Childhood-onset hypertrophic cardiomyopathy caused by thin-filament sarcomeric variants.

Up to 20% of children with sarcomeric hypertrophic cardiomyopathy (HCM) have disease-causing variants in genes coding for thin-filament proteins. However, data on genotype-phenotype correlations for thin-filament disease are limited. This study describes the natural history and outcomes of children with thin-filament-associated HCM and compares it to thick-filament-associated disease.Longitudinal data were collected from 40 children under 18 years with a disease-causing variant in a thin-filament protein from a single quaternary referral centre. Twenty-one (female n=6, 35.5%) were diagnosed with HCM at a median age of 13.0 years (IQR 8.3-14.0). Over a median follow-up of 5.0 years (IQR 4.0-8.5), three (14.3%) experienced one or more major adverse cardiac events (MACE) (two patients had an out-of-hospital arrest and eight appropriate implantable cardiac defibrillator (ICD) therapies in three patients). One gene carrier died suddenly at age 9 years. Compared with those with thick-filament disease, children with thin-filament variants more commonly experienced non-sustained ventricular tachycardia [NSVT; n=6 (28.6%) vs n=14 (10.8%), p=0.024] or underwent ICD insertion (thin, n=13 (61.9%) vs thick, n=50 (38.5%), p=0.040). However, there was no difference in the incidence of MACE (thin 2.47/100 pt years (95% CI 0.80 to 7.66) vs thick 3.63/100 pt years (95% CI 2.25 to 5.84)) or an arrhythmic event (thin 1.65/100 pt years (95% CI 0.41 to 6.58) vs thick 2.55/100 pt years (95% CI 1.45 to 4.48), p value 0.43).This study suggests that adverse events in thin-filament disease are predominantly arrhythmic and may occur in the absence of hypertrophy, but overall short-term outcomes do not differ significantly from thick-filament disease.

Biallelic PKP2 loss of function variants are associated with a lethal perinatal-onset biventricular dilated cardiomyopathy with excessive trabeculations and ventricular septal defects.

Homozygous plakophilin-2 (PKP2) variants have been identified as a cause of a lethal form of dilated cardiomyopathy with excessive trabeculations (DCM-ET) in three cases. We report three more cases from two families with homozygous pathogenic PKP2 variants and perinatal-onset, lethal DCM-ET. Identification of the genetic abnormalities played a key role in decision-making and family counselling in these cases. This case series supports the published evidence that biallelic loss of function PKP2 variants cause a lethal, perinatal-onset cardiomyopathy.

Cardiomyopathies in children and adolescents: aetiology, management, and outcomes in the European Society of Cardiology EURObservational Research Programme Cardiomyopathy and Myocarditis Registry.

BACKGROUND AND AIMS: Childhood-onset cardiomyopathies are rare and poorly characterized. This study examined the baseline characteristics and 1-year follow-up of children with cardiomyopathy in the first European Cardiomyopathy Registry. METHODS: Prospective data were collected on individuals aged 1-<18 years enrolled in the European Society of Cardiology EURObservational Research Programme Cardiomyopathy and Myocarditis long-term registry (June 2014-December 2016). RESULTS: A total of 633 individuals aged ≤18 years with hypertrophic [HCM; n = 388 (61.3%)], dilated [DCM; n = 206 (32.5%)], restrictive [RCM; n = 28 (4.4%)], and arrhythmogenic right ventricular cardiomyopathy [ARVC; n = 11 (1.7%)] were enrolled by 23 referral centres in 14 countries. Median age at diagnosis was 4.0 [interquartile range (IQR) 0-10] years, and there was a male predominance [n = 372 (58.8%)] across all subtypes, with the exception of DCM diagnosed <10 years of age; 621 (98.1%) patients were receiving cardiac medication and 80 (12.6%) had an implantable cardioverter-defibrillator. A total of 253 patients (253/535, 47.3%) had familial disease. Genetic testing was performed in 414 (67.8%) patients with a pathogenic or likely pathogenic variant reported in 250 (60.4%). Rare disease phenocopies were reported in 177 patients (28.0%) and were most frequent in patients under 10 years [142 (30.9%) vs. 35 (19.6%); P = .003]. Over a median follow-up of 12.5 months (IQR 11.3-15.3 months), 18 patients (3.3%) died [HCM n = 9 (2.6%), DCM n = 5 (3.0%), RCM n = 4 (16.0%)]. Heart failure events were most frequent in RCM patients (36.0%). CONCLUSIONS: The findings confirm the heterogeneous aetiology of childhood cardiomyopathies and show a high frequency of familial disease. Outcomes differed by cardiomyopathy subtype, highlighting a need for disease-specific evaluation and treatment.

Cardiac myosin binding protein-C variants in paediatric-onset hypertrophic cardiomyopathy: natural history and clinical outcomes.

BACKGROUND: Variants in the cardiac myosin-binding protein C gene (MYBPC3) are a common cause of hypertrophic cardiomyopathy (HCM) in adults and have been associated with late-onset disease, but there are limited data on their role in paediatric-onset HCM. The objective of this study was to describe natural history and clinical outcomes in a large cohort of children with HCM and pathogenic/likely pathogenic (P/LP) MYBPC3 variants. METHODS AND RESULTS: Longitudinal data from 62 consecutive patients diagnosed with HCM under 18 years of age and carrying at least one P/LP MYBPC3 variant were collected from a single specialist referral centre. The primary patient outcome was a major adverse cardiac event (MACE). Median age at diagnosis was 10 (IQR: 2-14) years, with 12 patients (19.4%) diagnosed in infancy. Forty-seven (75%) were boy and 31 (50%) were probands. Median length of follow-up was 3.1 (IQR: 1.6-6.9) years. Nine patients (14.5%) experienced an MACE during follow-up and five (8%) died. Twenty patients (32.3%) had evidence of ventricular arrhythmia, including 6 patients (9.7%) presenting with out-of-hospital cardiac arrest. Five-year freedom from MACE for those with a single or two MYBPC3 variants was 95.2% (95% CI: 78.6% to 98.5%) and 68.4% (95% CI: 40.6% to 88.9%), respectively (HR 4.65, 95% CI: 1.16 to 18.66, p=0.03). CONCLUSIONS: MYBPC3 variants can cause childhood-onset disease, which is frequently associated with life-threatening ventricular arrhythmia. Clinical outcomes in this cohort vary substantially from aetiologically and genetically mixed paediatric HCM cohorts described previously, highlighting the importance of identifying specific genetic subtypes for clinical management of childhood HCM.

Interpretation and actionability of genetic variants in cardiomyopathies: a position statement from the European Society of Cardiology Council on cardiovascular genomics.

This document describes the contribution of clinical criteria to the interpretation of genetic variants using heritable Mendelian cardiomyopathies as an example. The aim is to assist cardiologists in defining the clinical contribution to a genetic diagnosis and the interpretation of molecular genetic reports. The identification of a genetic variant of unknown or uncertain significance is a limitation of genetic testing, but current guidelines for the interpretation of genetic variants include essential contributions from clinical family screening that can establish a de novo assignment of the variant or its segregation with the phenotype in the family. A partnership between clinicians and patients helps to solve major uncertainties and provides reliable and clinically actionable information.

Indications and management of implantable cardioverter-defibrillator therapy in childhood hypertrophic cardiomyopathy.

Sudden cardiac death is the most common mode of death during childhood and adolescence in hypertrophic cardiomyopathy, and identifying those individuals at highest risk is a major aspect of clinical care. The mainstay of preventative therapy is the implantable cardioverter-defibrillator, which has been shown to be effective at terminating malignant ventricular arrhythmias in children with hypertrophic cardiomyopathy but can be associated with substantial morbidity. Accurate identification of those children at highest risk who would benefit most from implantable cardioverter-defibrillator implantation while minimising the risk of complications is, therefore, essential. This position statement, on behalf of the Association for European Paediatric and Congenital Cardiology (AEPC), reviews the currently available data on established and proposed risk factors for sudden cardiac death in childhood-onset hypertrophic cardiomyopathy and current approaches for risk stratification in this population. It also provides guidance on identification of individuals at risk of sudden cardiac death and optimal management of implantable cardioverter-defibrillators in children and adolescents with hypertrophic cardiomyopathy.

The heart in RASopathies.

The cardiovascular phenotype associated with RASopathies has expanded far beyond the original descriptions of pulmonary valve stenosis by Dr Jaqueline Noonan in 1968 and hypertrophic cardiomyopathy by Hirsch et al. in 1975. Because of the common underlying RAS/MAPK pathway dysregulation, RASopathy syndromes usually present with a typical spectrum of overlapping cardiovascular anomalies, although less common cardiac defects can occur. The identification of the causative genetic variants has enabled the recognition of specific correlations between genotype and cardiac phenotype. Characterization and understanding of genotype-phenotype associations is not only important for counseling a family of an infant with a new diagnosis of a RASopathy condition but is also critical for their clinical prognosis with respect to cardiac disease, neurodevelopment and other organ system involvement over the lifetime of the patient. This review will focus on the cardiac manifestations of the most common RASopathy syndromes, the relationship between cardiac defects and causal genetic variation, the contribution of cardiovascular abnormalities to morbidity and mortality and the most relevant follow-up issues for patients affected by RAS/MAPK pathway diseases, with respect to cardiac clinical outcomes and management, in children and in the adult population.

Prevalence of Inherited Cardiac Conditions in Pediatric First-Degree Relatives of Patients with Idiopathic Ventricular Fibrillation.

Idiopathic ventricular fibrillation (IVF) is diagnosed in out-of-hospital VF survivors after comprehensive investigations have excluded structural heart disease or inherited channelopathies. Current guidelines recommend clinical screening of first-degree relatives of IVF survivors, but this approach has not been validated in children. This study aimed to assess the yield of clinical cardiac screening in child first-degree relatives of IVF victims. A retrospective observational study was conducted of all consecutive pediatric first-degree relatives of IVF patients referred to our center between December 2007 and April 2020. Patients underwent systematic evaluation including medical and family history; 12-lead resting, signal-averaged, and ambulatory electrocardiogram (ECG); echocardiogram; exercise testing; cardiac magnetic resonance imaging; and ajmaline provocation testing. Sixty child first-degree relatives of 32 IVF survivors were included [median follow-up time of 55 months (IQR 27.0-87.0 months); 30 (50%) females]. Eight patients (13.3%) from 6 families (18.8%) received a cardiac diagnosis: long QT syndrome (n = 4); Brugada syndrome (n = 3); and dilated cardiomyopathy (n = 1). There were no deaths during follow-up. This study demonstrates a high yield of clinical screening for inherited cardiac disease in child first-degree relatives of IVF survivors. These findings highlight the variable expression of inherited cardiac conditions and the importance of comprehensive clinical evaluation in pediatric relatives, even when extensive investigations in the proband have not identified a clear etiology. Moreover, our results support the validity of the investigations proposed by current guidelines in family relatives of IVF survivors.

Analysis of buccal mucosa as a prognostic tool in children with arrhythmogenic cardiomyopathy.

Background: The diagnosis of arrhythmogenic cardiomyopathy (ACM) is challenging especially in children at risk of adverse events. Analysis of cardiac myocyte junctional protein distribution may have diagnostic and prognostic implications, but its utility is limited by the need for a myocardial sample. We previously reported that buccal mucosa cells show junctional protein redistribution similar to that seen in cardiac myocytes of adult patients with ACM. Objectives: We aimed to determine when junctional protein distribution abnormalities first occur in children with ACM variants and whether they correlate with progression of clinically apparent disease. Methods: We analyzed buccal mucosa samples of children and adolescents with a family history of ACM (n = 13) and age-matched controls (n = 13). Samples were immunostained for plakoglobin, desmoplakin, plakophilin-1 and connexin43 and analyzed by confocal microscopy. All participants were swabbed at least twice with an average interval of 12-18 months between samplings. Results: Junctional protein re-localization in buccal mucosa cells did not correlate with the presence of ACM-causing variants but instead occurred with clinical onset of disease. No changes in protein distribution were seen unless and until there was clinical evidence of disease. In addition, progressive shifts in the distribution of key proteins correlated with worsening of the disease phenotype. Finally, we observed restoration of junctional signal for Cx43 in patient with a favorable response to anti-arrhythmic therapy. Conclusions: Due to ethical concerns about obtaining heart biopsies in children with no apparent disease, it has not been possible to analyze molecular changes in cardiac myocytes with the onset/progression of clinical disease. Using buccal smears as a surrogate for the myocardium may facilitate future studies of mechanisms and pathophysiological consequences of junctional protein redistribution in ACM. Buccal cells may also be a safe and inexpensive tool for risk stratification and potentially monitoring response to treatment in children bearing ACM variants.

The Risk of Sudden Death in Children with Hypertrophic Cardiomyopathy.

Sudden cardiac death (SCD) is the most common cause of death in childhood hypertrophic cardiomyopathy (HCM) and occurs more frequently than in adult patients. Risk stratification strategies have traditionally been extrapolated from adult practice, but newer evidence has highlighted important differences between childhood and adult cohorts, with the implication that pediatric-specific risk stratification strategies are required. Current guidelines use cumulative risk factor thresholds to recommend implantable cardioverter defibrillator (ICD) implantation but have been shown to have limited discriminatory ability. Newer pediatric models that allow clinicians to calculate individualized estimates of 5-year risk allowing, for the first time, personalization of ICD implantation decision-making have been developed. This article describes the pathophysiology, risk factors, and approach to risk stratification for SCD in childhood HCM and highlights unanswered questions.

An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.

BACKGROUND: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. METHODS: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. RESULTS: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6-52.2]; P=0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3-10.8], P=0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). CONCLUSIONS: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.

Clinical outcomes and programming strategies of implantable cardioverter-defibrillator devices in paediatric hypertrophic cardiomyopathy: a UK National Cohort Study.

AIMS: Sudden cardiac death (SCD) is the most common mode of death in paediatric hypertrophic cardiomyopathy (HCM). This study describes the implant and programming strategies with clinical outcomes following implantable cardioverter-defibrillator (ICD) insertion in a well-characterized national paediatric HCM cohort. METHODS AND RESULTS: Data from 90 patients undergoing ICD insertion at a median age 13 (±3.5) for primary (n = 67, 74%) or secondary prevention (n = 23, 26%) were collected from a retrospective, longitudinal multi-centre cohort of children (<16 years) with HCM from the UK. Seventy-six (84%) had an endovascular system [14 (18%) dual coil], 3 (3%) epicardial, and 11 (12%) subcutaneous system. Defibrillation threshold (DFT) testing was performed at implant in 68 (76%). Inadequate DFT in four led to implant adjustment in three patients. Over a median follow-up of 54 months (interquartile range 28-111), 25 (28%) patients had 53 appropriate therapies [ICD shock n = 45, anti-tachycardia pacing (ATP) n = 8], incidence rate 4.7 per 100 patient years (95% CI 2.9-7.6). Eight inappropriate therapies occurred in 7 (8%) patients (ICD shock n = 4, ATP n = 4), incidence rate 1.1/100 patient years (95% CI 0.4-2.5). Three patients (3%) died following arrhythmic events, despite a functioning device. Other device complications were seen in 28 patients (31%), including lead-related complications (n = 15) and infection (n = 10). No clinical, device, or programming characteristics predicted time to inappropriate therapy or lead complication. CONCLUSION: In a large national cohort of paediatric HCM patients with an ICD, device and programming strategies varied widely. No particular strategy was associated with inappropriate therapies, missed/delayed therapies, or lead complications.

Clinical significance of inferolateral early repolarisation and late potentials in children with Brugada Syndrome.

INTRODUCTION: The clinical utility of inferolateral early repolarisation (ER) and late potentials (LP) in children with Brugada Syndrome (BrS) has not been previously evaluated. The aim of this study was to determine the prevalence of electrocardiographic (ECG) abnormalities in children with BrS, and to investigate their relationship with clinical outcomes. METHODS: 43 patients with BrS and 47 controls aged ≤18 undergoing systematic clinical and ECG evaluation, including signal-averaged ECG (SAECG) and pharmacological provocation testing, between 2003 and 2019 were included. RESULTS: Four patients with BrS (9%) presented with a spontaneous type 1 Brugada pattern; the remaining 39 (91%) were diagnosed following ajmaline provocation testing. Twelve BrS patients (28%) had late potentials (LP) on SAECG compared to 1 (2%) in controls (p = 0.001). LP were more common in 5 patients with a high-risk phenotype (60% vs 24%) but this was not statistically significant. Twelve patients with BrS (28%) had inferolateral early repolarisation (ER) and 2 (5%) had fractionated QRS (f-QRS), but there were no statistically-significant differences with controls in these parameters. A significant arrhythmia (non-sustained ventricular tachycardia or atrial fibrillation) was seen in 4 patients (9%). CONCLUSIONS: This study shows a high prevalence of SAECG abnormalities in children with BrS compared with controls, but this was not significantly associated with a high-risk phenotype.

Yield of Clinical Screening for Hypertrophic Cardiomyopathy in Child First-Degree Relatives.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a heritable myocardial disease with age-related penetrance. Current guidelines recommend clinical screening of relatives beginning at 10 years of age, but the clinical value of this approach has not been systematically evaluated. METHODS: Anonymized clinical data were collected from children referred for family screening between 1994 and 2017 after diagnosis of HCM in a first-degree relative. RESULTS: Of 1198 consecutive children (≤18 years of age) from 594 families who underwent serial evaluation (median, 3.5 years; interquartile range, 1.2-7), 32 individuals met diagnostic criteria at baseline (median maximal left ventricular wall thickness, 13 mm; interquartile range, 8-21 mm), and 25 additional patients developed HCM during follow-up. Median age at diagnosis was 10 years (interquartile range, 4-13 years); 44 (72%) were ≤12 years of age. Median age of affected patients at the last follow-up was 14 years (interquartile range, 9.5-18.2 years). A family history of childhood HCM was more common in those patients diagnosed with HCM (n=32 [56%] versus n=257 [23%]; P<0.001). Eighteen patients (32%) were started on medication for symptoms; 2 (4%) underwent a septal myectomy; 14 (25%) received an implantable cardioverter-defibrillator; 1 underwent cardiac transplantation; 2 had a resuscitated cardiac arrest; and 1 died after a cerebrovascular accident. CONCLUSIONS: Almost 5% of first-degree child relatives undergoing screening meet diagnostic criteria for HCM at first or subsequent evaluations, with the majority presenting as preadolescents; a diagnosis in a child first-degree relative is made in 8% of families screened. The phenotype of familial HCM in childhood is varied and includes severe disease, suggesting that clinical screening should begin at a younger age.

Incidence and Progression of Echocardiographic Abnormalities in Older Children with Human Immunodeficiency Virus and Adolescents Taking Antiretroviral Therapy: A Prospective Cohort Study.

BACKGROUND: A high prevalence of cardiac abnormalities has been reported in children with human immunodeficiency virus (HIV) taking antiretroviral therapy (ART) in sub-Saharan Africa. We investigated the incidence and progression of cardiac abnormalities among children taking ART in Zimbabwe. METHODS: A prospective cohort study was conducted at a pediatric HIV clinic from 2014 to 2017. Children with HIV aged between 6 and 16 years and taking ART ≥6 months were enrolled. Transthoracic echocardiography was performed at baseline and after 18 months. RESULTS: Of 197 participants recruited at baseline, 175 (89%; 48% female; median age 12 years, interquartile range 10-14 years) were followed up. The incidences of left and right heart abnormalities were 3.52 and 5.64 per 100 person-years, respectively. Stunting was associated with the development of any cardiac abnormality (adjusted odds ratio 2.59, 95% confidence interval 1.03-6.49; P = .043). Right ventricular (RV) dilatation persisted at follow-up in 92% of participants and left ventricular (LV) diastolic dysfunction in 88%. Cardiac abnormalities present at baseline reverted to normal over the follow-up period in 11 (6%). There was an overall increase in mean z scores for LV, left atrium (LA), RV, interventricular septum, and LV posterior wall diameters at 18 months (P < .001). CONCLUSIONS: Despite ART, children with HIV have a high incidence of cardiac abnormalities, with only a minority being transient. Mean z scores for LV, LA, RV, interventricular septum, and LV posterior wall diameters increased over a relatively short follow-up period, suggesting the potential for progression of cardiac abnormalities. Longer follow-up is required to understand the clinical implications of these abnormalities.

Clinical presentation and survival of childhood hypertrophic cardiomyopathy: a retrospective study in United Kingdom.

AIMS: Understanding the spectrum of disease, symptom burden and natural history are essential for the management of children with hypertrophic cardiomyopathy (HCM). The effect of changing screening practices over time has not previously been studied. This study describes the clinical characteristics and outcomes of childhood HCM over four decades in a well-characterized United Kingdom cohort. METHODS AND RESULTS: Six hundred and eighty-seven patients with HCM presented at a median age of 5.2 years (range 0-16). Aetiology was: non-syndromic (n = 433, 63%), RASopathy (n = 126, 18.3%), Friedreich's ataxia (n = 59, 8.6%) or inborn errors of metabolism (IEM) (n = 64, 9%). In infants (n = 159, 23%) underlying aetiology was more commonly a RASopathy (42% vs. 11.2%, P < 0.0001) or IEM (18.9% vs. 6.4% P < 0.0001). In those with familial disease, median age of presentation was higher (11 years vs. 6 years, P < 0.0001), 141 (58%) presented <12 years. Freedom from death or transplantation was 90.6% (87.9-92.7%) at 5 years (1.5 per 100 patient years) with no era effect. Mortality was most frequently sudden cardiac death (SCD) (n = 20, 2.9%). Children diagnosed during infancy or with an IEM had a worse prognosis (5-year survival 80.5% or 66.4%). Arrhythmic events occurred at a rate of 1.2 per 100 patient years and were more likely in non-syndromic patients (n = 51, 88%). CONCLUSION: This national study describes a heterogeneous disease whose outcomes depend on the age of presentation and aetiology. Overall mortality and SCD rates have not changed over time, but they remain higher than in adults with HCM, with events occurring in syndromic and non-syndromic patients.

A validation study of the European Society of Cardiology guidelines for risk stratification of sudden cardiac death in childhood hypertrophic cardiomyopathy.

AIMS: Sudden cardiac death (SCD) is the most common cause of death in children with hypertrophic cardiomyopathy (HCM). The European Society of Cardiology (ESC) recommends consideration of an implantable cardioverter-defibrillator (ICD) if two or more clinical risk factors (RFs) are present, but this approach to risk stratification has not been formally validated. METHODS AND RESULTS: Four hundred and eleven paediatric HCM patients were assessed for four clinical RFs in accordance with current ESC recommendations: severe left ventricular hypertrophy, unexplained syncope, non-sustained ventricular tachycardia, and family history of SCD. The primary endpoint was a composite outcome of SCD or an equivalent event (aborted cardiac arrest, appropriate ICD therapy, or sustained ventricular tachycardia), defined as a major arrhythmic cardiac event (MACE). Over a follow-up period of 2890 patient years (median 5.5 years), MACE occurred in 21 patients (7.5%) with 0 RFs, 19 (16.8%) with 1 RFs, and 3 (18.8%) with 2 or more RFs. Corresponding incidence rates were 1.13 [95% confidence interval (CI) 0.7-1.73], 2.07 (95% CI 1.25-3.23), and 2.52 (95% CI 0.53-7.35) per 100 patient years at risk. Patients with two or more RFs did not have a higher incidence of MACE (log-rank test P = 0.34), with a positive and negative predictive value of 19% and 90%, respectively. The C-statistic was 0.62 (95% CI 0.52-0.72) at 5 years. CONCLUSIONS: The incidence of MACE is higher for patients with increasing numbers of clinical RFs. However, the current ESC guidelines have a low ability to discriminate between high- and low-risk individuals.

The Cardiomyopathy Registry of the EURObservational Research Programme of the European Society of Cardiology: baseline data and contemporary management of adult patients with cardiomyopathies.

Aims: The Cardiomyopathy Registry of the EURObservational Research Programme is a prospective, observational, and multinational registry of consecutive patients with four cardiomyopathy subtypes: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and restrictive cardiomyopathy (RCM). We report the baseline characteristics and management of adults enrolled in the registry. Methods and results: A total of 3208 patients were enrolled by 69 centres in 18 countries [HCM (n = 1739); DCM (n = 1260); ARVC (n = 143); and RCM (n = 66)]. Differences between cardiomyopathy subtypes (P < 0.001) were observed for age at diagnosis, history of familial disease, history of sustained ventricular arrhythmia, use of magnetic resonance imaging or genetic testing, and implantation of defibrillators. When compared with probands, relatives had a lower age at diagnosis (P < 0.001), but a similar rate of symptoms and defibrillators. When compared with the Long-Term phase, patients of the Pilot phase (enrolled in more expert centres) had a more frequent rate of familial disease (P < 0.001), were more frequently diagnosed with a rare underlying disease (P < 0.001), and more frequently implanted with a defibrillator (P = 0.023). Comparing four geographical areas, patients from Southern Europe had a familial disease more frequently (P < 0.001), were more frequently diagnosed in the context of a family screening (P < 0.001), and more frequently diagnosed with a rare underlying disease (P < 0.001). Conclusion: By providing contemporary observational data on characteristics and management of patients with cardiomyopathies, the registry provides a platform for the evaluation of guideline implementation. Potential gaps with existing recommendations are discussed as well as some suggestions for improvement of health care provision in Europe.