Inherited cardiomyopathies are a prevalent cause of heart failure and sudden cardiac death. Both hypertrophic (HCM) and dilated cardiomyopathy (DCM) are genetically heterogeneous and typically ...present with an autosomal dominant mode of transmission. Whole exome sequencing and autozygosity mapping was carried out in eight un-related probands from consanguineous Middle Eastern families presenting with HCM/DCM followed by bioinformatic and co-segregation analysis to predict the potential pathogenicity of candidate variants. We identified homozygous missense variants in
,
, and
linked with a dilated phenotype, in
linked with a mixed phenotype of dilated/hypertrophic, and in
linked with a mixed phenotype of dilated/hypertrophic and non-compaction features. Co-segregation analysis in family members confirmed autosomal recessive inheritance presenting in early childhood/early adulthood. Our findings add to the mutational spectrum of recessive cardiomyopathies, supporting inclusion of
,
and
as disease-causing genes. We also provide evidence for novel (recessive) modes of inheritance of a well-established gene
and expand our knowledge of the clinical heterogeneity of cardiomyopathies. A greater understanding of the genetic causes of recessive cardiomyopathies has major implications for diagnosis and screening, particularly in underrepresented populations, such as those of the Middle East.
Aims
Children presenting with hypertrophic cardiomyopathy (HCM) in infancy are reported to have a poor prognosis, but this heterogeneous group has not been systematically characterized. This study ...aimed to describe the aetiology, phenotype, and outcomes of infantile HCM in a well‐characterized multicentre European cohort.
Methods and results
Of 301 children diagnosed with infantile HCM between 1987 and 2019 presenting to 17 European centres male n = 187 (62.1%), underlying aetiology was non‐syndromic (n = 138, 45.6%), RASopathy (n = 101, 33.6%), or inborn error of metabolism (IEM) (n = 49, 16.3%). The most common reasons for presentation were symptoms (n = 77, 29.3%), which were more prevalent in those with syndromic disease (n = 62, 61.4%, P < 0.001), and an isolated murmur (n = 75, 28.5%). One hundred and sixty‐one (53.5%) had one or more co‐morbidities. Genetic testing was performed in 163 (54.2%) patients, with a disease‐causing variant identified in 115 (70.6%). Over median follow‐up of 4.1 years, 50 (16.6%) underwent one or more surgical interventions; 15 (5.0%) had an arrhythmic event (6 in the first year of life); and 48 (15.9%) died, with an overall 5 year survival of 85%. Predictors of all‐cause mortality were an underlying diagnosis of IEM hazard ratio (HR) 4.4, P = 0.070, cardiac symptoms (HR 3.2, P = 0.005), and impaired left ventricular systolic function (HR 3.0, P = 0.028).
Conclusions
This large, multicentre study of infantile HCM describes a complex cohort of patients with a diverse phenotypic spectrum and clinical course. Although overall outcomes were poor, this was largely related to underlying aetiology emphasizing the importance of comprehensive aetiological investigations, including genetic testing, in infantile HCM.
Aims
Cardiomyopathies comprise a heterogeneous group of diseases, often of genetic origin. We assessed the current practice of genetic counselling and testing in the prospective European Society of ...Cardiology EURObservational Research Programme Cardiomyopathy Registry.
Methods and results
A total of 3208 adult patients from 69 centres in 18 countries were enrolled. Genetic counselling was performed in 60.8% of all patients 75.4% in hypertrophic cardiomyopathy (HCM), 39.2% in dilated cardiomyopathy (DCM), 70.8% in arrhythmogenic right ventricular cardiomyopathy (ARVC), and 49.2% in restrictive cardiomyopathy (RCM), P < 0.001. Comparing European geographical areas, genetic counselling was performed from 42.4% to 83.3% (P < 0.001). It was provided by a cardiologist (85.3%), geneticist (15.1%), genetic counsellor (11.3%), or a nurse (7.5%) (P < 0.001). Genetic testing was performed in 37.3% of all patients (48.8% in HCM, 18.6% in DCM, 55.6% in ARVC, and 43.6% in RCM, P < 0.001). Index patients with genetic testing were younger at diagnosis and had more familial disease, family history of sudden cardiac death, or implanted cardioverter defibrillators but less co‐morbidities than those not tested (P < 0.001 for each comparison). At least one disease‐causing variant was found in 41.7% of index patients with genetic testing (43.3% in HCM, 33.3% in DCM, 51.4% in ARVC, and 42.9% in RCM, P = 0.13).
Conclusions
This is the first detailed report on the real‐life practice of genetic counselling and testing in cardiomyopathies in Europe. Genetic counselling and testing were performed in a substantial proportion of patients but less often than recommended by European guidelines and much less in DCM than in HCM and ARVC, despite evidence for genetic background.
Sudden cardiac death (SCD) is the most common cause of death in children with HCM. Although recent population-based studies have shown that SCD rates are lower than previously thought, it still ...occurs more frequently than in adult patients, highlighting the importance of accurate identification of those at risk.
This review highlights risk factors for SCD in childhood HCM, current risk stratification guidelines, and novel personalized models for risk prediction.
The traditional approach to risk prediction in childhood-onset HCM, using cumulative risk factor thresholds and adopted by current international guidelines, has involved extrapolation of adult data, but recent evidence has demonstrated that this approach does not accurately discriminate high-risk from low-risk individuals. In response to this knowledge gap, novel pediatric-specific risk stratification models have been developed that allow calculation of individualized estimates of SCD risk and enable a personalized and shared decision-making approach to ICD implantation.
•Sudden cardiac death (SCD) is the commonest cause of death in childhood hypertrophic cardiomyopathy (HCM)•Current risk stratification algorithms have poor discriminatory ability in children with HCM•The HCM Risk-Kids SCD risk prediction model provides individualised 5 year SCD risk estimates (https://hcmriskkids.org)•Future work to refine these models with the addition of novel risk factors is required
Nuclear factor κB (NF-κB) signaling in cardiac myocytes causes disease in a mouse model of arrhythmogenic cardiomyopathy (ACM) by mobilizing CCR2-expressing macrophages that promote myocardial injury ...and arrhythmias. Buccal mucosa cells exhibit pathologic features similar to those seen in cardiac myocytes in patients with ACM.
We sought to determine if persistent innate immune signaling via NF-κB occurs in cardiac myocytes in patients with ACM and if this is associated with myocardial infiltration of proinflammatory cells expressing CCR2. We also determined if buccal mucosa cells from young subjects with inherited disease alleles exhibit NF-κB signaling.
We analyzed myocardium from ACM patients who died suddenly or required cardiac transplantation. We also analyzed buccal mucosa cells from young subjects with inherited disease alleles. The presence of immunoreactive signal for RelA/p65 in nuclei of cardiac myocytes and buccal cells was used as a reliable indicator of active NF-κB signaling. We also counted myocardial CCR2-expressing cells.
RelA/p65 signal was seen in numerous cardiac myocyte nuclei in 34 of 36 cases of ACM but not in 19 age-matched control individuals. Cells expressing CCR2 were increased in patient hearts in numbers directly correlated with the number of cardiac myocytes showing NF-κB signaling. NF-κB signaling was observed in buccal cells in young subjects with active disease.
Patients with clinically active ACM exhibit persistent innate immune responses in cardiac myocytes and buccal mucosa cells, reflecting a local and systemic inflammatory process. Such individuals may benefit from anti-inflammatory therapy.
Background The natural history and long-term outcome in pediatric patients with idiopathic ventricular fibrillation ( IVF ) are poorly characterized. We sought to define the clinical characteristics ...and long-term outcomes of a pediatric cohort with an initial diagnosis of IVF . Methods and Results Patients were included from an International Registry of IVF (consisting of 496 patients). Inclusion criteria were: (1) VF with no identifiable cause following comprehensive analysis for ischemic, electrical or structural heart disease and (2) age ≤16 years. These included 54 pediatric IVF cases (age 12.7±3.7 years, 59% male) among whom 28 (52%) had a previous history of syncope (median 2 syncopal episodes interquartile range 1). Thirty-six (67%) had VF in situations associated with high adrenergic tone. During a median 109±12 months of follow-up, 31 patients (57%) had recurrence of ventricular arrhythmias, mainly VF . Two patients developed phenotypic expression of an inherited arrhythmia syndrome during follow-up (hypertrophic cardiomyopathy and long QT syndrome, respectively). A total of 15 patients had positive genetic testing for inherited arrhythmia syndromes. Ten patients (18%) experienced device-related complications. Three patients (6%) died, 2 due to VF storm. Conclusions In pediatric patients with IVF , a minority develop a definite clinical phenotype during long-term follow-up. Recurrent VF is common in this patient group.
Aims
This study aimed to describe the natural history and predictors of all‐cause mortality and sudden cardiac death (SCD)/equivalent events in children with a RASopathy syndrome and hypertrophic ...cardiomyopathy (HCM).
Methods and results
This is a retrospective cohort study from 14 paediatric cardiology centres in the United Kingdom and Ireland. We included children <18 years with HCM and a clinical and/or genetic diagnosis of a RASopathy syndrome Noonan syndrome (NS), NS with multiple lentigines (NSML), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFCS), and NS with loose anagen hair (NS‐LAH). One hundred forty‐nine patients were recruited 111 (74.5%) NS, 12 (8.05%) NSML, 6 (4.03%) CS, 6 (4.03%) CFCS, 11 (7.4%) Noonan‐like syndrome, and 3 (2%) NS‐LAH. NSML patients had higher left ventricular outflow tract (LVOT) gradient values 60 (36–80) mmHg, P = 0.004. Over a median follow‐up of 197.5 inter‐quartile range (IQR) 93.58–370 months, 23 patients (15.43%) died at a median age of 24.1 (IQR 5.6–175.9) months. Survival was 96.45% 95% confidence interval (CI) 91.69–98.51, 90.42% (95% CI 84.04–94.33), and 84.12% (95% CI 75.42–89.94) at 1, 5, and 10 years, respectively, but this varied by RASopathy syndrome. RASopathy syndrome, symptoms at baseline, congestive cardiac failure (CCF), non‐sustained ventricular tachycardia (NSVT), and maximal left ventricular wall thickness were identified as predictors of all‐cause mortality on univariate analysis, and CCF, NSVT, and LVOT gradient were predictors for SCD or equivalent event.
Conclusions
These findings highlight a distinct category of patients with Noonan‐like syndrome with a milder HCM phenotype but significantly worse survival and identify potential predictors of adverse outcome in patients with RASopathy‐related HCM.
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.
PDF
