from the earlier hypertrophic cardiomyopathy guidelines have been updated with new evidence or a better understanding of earlier evidence. This summary operationalizes the recommendations from the full guideline and presents a combination of diagnostic work-up, genetic and family screening, risk stratification approaches, lifestyle modifications, surgical and catheter interventions, and medications that constitute components of guideline directed medical therapy. For both guideline-directed medical therapy and other recommended drug treatment regimens, the reader is advised to follow dosing, contraindications and drug-drug interactions based on product insert materials.

Background Previous studies on paediatric cardiomyopathies have provided useful information on their epidemiology and clinical presentation but have been limited by a lack of detailed data on genetic testing and aetiology. Purpose The purpose of this study was to examine the frequency of familial and genetic disease among children with cardiomyopathy enrolled in the European Society of Cardiology (ESC) Cardiomyopathy and Myocarditis EORP Long-Term Registry (CMY-LT). Methods 633 individuals aged Results Overall, 253 patients (47% of those reported) had familial disease; in those diagnosed between 10 and 18 years of age, familial disease was most frequent in HCM and least frequent in DCM [57 (55%) vs 12 (32%); p=0.046]. Genetic testing was performed in 414 (68%) patients. In those diagnosed Conclusion This study confirms the heterogeneous aetiology of childhood cardiomyopathies and demonstrate a higher prevalence of familial disease than previously reported in paediatric populations. Genetic testing is performed in a high proportion of patients, with a high yield of reported causative variants. Funding Acknowledgement Type of funding source: None

Background The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), demonstrated that tafamidis was an effective treatment for patients with transthyretin amyloid cardiomyopathy (ATTR-CM). Tafamidis, at an 80 mg daily dose, was subsequently approved in several countries for the treatment of ATTR-CM. Patients who completed ATTR-ACT were eligible to enroll in an ongoing long-term extension study (LTE) which provides additional data on the long-term efficacy of tafamidis. Purpose To assess the long-term benefit of tafamidis in patients with ATTR-CM and to determine median survival times with treatment. Methods Patients with ATTR-CM who completed ATTR-ACT (in which they were randomized to tafamidis meglumine 80 mg, 20 mg or placebo for 30 months) could enroll in the ongoing LTE in which patients continued to be treated with the same dose of tafamidis or, if previously treated with placebo, were randomized to tafamidis meglumine 80 mg or 20 mg. Tafamidis free acid 61 mg is a new formulation (bioequivalent to tafamidis meglumine 80 mg) developed for patient convenience and all patients in the LTE transitioned to tafamidis free acid 61 mg as of 1 Aug, 2018. All-cause mortality (with heart transplant or cardiac mechanical assist device [CMAD] implantation counted as death) was assessed using a Cox proportional hazards model (as of 1 Aug, 2019). Patients treated with tafamidis meglumine 80 mg in ATTR-ACT and the LTE who transitioned to tafamidis free acid 61 mg (tafamidis 80/61 mg) were compared with patients treated with placebo in ATTR-ACT who transitioned to tafamidis in the LTE (placebo/tafamidis). Results There were a total of 176 tafamidis 80/61 mg patients and 177 placebo/tafamidis patients. Median treatment duration was 51.9 months with tafamidis 80/61 mg and 51.4 months with placebo/tafamidis. With tafamidis 80/61 mg, there were 75 (42.6%) all-cause deaths; consisting of 67 (38.1%) deaths, 6 (3.4%) heart transplants, and 2 (1.1%) CMAD implantations. With placebo/tafamidis, there were 108 (61.0%) all-cause deaths; consisting of 102 (57.6%) deaths and 6 (3.4%) heart transplants. There was a significant reduction of 41.1% in the risk of all-cause mortality with tafamidis 80/61 mg compared with placebo/tafamidis (hazard ratio [95% CI], 0.5888 [0.4370, 0.7931]; P=0.0004). Median survival time with placebo/tafamidis was 35.8 months but was not reached with tafamidis 80/61 mg. Conclusions Treatment with tafamidis significantly improves long-term survival in patients with ATTR-CM. The comparatively poorer survival in patients treated with placebo in ATTR-ACT who transitioned to tafamidis in the LTE highlights the importance of early diagnosis and treatment. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): This study was sponsored by Pfizer.

Background Dilated cardiomyopathy (DCM) has an estimated population prevalence of 1/250 and is the underlying diagnosis in a third of heart failure patients. A substantial proportion of patients have familial disease caused by dominant mutations in one of more than 50 genes, but clinical practice guidelines recommend genetic testing in young patients with idiopathic DCM. There is an absence of robust data on the influence of age on the diagnostic yield of genetic testing. Methods The study cohort comprised 825 consecutive and unrelated patients (524 male (63.5%)) with DCM who underwent genetic testing from 2015 to 2019. Genetic variants were classified using American College of Medical Genetics (ACMG) criteria. Analyses were stratified by age and sex. Results 173 (20.1%) patients had a positive genetic test (“pathogenic” or “likely pathogenic” variant); 292 (34.4%) had a variant of unknown significance. Mean age at genetic testing was 49.9±14.4 years. Mean age of patients with a positive test was 47.6±13.6 years. 99 (18.9%) men and 67 (22.3%) women had a positive test (p=0.246). Mutations in the TTN gene, encoding for titin, accounted for 46.1% of positive results. 13.8% of mutations were in DSP, 8.4% in RBM20, 6% in FLNC, 4.2% in LMNA, 3.6% in BAG3 and 3.6% in MYH7. There was a trend to declining yield with age (likelihood ratio chi-square p value = 0.047). The yield was 17.2% in the 56–65 year age group and 11.5% above 66 years of age (figure 1). Conclusions Approximately 1 in 5 patients with DCM had a positive genetic test. The yield declined in patients over 66 years but remained above 11%, suggesting that genetic testing should not be confined to younger patients with DCM. Figure 1. Yield of Genetic Testing by Age Funding Acknowledgement Type of funding source: None

Introduction Early detection of affected family relatives of patients with dilated cardiomyopathy (DCM) is essential in order to guide follow up, outcomes and initiate early treatment. Myocardial work analysis is a novel method which integrated strain imaging and blood pressure and has the potential to identify patients with subclinical disease. Purpose We analysed myocardial work in family relatives of DCM patients with positive genotype but negative phenotype in order to identify whether myocardial work can identify early changes. Methods Seventy-four family relatives of DCM patients attending for screening were examined. All individuals were asymptomatic with either positive (45/74, G+) or negative (29/74, G-) genotype and no echocardiographic evidence of left ventricular dilatation or systolic impairment. Non-invasive myocardial work analysis using two-dimensional (2D) speckle tracking echocardiography was analysed. Global longitudinal strain (GLS) was measured by the same vendor specific software used for myocardial work analysis. Left ventricular (LV) ejection fraction (EF) was measured with the Simpson's biplane method. The peak systolic arm cuff blood pressure (BP) measurement at the time of echocardiography was used for the myocardial work study. Results In total we included 74 individuals (37±15 years old, 50.7% women) with mean systolic and diastolic BP of 121.3±14 and 73.2±10 mmHg respectively, mean EF was 58±5% and mean GLS at 18.4±2.5%. G+ individuals had pathogenic and very likely pathogenic mutations in 8 different genes (TTN, BAG3, DSP, FLNC, LMNA, DMD, RBM20, TPM1). There was no difference in age, systemic hypertension, diabetes or medical treatment between the 2 groups. No significant difference was found among G+ and G- individuals in mean systolic and diastolic BP (121.2±14.7 vs 121.2±15.2 mmHg), mean EF (57.3±5 vs 59.1±4%), GLS (−18.2±1.5 vs −18.6±2.9%), mean global work index (1818±403 vs 1928±295 mmHg%) and global constructive work (2192±464 vs 2260±318 mmHg%). However, we found significant reduction of the global work efficiency (GWE) with a GWE of 94.4±2.7% in the G+ versus 95.9±1.6% in the G- individuals (p 0.02). Moreover, the global wasted work (GWW) was increased in the G+ with a GWW of 111±58 mmHg% versus 82±41 mmHg% in the G- individuals (p 0.03). Conclusion DCM gene carriers show, early on, decreased myocardial work efficiency and increased wasted work compared to unaffected family members, which appears to be earlier than other parameters such as EF and GLS. Myocardial work analysis could potentially recognize individuals showing early cardiac involvement and guide closer follow up and early initiation of treatment. Funding Acknowledgement Type of funding source: None

Background Cardiomyopathies frequently cause heart failure (HF), however their prevalence in the general population and the natural history of incident HF across the spectrum of cardiomyopathy phenotypes is poorly understood. Improved understanding will help guide rational selection of diagnostic tests and accelerate the recognition of underlying causes of HF. Purpose To estimate the prevalence of cardiomyopathies using electronic health records; to compare clinical characteristics between patients with cardiomyopathy phenotypes; and to describe the temporal relationship between diagnosis of cardiomyopathy and incident HF. Methods A population-based cohort of patients with cardiomyopathy (n=4058) was provided by the UK Clinical Practice Research Datalink (CPRD) from a denominator sample of ∼9 million individuals. Patients were phenotyped into groups according to ESC criteria: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC) and restrictive cardiomyopathy (RCM). An additional group of transthyretin amyloid cardiomyopathy (ATTR-CM) was reported separately. Point prevalence was estimated for each cardiomyopathy subtype and clinical characteristics defined. An index date at first diagnosis of HF was determined for each patient and the time from/to first diagnosis of cardiomyopathy calculated relative to the index date and presented graphically. Results DCM was the most common cardiomyopathy phenotype among women and men with 3.4 and 7.7 cases per 10,000 population, respectively. The 2-fold increase in prevalence among men was consistent across DCM, HCM and RCM; the reverse trend was observed for ARVC which was found in 2.3 per 10,000 women and 1.1 per 10,000 men. At the time of first diagnosis of cardiomyopathy, most patients with ATTR-CM (73.5%), DCM (71.0%) and RCM (71.3%) had pre-existing HF though this proportion fell to 41.0% in ARVC and 31.0% in HCM. In relation to incident HF, a diagnosis of HCM and DCM were recorded earliest at a mean −2.2 years (SE 0.2) and −0.6 years (SE 0.1), respectively. We observed a clustering of diagnoses of RCM (mean −0.2 years, SE 0.4) and ARVC (mean 0.1 years, SE 0.1) around the time of onset of heart failure, whereas a diagnosis of ATTR-CM was first recorded at a mean of 0.9 years (SE 0.2) following the onset of heart failure. Conclusions Most diagnoses of ATTR-CM, DCM and RCM were preceded by clinical expression of HF whereas most people with ARVC or HCM developed HF after their cardiomyopathy diagnosis. Our findings in ARVC and HCM suggest a more indolent course with respect to cardiac function or better recognition in an asymptomatic phase. The clustering of a diagnosis of heart failure around the time of diagnosis of cardiomyopathy highlights a need for greater awareness of specific aetiologies of heart failure in routine practice and suggests opportunities for presymptomatic or earlier diagnosis. Temporality of HF in cardiomyopathies Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Pfizer

Background Cardiac magnetic resonance (CMR) constitutes a gold standard in the diagnosis of cardiomyopathies. Regardless of CMR advantages, the method is time-consuming, high-cost, with limited availability in some European regions. Purpose To assess the availability and applicability of CMR for establishing the diagnosis in different populations of patients with cardiomyopathies. Methods Overall, 3208 adult patients with cardiomyopathy (1119 / 34.9% females; median age at diagnosis: 49.0 years): 1260 with dilated (DCM), 1739 with hypertrophic (HCM), 66 with restrictive (RCM) and 143 with arrhythmogenic right ventricular cardiomyopathy (ARVC) enrolled in EURObservational Research Programme (EORP) – Cardiomyopathy/Myocarditis Long-Term Registry were analysed. Results CMR scan was performed as a baseline diagnostic method in 29.4% of patients; CMR was a single diagnostic method in 0.9% of patients and in 28.6% of patients CMR was used along with transthoracic echocardiography (TTE). In 67.6% of patients TTE was at the baseline the single diagnostic imaging method. Prevalence of CMR use in different cardiomyopathies was as follows: 20.6% in DCM, 33.8% in HCM, 36.4% in RCM and 51.1% in ARVC (p The population with CMR use was younger, less symptomatic, with decreased prevalence of other cardiovascular risk factors and of associated cardiovascular diseases as compared to the population diagnosed without CMR scanning (p Abnormal CMR results were present in 93.4% of patients with the highest percentage in RCM (95.8%) and HCM (94.9%) followed by DCM (91.5%) and the lowest abnormal CMR scan ratio in ARVC (87.7%) (p=0.030). The majority of CMR examinations comprised the assessment of late gadolinium enhancement (LGE, 93.3% at baseline). Presence of CMR LGE was observed in 69.3% of all patients: 59.1% in DCM, 73.8% in HCM, in 63.9% in ARVC and with the highest prevalence in RCM (83.3%) (p Conclusion The study reveals real-life data on the low availability and applicability of CMR in adult patients with cardiomyopathies. The analysis shows the advantages of CMR imaging but also identifies the gaps between recommendations and clinical practice. Improvement regarding access, training and reimbursement is necessary to offer CMR to cardiomyopathy patients in accordance with the ESC guidelines. Funding Acknowledgement Type of funding source: None

This chapter covers coronary artery disease (CAD) and myocardial infarction, starting with an introduction to the main causal and treatable risk factors for CAD and myocardial infarction, then goes on to discuss the Mendelian disorders associated with CAD (e.g. Tangier disease, sitosterolaemia, etc.) Association studies based on the candidate gene approach are discussed along with genomic studies, e.g. polygenic risk scores.

Aims The European Society of Cardiology (ESC) European Observational Research Programme (EORP) Cardiomyopathy Registry is a prospective multinational registry of consecutive patients with cardiomyopathies. The objective of this report is to describe the short-term outcomes of adult patients (≥18 years old). Methods and results Out of 3208 patients recruited, follow-up data at 1 year were obtained in 2713 patients (84.6%) [1420 with hypertrophic (HCM); 1105 dilated (DCM); 128 arrhythmogenic right ventricular (ARVC); and 60 restrictive (RCM) cardiomyopathies]. Improvement of symptoms (dyspnoea, chest pain, and palpitations) was globally observed over time (P Conclusions Despite symptomatic improvement, patients with cardiomyopathies remain prone to major clinical events in the short term. Outcomes were different not only according to cardiomyopathy subtypes but also in relatives vs. index patients, and according to European regions.

International audience; Aims: Cardiomyopathies are a heterogeneous group of disorders that increase the risk for atrial fibrillation (AF). The aim of the study is to assess the prevalence of AF, anticoagulation management, and risk of stroke/transient ischaemic attack (TIA) in patients with cardiomyopathy.Methods and results: Three thousand two hundred eight consecutive adult patients with cardiomyopathy (34.9% female; median age: 55.0 years) were prospectively enrolled as part of the EURObservational Research Programme Cardiomyopathy/Myocarditis Registry. At baseline, 903 (28.2%) patients had AF (29.4% dilated, 27.5% hypertrophic, 51.5% restrictive, and 14.7% arrhythmogenic right ventricular cardiomyopathy, P < 0.001). AF was associated with more advanced New York Heart Association class (P < 0.001), increased prevalence of cardiovascular risk factors and co-morbidities, and a history of stroke/TIA (P < 0.001). Oral anticoagulation was administered in 71.7% of patients with AF (vitamin K antagonist: 51.6%; direct oral anticoagulant: 20.1%). At 1 year follow-up, the incidence of cardiovascular endpoints was as follows: stroke/TIA 1.85% (AF vs. non-AF: 3.17% vs. 1.19%, P < 0.001), death from any cause 3.43% (AF vs. non-AF: 5.39% vs. 2.50%, P < 0.001), and death from heart failure 1.67% (AF vs. non-AF: 2.44% vs. 1.31%, P = 0.033). The independent predictors for stroke/TIA were as follows: AF [odds ratio (OR) 2.812, P = 0.005], history of stroke (OR 7.311, P = 0.010), and anaemia (OR 3.119, P = 0.006).Conclusions: The study reveals a high prevalence and diverse distribution of AF in patients with cardiomyopathies, inadequate anticoagulation regimen, and high risk of stroke/TIA in this population.

Background: Serum anti-heart autoantibodies (AHAs) and anti-intercalated disk autoantibodies (AIDAs) are autoimmune markers in myocarditis. Myocarditis has been reported in arrhythmogenic right ventricular cardiomyopathy (ARVC). To provide evidence for autoimmunity, we searched for AHAs and AIDAs in ARVC. Methods: We studied: 42 ARVC probands, 23 male, aged 42, interquartile range 33–49, 20 from familial and 22 nonfamilial pedigrees; 37 clinically affected relatives (ARs), 24 male aged 35, interquartile range 18–46; and 96 healthy relatives, 49 male, aged 27, interquartile range 17–45. Serum AHAs and AIDAs were tested by indirect immunofluorescence on human myocardium and skeletal muscle in 171 of the 175 ARVC individuals and in controls with noninflammatory cardiac disease (n=160), ischemic heart failure (n=141), and healthy blood donors (n=270). Screening of 5 desmosomal genes was performed in probands; when a sequence variant was identified, cascade family screening followed, blind to immunologic results. Results: AHA frequency was higher (36.8%) in probands, ARs (37.8%), and healthy relatives (25%) than in noninflammatory cardiac disease (1%), ischemic heart failure (1%), or healthy blood donors (2.5%; P =0.0001). AIDA frequency was higher in probands (8%, P =0.006), in ARs (21.6%, P =0.00001), and in healthy relatives (14.6%, P =0.00001) than in noninflammatory cardiac disease (3.75%), ischemic heart failure (2%), or healthy blood donors (0.3%). AHA-positive status was associated with higher frequency of palpitation ( P =0.004), implantable cardioverter defibrillator implantation ( P =0.021), lower left ventricular ejection fraction ( P =0.004), AIDA-positive status with both lower right ventricular and left ventricular ejection fractions ( P =0.027 and P =0.027, respectively). AHA- and/or AIDA-positive status in the proband and at least one of the respective relatives was more common in familial (17/20, 85%) than in sporadic (10/22, 45%) pedigrees ( P =0.007). Conclusions: The presence of AHAs and AIDAs provides evidence of autoimmunity in the majority of familial and in almost half of sporadic ARVC. In probands and in ARs, these antibodies were associated with features of disease severity. Longitudinal studies are needed to clarify whether they may predict ARVC development in healthy relatives or if they be a result of manifest ARVC.

Aims Cardiac death is the leading cause of mortality in patients with sarcoidosis, yet cardiac involvement often remains undetected. Cardiovascular magnetic resonance imaging (CMR) and 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) have been used to diagnose cardiac sarcoidosis (CS) yet never simultaneously in a cohort. This study sought to assess the diagnostic and prognostic utility of simultaneous hybrid cardiac PET/MR. Methods and results Fifty-one consecutive patients with suspected CS (age 50 ± 13 years, 31 males) underwent simultaneous PET/MR following a high-fat/low-carbohydrate diet and 12-h fast. Blinded image analysis of FDG uptake and late gadolinium enhancement (LGE) was performed using the American Heart Association (AHA) 16-segment model. The sensitivity and specificity of PET/MR for diagnosing CS was estimated using the Japanese Ministry of Health and Welfare guidelines. The primary endpoint was a composite of death, aborted sudden cardiac death, sustained ventricular arrhythmia, complete heart block, and hospital admission with decompensated heart failure. The secondary endpoints were a fall in left ventricular ejection fraction (LVEF) >10%, non-sustained ventricular tachycardia and other cardiac-related hospital admission. The prevalence of CS was 65% (n = 33). The sensitivity of PET and CMR alone for detecting CS was 0.85 and 0.82, respectively. Hybrid PET/MR was superior for detecting CS with sensitivity, specificity, positive, and negative predictive values of 0.94, 0.44, 0.76, and 0.80, respectively. There was poor inter-modality agreement for the location of cardiac abnormalities (k = 0.02). Over the median follow-up of 2.2 years, there were 18 (35%) adverse events. Cardiac RV PET abnormalities and presence of LGE were independent predictors of adverse events. Abnormalities found on both PET and magnetic resonance imaging was the strongest predictor of major adverse cardiac events. Conclusion Simultaneous PET/MR is an accurate method for diagnosing CS. FDG-PET and CMR combined offers complementary information on disease pathophysiology. The presence of LGE and FDG uptake on PET/MR identifies patients at higher risk of adverse events. PET and CMR should therefore be considered in the assessment of disease presence, stage, and prognosis in CS.

Importance: Truncating variants in the gene encoding filamin C (FLNCtv) are associated with arrhythmogenic and dilated cardiomyopathies with a reportedly high risk of ventricular arrhythmia.Objective: To determine the frequency of and risk factors associated with adverse events among FLNCtv carriers compared with individuals carrying TTN truncating variants (TTNtv).Design, Setting, and Participants: This cohort study recruited 167 consecutive FLNCtv carriers and a control cohort of 244 patients with TTNtv matched for left ventricular ejection fraction (LVEF) from 19 European cardiomyopathy referral units between 1990 and 2018. Data analyses were conducted between June and October, 2020.Main Outcomes and Measures: The primary end point was a composite of malignant ventricular arrhythmia (MVA) (sudden cardiac death, aborted sudden cardiac death, appropriate implantable cardioverter-defibrillator shock, and sustained ventricular tachycardia) and end-stage heart failure (heart transplant or mortality associated with end-stage heart failure). The secondary end point comprised MVA events only.Results: In total, 167 patients with FLNCtv were studied (55 probands [33%]; 89 men [53%]; mean [SD] age at baseline evaluation, 43 [18] years). For a median follow-up of 20 months (interquartile range, 7-60 months), 29 patients (17.4%) reached the primary end point (19 patients with MVA and 10 patients with end-stage heart failure). Eight (44%) arrhythmic events occurred among individuals with baseline mild to moderate left ventricular systolic dysfunction (LVSD) (LVEF = 36%-49%). Univariable risk factors associated with the primary end point included proband status, LVEF decrement per 10%, ventricular ectopy (≥500 in 24 hours) and myocardial fibrosis detected on cardiac magnetic resonance imaging. The LVEF decrement (hazard ratio [HR] per 10%, 1.83 [95% CI, 1.30-2.57]; P Conclusions and Relevance: The high frequency of MVA among patients with FLNCtv with mild to moderate LVSD suggests that higher LVEF values than those currently recommended should be considered for prophylactic implantable cardioverter-defibrillator therapy in FLNCtv carriers.

Aims Surgical intervention is used to treat dynamic left ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy. This study assesses the effect of different surgical strategies on long-term mortality and morbidity. Methods and results In total, 347 patients underwent surgical intervention for LVOTO (1988-2015). Group A (n = 272) underwent septal myectomy; Group B (n = 33), septal myectomy and mitral valve (MV) repair; Group C (n = 22), myectomy and MV replacement; and Group D (n = 20), MV replacement alone. Median follow-up was 5.2 years (interquartile range 1.9-7.9). The mean resting LVOT gradient improved post-operatively from 71.9 ± 39.6 mmHg to 13.4 ± 18.5 mmHg (P 1 New York Heart Association (NYHA) class; 58.9% of patients undergoing MV replacement alone did not improve their NYHA class. There were 5 perioperative deaths and 20 late deaths (>30 days). Survival rates at 1, 5 and 10 years respectively were 98.4, 96.9, 91.9% in Group A; 97.0, 92.4, 61.6% in Group B; 100.0, 100.0, 55.6% in Group C; and 94.7, 85.3, 85.3% in Group D (log-rank, P 30 days) complications included atrial fibrillation (29.6%), transient ischaemic attack/stroke (2.4%) and heart failure hospitalisation (3.2%). There were 16 repeat surgical interventions at 3.0 years. Conclusion Septal myectomy is a safe procedure resulting in symptomatic improvement in the majority of patients. The annual incidence of non-fatal disease-related complications after surgical treatment of LVOTO is relatively high. Patients who underwent MV replacements had poorer outcomes with less symptomatic benefit in spite of a similar reduction in LVOT gradients.

Aim: Anderson-Fabry disease (AFD) is a hereditary disorder caused by a deficiency in the lysosomal enzyme α-galactosidase A which causes dysfunctions in multiple organ systems. Cardiac manifestation includes left ventricular hypertrophy, thickening of the valves, conduction disturbances and in the late phase, extensive areas of myocardial fibrosis with increased risk of sudden cardiac death. Case example: A case of AFD with exclusive cardiac involvement is described. During follow-up, due to the high risk of life-threatening arrhythmic events, implantation of an implantable cardioverter defibrillator is performed. Conclusion: AFD patients with advanced cardiac disease might represent a subgroup of patients who may require an implantable cardioverter defibrillator for primary prevention of sudden cardiac death.

Cardiomyopathy is an important cause of sudden cardiac death particularly in adolescents and young adults. The risk of sudden cardiac death varies between individual cardiomyopathies and is dependent on the severity of disease, age and gender. Although rare in cardiomyopathies, a fundamental aspect of clinical management is a systematic and thorough clinical assessment to identify the small number of individuals who are at risk and who can be protected with prophylactic ICD therapy.

Purpose of Review Non-ischaemic dilated cardiomyopathy (DCM) occurs in 1 in 2500 individuals in the general population and is associated with considerable morbidity and mortality. Studies involving large numbers of unselected DCM patients have led to consensus guidelines recommending implantable cardioverter-defibrillator (ICD) implantation for protection against sudden cardiac death (SCD) in those with LVEF ≤35%. The purpose of this article is to review the literature for other potential markers including serological, electrocardiographic, echocardiographic, cardiac magnetic resonance, ambulatory ECG and genetic data, to highlight other potential markers that may optimise risk stratification for SCD in this cohort and thereby allow a more personalized approach to ICD-implantation. Recent Findings Recent studies including the Danish study to assess the efficacy of ICDs in patients with non-ischemic systolic heart failure on mortality (DANISH) trial have questioned the benefits of ICD implantation in this group of patients with no changes in all-cause mortality. Recent pooled cohorts of patients with genetic DCM and in particular in those with Lamin A/C (LMNA) mutations have identified patients at increased risk of SCD and allowed the creation of algorithms to prognosticate SCD risk in mutation carriers. Furthermore, genetic testing has identified other DCM-causing genes including filamin C (FLNC) and RBM20 which may be associated with higher rates of ventricular arrhythmia. Summary To date, risk-stratification for SCD has been hampered by the utilisation of heterogenous subsets of idiopathic DCM patients and by use of static risk models where predictions are based on a single time point with a lack of consideration of disease progression. The current focus of personalised risk-stratification for SCD is shifting towards better characterisation of underlying DCM aetiology and the development of multi-parametric risk-stratification models that incorporate time-dependent disease characteristics and novel biomarkers.

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Introduction Arrhythmogenic Cardiomyopathy (AC) is typically caused by mutations in the desmosomal genes, however non-desmosomal genes have been increasingly implicated. Desmin gene (DES) mutations have been previously reported in AC, but in many cases there are insufficient data to support their pathogenicity. Purpose We assessed our AC cohort for DES gene mutations and describe the clinical phenotype associated with a recurring variant present in 3 unrelated families. Methods Genetic testing was performed using next-generation sequencing for 41 genes in a total of 138 AC probands with a definite diagnosis of AC based on the revised 2010 Task Force diagnostic criteria. All candidate variants were confirmed using Sanger sequencing. Clinical and genetic cascade screening were expanded to the first-degree relatives of the probands. Retained tissue from deceased individuals was used for genetic testing. All living mutation carriers underwent clinical assessment including physical examination, 12-lead ECG, signal-averaged ECG, echocardiography, cardiac magnetic resonance imaging (MRI) and 24h Holter-monitoring. Results Two DES gene variants, p.Ser298Leu (n=1) and p.Leu115Ile (n=3), were identified in 4 out of the 138 probands (3%). The former coexisted with a pathogenic DSP gene mutation and has not been further evaluated. The latter is a novel variant, absent in control databases (gnomAD) and was the only variant present in 3 unrelated families (see figure). One carrier required heart transplant (A-II-1), two died suddenly (A-III-1, B-II-1) and one died of non-cardiac causes (B-I-2). Detailed clinical information was present in 8 mutation carriers (2 male, age 45±19 years). Seven (88%) had a definite diagnosis and one had a borderline diagnosis of AC. All cases (100%) had right ventricular (RV) wall motion abnormalities, 6 (75%) had a dilated RV, 6 (75%) a dilated LV and 6 (75%) had LV dysfunction (mild in 5 and severe in 1). LV late gadolinium enhancement (LGE) was present in all 6 carriers that had a cardiac MRI with a circumferential sub-epicardial distribution (see figure, case A-III-2). Non-sustained ventricular tachycardia (VT) was present in 7 (88%) and sustained VT in 2 cases (25%). The ventricular ectopic burden per 24h ranged from 426 to 10583 with a median value of 820. Figure 1 Conclusion Variants of the DES gene are rare causes of AC. The novel p.Leu115Ile variant seems to be prevalent in a large UK-based cohort and it causes a biventricular form of AC, with a characteristic scar pattern on MRI and severe outcomes. Acknowledgement/Funding Alexandros Protonotarios is supported by a BHF Clinical Research Training Fellowship no. FS/18/82/34024

Background Transthyretin amyloid cardiomyopathy (ATTR-CM), is an underdiagnosed, fatal disease caused by the deposition of transthyretin amyloid fibrils in the heart leading to heart failure. The Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), an international, multi-center, double-blind, placebo-controlled, randomized study, demonstrated the efficacy and safety of tafamidis treatment for patients with ATTR-CM due to variant (ATTRm) or wild-type (ATTRwt) TTR. Purpose This is a pooled analysis of data from ATTR-ACT and interim data from the ongoing, long-term, extension study to evaluate longer term data on the efficacy of tafamidis in patients with ATTR-CM. Methods Patients who completed ATTR-ACT (which had a duration of 30 months) were eligible to be enrolled in a long-term, extension study in which patients either continued to receive tafamidis meglumine at the same dose (the tafamidis/tafamidis [T/T] group) or, for patients previously treated with placebo, were randomised (in a 1:2 ratio) to tafamidis meglumine 20 mg or 80 mg (the placebo/tafamidis [P/T] group) for up to 60 months. The primary efficacy outcome was all-cause mortality. This analysis combined data from the completed ATTR-ACT with interim data from the extension study (cut-off date: 15 Feb, 2018), and included patients treated with tafamidis meglumine across the two studies with a median follow up of 36 months. Results All-cause mortality was significantly lower in the T/T group (n=264; 88 events, 33.3%) compared with the P/T group (n=177; 88 events, 50.3%); hazard ratio (95% CI), 0.64 (0.47, 0.85); P=0.001. In the subgroup of ATTRwt patients, all-cause mortality was significantly reduced in the T/T group (55/201; 27.4%) compared with the P/T group (60/134; 44.8%); 0.64 (0.44, 0.92); P=0.002. In the 106 (24.0%) ATTRm patients, there was a trend towards a reduction in all-cause mortality in the T/T group (33/63; 52.4%) compared with the P/T group (29/43; 67.4%); 0.66 (0.39, 1.09); P=0.17. In patients who were NYHA Class I or II at baseline, all-cause mortality was significantly reduced in the T/T group (38/186; 20.4%) compared with the P/T group (45/114; 39.5%); 0.49 (0.32, 0.75); P=0.001. In those patients with more severe symptoms at baseline (NYHA Class III), there were fewer deaths in the T/T group (50/78; 64.1%) compared with the P/T group (44/63; 69.8%); 0.80 (0.53, 1.21), but this difference was not statistically significant (P=0.50). Conclusions In ATTR-ACT, tafamidis was shown to significantly improve survival, functional capacity, and quality of life in patients with ATTR-CM. This pooled analysis with data from the ongoing extension study further supports the efficacy of tafamidis in patients over a longer period of time and the importance of early diagnosis and treatment. Acknowledgement/Funding This study was sponsored by Pfizer.

Background An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter defibrillator (ICD) implantation. Methods We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as a) sudden cardiac death or b) ICD-treated or hemodynamically unstable VTA. The prognostic model was derived using Fine-Gray's regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (standard deviation) or medians [interquartile range]. Results We included 444 patients 40.6 (14.1) years of age in the derivation sample and 145 patients 38.2 (15.0) years in the validation sample, of whom 86 (19.3%) and 34 (23.4%) suffered LTVTA over 3.6 [1.0–7.2] and 5.1 [2.0–9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, non-missense LMNA mutation, 1st degree and higher atrioventricular block, non-sustained ventricular tachycardia, and left ventricular ejection fraction. In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711–0.842). In the external validation sample, the C-index was 0.800 (0.642–0.959) and calibration slope 1.082 (95% CI, 0.643–1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA compared with the guidelines-based approach. Conclusions Compared to the current standard of care, this risk prediction model for LTVTA in laminopathies facilitated significantly the choice of ICD candidates. Acknowledgement/Funding AFM Téléthon

Aims Myocardial scar detected by cardiovascular magnetic resonance has been associated with sudden cardiac death in dilated cardiomyopathy (DCM). Certain genetic causes of DCM may cause a malignant arrhythmogenic phenotype. The concepts of arrhythmogenic left ventricular (LV) cardiomyopathy (ALVC) and arrhythmogenic DCM are currently ill-defined. We hypothesized that a distinctive imaging phenotype defines ALVC. Methods and results Eighty-nine patients with DCM-associated mutations [desmoplakin (DSP) n = 25, filamin C (FLNC) n = 7, titin n = 30, lamin A/C n = 12, bcl2-associated athanogene 3 n = 3, RNA binding motif protein 20 n = 3, cardiac sodium channel NAv1.5 n = 2, and sarcomeric genes n = 7] were comprehensively phenotyped. Clustering analysis resulted in two groups: ‘DSP/FLNC genotypes’ and ‘non-DSP/FLNC’. There were no significant differences in age, sex, symptoms, baseline electrocardiography, arrhythmia burden, or ventricular volumes between the two groups. Subepicardial LV late gadolinium enhancement with ring-like pattern (at least three contiguous segments in the same short-axis slice) was observed in 78.1% of DSP/FLNC genotypes but was absent in the other DCM genotypes (P Conclusion DSP/FLNC genotypes cause more regionality in LV impairment. The most defining characteristic is a subepicardial ring-like scar pattern in DSP/FLNC, which should be considered in future diagnostic criteria for ALVC.

Transthyretin (TTR) related cardiomyopathy is an underdiagnosed cause of heart failure but is increasingly recognized in various settings – from patients admitted with heart failure to symptomatic aortic stenosis – and is rapidly becoming the most frequent form of systemic amyloidosis. Following the recent publication of the landmark ATTR-ACT trial that showed tafamidis to be the first treatment to improve survival in patients with TTR-related cardiac amyloidosis and heart failure, we reviewed the drug's rationale, characteristics and evidence supporting its use in TTR amyloidosis.

Percutaneous alcohol septal ablation (ASA) is an effective and minimally invasive therapeutic strategy to resolve left ventricular outflow tract obstruction (LVOTO) in patients with hypertrophic cardiomyopathy who remain symptomatic on maximally tolerated medical therapy. First performed by Sigwart in 1994, the procedure consists in determining an iatrogenic infarction of the basal interventricular septum to reduce LVOTO and alleviate symptoms. Since its first description, numerous studies have demonstrated its efficacy and safety, proposing ASA as a valid and attractive alternative to surgical septal myectomy. The success rate of the intervention is profoundly affected by patient selection and centre experience. In this review, we sought to summarise current evidence on ASA, describing the procedure and proposing a cardiomyopathy team-based approach to resolve clinical disputes in clinical practice.

Objective Atrial fibrillation (AF) is common in hypertrophic cardiomyopathy (HCM) and is associated with a high risk of stroke. The efficacy and safety of catheter ablation in this setting is poorly characterised. We aimed to systematically review the existing literature and to perform a meta-analysis to determine the efficacy and safety of catheter ablation of AF in patients with HCM. Methods Random-effects meta-analysis of studies comparing HCM versus non-HCM controls. The outcomes of freedom from AF/atrial tachycardia, and acute procedure-related complications were assessed. Studies were searched on MEDLINE, EMBASE, COCHRANE and clinicaltrials.gov. Results Fourteen studies were considered eligible for the systematic review, of which five were included in the meta-analysis. Freedom from AF/atrial tachycardia relapse was higher in patients without HCM (after a single procedure: 38.7% HCM vs 49.8% controls, OR=2.25, 95% CI 1.09 to 4.64, p=0.03; after ≥1 procedure: 51.8% HCM vs 71.2% controls, OR=2.62, 95% CI 1.52 to 4.51, p=0.0006; I 2 =33% and 26%, respectively). Risk of procedure-related adverse events was low. Repeat procedures (mean difference=0.16, 95% CI 0.0 to 0.32, p=0.05, I 2 =53%) and antiarrhythmic drugs (OR=4.70, 95% CI 2.31 to 9.55, p 2 =0%) are more frequently needed in patients with HCM to prevent arrhythmia relapse. Sensitivity analyses suggested that the outcome in patients with HCM with less dilated atria and paroxysmal AF may be more comparable to the general population. Conclusions The observed complication rate of catheter ablation of AF in patients with HCM was low. Even though the risk of relapse is twofold higher, catheter ablation can be effective in patients with HCM and AF, particularly in patients with paroxysmal AF and smaller atria.