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Aims: To conduct a contemporary cost-effectiveness analysis examining the use of implantable cardioverter defibrillators (ICDs) for primary prevention in patients with hypertrophic cardiomyopathy (HCM)., Methods: A discrete-time Markov model was used to determine the cost-effectiveness of different ICD decision-making rules for implantation. Several scenarios were investigated, including the reference scenario of implantation rates according to observed real-world practice. A 12-year time horizon with an annual cycle length was used. Transition probabilities used in the model were obtained using Bayesian analysis. The study has been reported according to the Consolidated Health Economic Evaluation Reporting Standards checklist., Results: Using a 5-year SCD risk threshold of 6% was cheaper than current practice and has marginally better total quality adjusted life years (QALYs). This is the most cost-effective of the options considered, with an incremental cost-effectiveness ratio of £834 per QALY. Sensitivity analyses highlighted that this decision is largely driven by what health-related quality of life (HRQL) is attributed to ICD patients and time horizon., Conclusion: We present a timely new perspective on HCM-ICD cost-effectiveness, using methods reflecting real-world practice. While we have shown that a 6% 5-year SCD risk cut-off provides the best cohort stratification to aid ICD decision-making, this will also be influenced by the particular values of costs and HRQL for subgroups or at a local level. The process of explicitly demonstrating the main factors, which drive conclusions from such an analysis will help to inform shared decision-making in this complex area for all stakeholders concerned., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies., Methods and Results: In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94-30.02, P = 8.05e-11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31-24.87, P < 2.2e-16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP-), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP- and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP- and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation., Conclusions: Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Diabetes mellitus (DM) aggravates the clinical features of ischaemic and hypertensive heart diseases and worsens the prognosis of heart failure patients. Hypertrophic cardiomyopathy (HCM) and diabetes coexist fairly frequently in elderly patients but the impact of DM on the clinical phenotype of HCM is yet unknown. We sought to describe if predominant features of heart failure in DM patients exist independently in HCM., Methods and Results: We reviewed clinical characteristics of 937 patients, age ≥40, diagnosed with HCM, from two tertiary medical centres in Spain and Israel. A propensity score matched cohort of 294 patients was also analysed. Our cohort comprised 102 HCM patients with diabetes (8.7%). Patients with DM were older at diagnosis {median 56 [interquartile range (IQR) 47-67] vs. 53 (IQR 43-63), P = 0.02} and had a higher prevalence of comorbidities. Hypertrophic cardiomyopathy patients with DM had a higher prevalence of diastolic dysfunction, pulmonary hypertension, significant mitral regurgitation, and pacemaker implantation. Hypertrophic cardiomyopathy patients with DM had a higher New York Heart Association (NYHA) class (P < 0.001) and lower exercise capacity [7.0 METS (IQR 5.0-10.0) vs. 9.0 METS (IQR 6.6-11.0), P = 0.002]. These findings were independent of age, gender, country of origin, hypertension, and coronary artery disease. Patients with diabetes had a significantly higher 15-year mortality (22% vs. 15%, P = 0.03), with no differences in sudden cardiac death, appropriate implanted cardioverter-defibrillator therapy, or heart transplantation., Conclusion: Hypertrophic cardiomyopathy patients with diabetes are older and have a higher cardiovascular risk profile. They have a lower functional capacity and more heart failure symptoms due to diastolic dysfunction., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Objective: Sex hormone-binding globulin (SHBG) binds and transports testosterone and estradiol in plasma. The possibility that SHBG is a mixture of transporting proteins has been postulated. We analyzed in parallel the effects of obesity status on the levels and binding capacity of circulating SHBG and their relationship with testosterone and estradiol., Design: Anthropometric measures and plasma were obtained from apparently healthy young (i.e. 35 ± 7 years) premenopausal women ( n =  32) and men ( n =  30), with normal weight and obesity (BMI >30 kg/m 2 )., Methods: SHBG protein (Western blot), as well as the plasma levels of testosterone, estradiol, cortisol and insulin (ELISA) were measured. Specific binding of estradiol and testosterone to plasma SHBG was analyzed using tritium-labeled hormones., Results: Significant differences in SHBG were observed within the obesity status and gender, with discordant patterns of change in testosterone and estradiol. In men, testosterone occupied most of the binding sites. Estrogen binding was much lower in all subjects. Lower SHBG of morbidly obese (BMI >40 kg/m 2 ) subjects affected testosterone but not estradiol. The ratio of binding sites to SHBG protein levels was constant for testosterone, but not for estradiol. The influence of gender was maximal in morbid obesity, with men showing the highest binding / SHBG ratios., Conclusions: The results reported here are compatible with SHBG being a mixture of at least two functionally different hormone-binding globulins, being affected by obesity and gender and showing different structure, affinities for testosterone and estradiol and also different immunoreactivity., (© 2017 European Society of Endocrinology.)

Motivation: High-throughput sequencing platforms are increasingly used to screen patients with genetic disease for pathogenic mutations, but prediction of the effects of mutations remains challenging. Previously we developed SAAPdap (Single Amino Acid Polymorphism Data Analysis Pipeline) and SAAPpred (Single Amino Acid Polymorphism Predictor) that use a combination of rule-based structural measures to predict whether a missense genetic variant is pathogenic. Here we investigate whether the same methodology can be used to develop a differential phenotype predictor, which, once a mutation has been predicted as pathogenic, is able to distinguish between phenotypes-in this case the two major clinical phenotypes (hypertrophic cardiomyopathy, HCM and dilated cardiomyopathy, DCM) associated with mutations in the beta-myosin heavy chain (MYH7) gene product (Myosin-7)., Results: A random forest predictor trained on rule-based structural analyses together with structural clustering data gave a Matthews' correlation coefficient (MCC) of 0.53 (accuracy, 75%). A post hoc removal of machine learning models that performed particularly badly, increased the performance (MCC = 0.61, Acc = 79%). This proof of concept suggests that methods used for pathogenicity prediction can be extended for use in differential phenotype prediction., Availability and Implementation: Analyses were implemented in Perl and C and used the Java-based Weka machine learning environment. Please contact the authors for availability., Contacts: andrew@bioinf.org.uk or andrew.martin@ucl.ac.uk, Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Authors 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Aim: Numerous genes are known to cause dilated cardiomyopathy (DCM). However, until now technological limitations have hindered elucidation of the contribution of all clinically relevant disease genes to DCM phenotypes in larger cohorts. We now utilized next-generation sequencing to overcome these limitations and screened all DCM disease genes in a large cohort., Methods and Results: In this multi-centre, multi-national study, we have enrolled 639 patients with sporadic or familial DCM. To all samples, we applied a standardized protocol for ultra-high coverage next-generation sequencing of 84 genes, leading to 99.1% coverage of the target region with at least 50-fold and a mean read depth of 2415. In this well characterized cohort, we find the highest number of known cardiomyopathy mutations in plakophilin-2, myosin-binding protein C-3, and desmoplakin. When we include yet unknown but predicted disease variants, we find titin, plakophilin-2, myosin-binding protein-C 3, desmoplakin, ryanodine receptor 2, desmocollin-2, desmoglein-2, and SCN5A variants among the most commonly mutated genes. The overlap between DCM, hypertrophic cardiomyopathy (HCM), and channelopathy causing mutations is considerably high. Of note, we find that >38% of patients have compound or combined mutations and 12.8% have three or even more mutations. When comparing patients recruited in the eight participating European countries we find remarkably little differences in mutation frequencies and affected genes., Conclusion: This is to our knowledge, the first study that comprehensively investigated the genetics of DCM in a large-scale cohort and across a broad gene panel of the known DCM genes. Our results underline the high analytical quality and feasibility of Next-Generation Sequencing in clinical genetic diagnostics and provide a sound database of the genetic causes of DCM., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Aims: We have observed that wall motion abnormalities (WMAs) during exercise echocardiography (ExE) are associated to events in hypertrophic cardiomyopathy (HCM). Our objective was to evaluate ExE and cardiac magnetic resonance (CMR) to predict outcome in HCM., Methods and Results: ExE and CMR were performed in 148 patients with HCM. During follow-up (7.1 ± 2.7 years), there were 7 hard events (Hard-E) and 26 combined events (Comb-E). Exercise WMAs were observed in 13 patients (8.8%), perfusion defects in 10 (6.8%), and late gadolinium enhancement (LGE) in 48 (32.4%). WMAs were seen in 57% of patients with Hard-E vs. 6% without (P = 0.001) and in 23 and 6% with and without Comb-E (P = 0.005). Perfusion defects were also more frequent in patients with Hard-E than without (43 vs. 5%, P = 0.007) and in patients with Comb-E than without (23 vs. 5%, P = 0.002). LGE (g) was greater in patients with Comb-E than without [median (25th-75th percentile) 0 (0-21.1) vs. 0 (0-9.3) g P = 0.04]. Univariable predictors of Comb-E included NYHA class ≥2, peak double product, ΔWMSI, and CMR data. Peak double product [Hazard ratios (HR) = 0.99, confidence intervals (CI) 95% 0.99-0.99, P = 0.02] and ΔWMSI (HR = 404, CI 95% 12-13681, P = 0.001) remained independent predictors. Peak WMSI correlated with myocardial mass with LGE (r = 0.20, P = 0.02) and with perfusion defect area (r = 0.40, P < 0.001). LGE affecting ≥15% of the left ventricle was observed in 38% of patients with exercise WMAs vs. 12% without (P = 0.009)., Conclusion: CMR data are associated to exercise WMAs in patients with HCM. ExE and CMR may help to predict outcome in them., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Aims: Risk stratification for sudden death in arrhythmogenic right ventricular cardiomyopathy (ARVC) is challenging in clinical practice. We lack recommendations for the risk stratification of exclusive left-sided phenotypes. The aim of this study was to investigate genotype-phenotype correlations in patients carrying a novel DSP c.1339C>T, and to review the literature on the clinical expression and the outcomes in patients with DSP truncating mutations., Methods and Results: Genetic screening of the DSP gene was performed in 47 consecutive patients with a phenotype of either an ARVC (n = 24) or an idiopathic dilated cardiomyopathy (DCM), who presented with ventricular arrhythmias or a family history of sudden death (n = 23) (aged 40 ± 19 years, 62% males). Three unrelated probands with DCM were found to be carriers of a novel mutation (c.1339C>T). Cascade family screening led to the identification of 15 relatives who are carriers. Penetrance in c.1339C>T carriers was 83%. Sustained ventricular tachycardia was the first clinical manifestation in six patients and nine patients were diagnosed with left ventricular impairment (two had overt severe disease and seven had a mild dysfunction). Cardiac magnetic resonance revealed left ventricular involvement in nine cases and biventricular disease in three patients. Extensive fibrotic patterns in six and non-compaction phenotype in five patients were the hallmark in imaging., Conclusion: DSP c.1339C>T is associated with an aggressive clinical phenotype of left-dominant arrhythmogenic cardiomyopathy and left ventricular non-compaction. Truncating mutations in desmoplakin are consistently associated with aggressive phenotypes and must be considered as a risk factor of sudden death. Since ventricular tachycardia occurs even in the absence of severe systolic dysfunction, an implantable cardioverter-defibrillator should be indicated promptly., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Aims: Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death (SCD) in young adults. Current risk algorithms provide only a crude estimate of risk and fail to account for the different effect size of individual risk factors. The aim of this study was to develop and validate a new SCD risk prediction model that provides individualized risk estimates., Methods and Results: The prognostic model was derived from a retrospective, multi-centre longitudinal cohort study. The model was developed from the entire data set using the Cox proportional hazards model and internally validated using bootstrapping. The cohort consisted of 3675 consecutive patients from six centres. During a follow-up period of 24 313 patient-years (median 5.7 years), 198 patients (5%) died suddenly or had an appropriate implantable cardioverter defibrillator (ICD) shock. Of eight pre-specified predictors, age, maximal left ventricular wall thickness, left atrial diameter, left ventricular outflow tract gradient, family history of SCD, non-sustained ventricular tachycardia, and unexplained syncope were associated with SCD/appropriate ICD shock at the 15% significance level. These predictors were included in the final model to estimate individual probabilities of SCD at 5 years. The calibration slope was 0.91 (95% CI: 0.74, 1.08), C-index was 0.70 (95% CI: 0.68, 0.72), and D-statistic was 1.07 (95% CI: 0.81, 1.32). For every 16 ICDs implanted in patients with ≥4% 5-year SCD risk, potentially 1 patient will be saved from SCD at 5 years. A second model with the data set split into independent development and validation cohorts had very similar estimates of coefficients and performance when externally validated., Conclusion: This is the first validated SCD risk prediction model for patients with HCM and provides accurate individualized estimates for the probability of SCD using readily collected clinical parameters., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2013. For permissions please email: journals.permissions@oup.com.)

Aims: Cardiotrophin-1 (CT-1) is a cytokine that induces hypertrophy in cardiomyocytes and is associated with left ventricular hypertrophy (LVH) in hypertensive patients. The objective of this study was to evaluate whether plasma CT-1 is associated with hypertrophic cardiomyopathy (HCM)., Methods and Results: The study was performed in 124 patients with HCM. All patients underwent a full clinical evaluation and an echocardiogram. Left ventricular hypertrophy was evaluated by the measurement of the maximal LV wall thickness and the Spirito's LVH score. Plasma CT-1 was measured by an enzyme-linked immunosorbent assay. Compared with controls, patients with HCM exhibited higher (P < 0.001) plasma CT-1 levels. Significant correlations were found between CT-1 and maximal LV wall thickness (r = 0.284, P = 0.001) and the Spirito's LVH score (r = 0.287, P = 0.006) in HCM patients. In addition, the levels of CT-1 were higher (P = 0.02) in patients with severe LVH (maximal LV wall thickness ≥30 mm) than in patients with mild or moderate LVH (maximal LV wall thickness <30 mm)., Conclusions: These findings show that plasma CT-1 is associated with the severity of LVH in patients with HCM. Further studies are required to ascertain whether CT-1 is a diagnostic biomarker of this cardiomyopathy.

Advances in molecular genetics present new opportunities and challenges for cardiologists who manage patients and families with cardiomyopathies. The aims of this position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases are to review the general issues related to genetic counselling, family screening and genetic testing in families with a cardiomyopathy, and to provide key messages and suggestions for clinicians involved in their management.

In biology, classification systems are used to promote understanding and systematic discussion through the use of logical groups and hierarchies. In clinical medicine, similar principles are used to standardise the nomenclature of disease. For more than three decades, heart muscle diseases have been classified into primary or idiopathic myocardial diseases (cardiomyopathies) and secondary disorders that have similar morphological appearances, but which are caused by an identifiable pathology such as coronary artery disease or myocardial infiltration (specific heart muscle diseases). In this document, The European Society of Cardiology Working Group on Myocardial and Pericardial Diseases presents an update of the existing classification scheme. The aim is to help clinicians look beyond generic diagnostic labels in order to reach more specific diagnoses.

Aims: The E101K mutation in the alpha-cardiac actin gene (ACTC) has been associated with apical hypertrophic cardiomyopathy (HCM). As prominent trabeculations were described in some carriers, we screened for the E101K mutation in our index patients with HCM, dilated cardiomyopathy (DCM), or left ventricular non-compaction (LVNC)., Methods and Results: Clinical, echocardiographic, and genetic screening by restriction fragment length polymorphism of the ACTC E101K mutation in 247 families with HCM, DCM, or LVNC. The mutation was found in five index patients (one with LVNC and four with HCM). Clinical and morphological data were obtained from 94 family members. Forty-six individuals had cardiomyopathy (43 with the mutation and three with no genetic study): 23 fulfilled criteria for LVNC, 22 were diagnosed as apical HCM, and one had been diagnosed as restrictive cardiomyopathy. There had been one heart transplant and one congestive heart failure death in patients with severe diastolic dysfunction, and five premature sudden deaths. The E101K mutation was not found in 48 unaffected relatives. Septal defects (eight atrial and one ventricular) were found in nine mutant carriers from four families, and were absent in relatives without the mutation (P = 0.003)., Conclusion: LVNC and HCM may appear as overlapping entities. The ACTC E101K mutation should be considered in the genetic diagnosis of LVNC, apical HCM, and septal defects.

The publisher regrets that this was an accidental duplication of an article that has already been published in Eur. J. Echocardiogr., 4 (2003) 182-190, . The duplicate article has therefore been withdrawn.

Aims: To clarify the mechanisms of electrocardiographic abnormalities in hypertrophic cardiomyopathy, 102 patients were examined with cardiac magnetic resonance. Distribution and magnitude of hypertrophy and late-enhancement were correlated with electrocardiographic abnormalities., Methods and Results: Abnormal Q waves were associated with greater upper anterior septal thickness (22+/-7 mm vs. 18+/-5 mm, P=0.001) and increased ratios of upper anterior septum to mean inferolateral (P=0.01), anterolateral (P=0.002), apical (P=0.001), and right ventricular (P=0.001) wall thickness. There was no relation between abnormal Q waves and late-enhancement, except for Q waves >/=40 ms (P=0.02). Conduction disturbances and absent septal Q waves were associated with late-enhancement (89 vs. 45%, P=0.01 and 75 vs. 39%, P=0.002, respectively). The depth of negative T waves was related to an increased ratio of the mean thickness between apical and basal level (P=0.01), and to the presence of apical late-enhancement (P=0.03)., Conclusion: Abnormal Q waves reflect the interrelation between upper anterior septal thickness and other regions of the left and right ventricles, and wider Q waves are associated with late-enhancement. Conduction disturbances and absent septal Q waves are associated with late-enhancement. The depth of negative T waves is related to craniocaudal asymmetry and apical late-enhancement.

Aims: Although peak exercise echocardiography has been reported for both bicycle and treadmill exercise and has shown higher sensitivity than post-exercise imaging, little is known about its utility for identifying multivessel involvement. We sought to compare feasibility and accuracy of peak treadmill exercise echocardiography vs post-exercise echocardiography for identification of multivessel coronary artery disease and to assess its incremental value when combined with clinical and exercise test variables., Methods and Results: The study group included 335 patients (228 men; mean (+/- SD) age 60 +/- 11 years). Two hundred and seventy-nine patients were included on the basis of having had an exercise echocardiography and a coronary angiography within 4 months of the exercise test. To avoid bias to coronary angiography, a subgroup of 56 consecutive non-diabetic patients referred for exercise echocardiography with pretest probability of coronary artery disease <10% and had atypical chest pain or were asymptomatic were also included and considered as having no coronary artery disease. Multivessel coronary artery disease (> or = 50% diameter stenosis in >1 vessel) was confirmed in 170 patients, whereas 165 patients were considered to have one-vessel coronary artery disease or no coronary lesions. Positive exercise echocardiography was defined as ischaemia or necrosis in at least two coronary territories. Post-exercise images were acquired within 125 s after exercise (49 +/- 15). Mean heart rate (bpm) was 139 +/- 19 at peak vs 117 +/- 22 at post-exercise imaging (P<0.001). Interpretable peak and post-exercise images were obtained for all patients. Sensitivity for predicting multivessel disease was higher with peak than with post-exercise imaging (79 vs 55%, P<0.001), with lower specificity (79 vs 88%, P<0.05). Predictive positive value was similar (80 vs 83%). Negative predictive value was again higher with peak imaging (78 vs 66%, P<0.01). Total accuracy was not different (79 vs 72%). A stepwise logistic regression analysis identified peak exercise echocardiography positivity for multivessel coronary artery disease as the strongest independent predictor of multivessel disease (odds ratio (OR): 7.36); also significant were male gender (OR: 4.22), diabetes mellitus (OR: 4.28), previous myocardial infarction (OR: 3.12) and increment of product heart rate x blood pressure (OR: 1.00)., Conclusions: Peak treadmill exercise echocardiography is technically feasible and has higher sensitivity and negative predictive value for predicting multivessel disease than post-treadmill exercise echocardiography. This method adds independent and incremental values to clinical and exercise variables for the diagnosis of multivessel coronary artery disease. Therefore, in the clinical setting, peak exercise echocardiography should be performed to diagnose multivessel coronary artery disease.