Prevention of sudden cardiac death in childhood-onset hypertrophic cardiomyopathy

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. AIMS OF REVIEW: This review highlights risk factors for SCD in childhood HCM, current risk stratification guidelines, and novel personalized models for risk prediction. KEY SCIENTIFIC CONCEPTS OF REVIEW: 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

Childhood Hypertrophic Cardiomyopathy: A Disease of the Cardiac Sarcomere

Hypertrophic cardiomyopathy is the second most common cause of cardiomyopathy presenting during childhood and whilst its underlying aetiology is variable, the majority of disease is caused by sarcomeric protein gene variants. Sarcomeric disease can present at any age with highly variable disease phenotype, progression and outcomes. The majority have good childhood-outcomes with reported 5-year survival rates above 80%. However, childhood onset disease is associated with considerable life-long morbidity and mortality, including a higher SCD rate during childhood than seen in adults. Management is currently focused on relieving symptoms and preventing disease-related complications, but the possibility of future disease-modifying therapies offers an exciting opportunity to modulate disease expression and outcomes in these young patients

Risk stratification in childhood hypertrophic cardiomyopathy

The true prevalence of hypertrophic cardiomyopathy (HCM) in childhood is unknown, but population-based studies have reported an annual incidence between 0.24–0.47 per 100,000 children. The aetiology of disease is more heterogeneous than that seen in adult populations, with up to 30% of patients having an inborn error of metabolism, malformation syndrome or neuromuscular syndrome. However, as in adults, most cases are caused by mutations in the cardiac sarcomere protein genes, even in young children. The long-term outcome of childhood HCM is highly variable and has been shown to depend partly on the age of presentation and underlying aetiology. Outside of infancy, the most frequent cause of mortality is sudden cardiac death (SCD), and one of the greatest challenges in managing young patients with HCM is identifying those at greatest risk of an arrhythmic event

La relación personal en el tratamiento de la diversidad

El autor centra su aportación en diferentes características de los organismos vivos, para incorporarlas a las perspectivas interpretativas y operativas, y de los métodos actuales de intervención educativa. En el texto también se trata el enfoque positivo desde la dimensión técnica y no «voluntarista», teniendo en cuenta que los especialistas que adoptan la perspectiva del enfoque positivo dan mucha importancia al tema de la calidad de vida.L'autor centra la seva aportació en diferents característiques dels organismes vius, per incorporar- les a les perspectives interpretatives i operatives, i dels mètodes actuals d'intervenció educativa. Al text també es tracta l'enfocament positiu des de la seva dimensió tècnica i no «voluntarista», tenint en compte que els especialistes que adopten la perspectiva de l'enfocament positiu donen molta importància al tema de la qualitat de vida.The author focuses on the different characteristics of the alive organisms in order to include them into the interpretative and operative views of the current methods of educational intervention. He also deals with the positive focus, from the technical and «no voluntary» dimension, taking into account that those specialists having this kind of view do emphasize a lot on the quality of life issue

An Improved Implementation and Abstract Interface for Hybrid

Hybrid is a formal theory implemented in Isabelle/HOL that provides an interface for representing and reasoning about object languages using higher-order abstract syntax (HOAS). This interface is built around an HOAS variable-binding operator that is constructed definitionally from a de Bruijn index representation. In this paper we make a variety of improvements to Hybrid, culminating in an abstract interface that on one hand makes Hybrid a more mathematically satisfactory theory, and on the other hand has important practical benefits. We start with a modification of Hybrid's type of terms that better hides its implementation in terms of de Bruijn indices, by excluding at the type level terms with dangling indices. We present an improved set of definitions, and a series of new lemmas that provide a complete characterization of Hybrid's primitives in terms of properties stated at the HOAS level. Benefits of this new package include a new proof of adequacy and improvements to reasoning about object logics. Such proofs are carried out at the higher level with no involvement of the lower level de Bruijn syntax.Comment: In Proceedings LFMTP 2011, arXiv:1110.668

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

Friedreich's ataxia-associated childhood hypertrophic cardiomyopathy: a national cohort study

OBJECTIVE: Hypertrophic cardiomyopathy (HCM) is an important predictor of long-term outcomes in Friedreich's ataxia (FA), but the clinical spectrum and survival in childhood is poorly described. This study aimed to describe the clinical characteristics of children with FA-HCM. DESIGN AND SETTING: Retrospective, longitudinal cohort study of children with FA-HCM from the UK. PATIENTS: 78 children (<18 years) with FA-HCM diagnosed over four decades. INTERVENTION: Anonymised retrospective demographic and clinical data were collected from baseline evaluation and follow-up. MAIN OUTCOME MEASURES: The primary study end-point was all-cause mortality (sudden cardiac death, atrial arrhythmia-related death, heart failure-related death, non-cardiac death) or cardiac transplantation. RESULTS: The mean age at diagnosis of FA-HCM was 10.9 (±3.1) years. Diagnosis was within 1 year of cardiac referral in 34 (65.0%) patients, but preceded the diagnosis of FA in 4 (5.3%). At baseline, 65 (90.3%) had concentric left ventricular hypertrophy and 6 (12.5%) had systolic impairment. Over a median follow-up of 5.1 years (IQR 2.4-7.3), 8 (10.5%) had documented supraventricular arrhythmias and 8 (10.5%) died (atrial arrhythmia-related n=2; heart failure-related n=1; non-cardiac n=2; or unknown cause n=3), but there were no sudden cardiac deaths. Freedom from death or transplantation at 10 years was 80.8% (95% CI 62.5 to 90.8). CONCLUSIONS: This is the largest cohort of childhood FA-HCM reported to date and describes a high prevalence of atrial arrhythmias and impaired systolic function in childhood, suggesting early progression to end-stage disease. Overall mortality is similar to that reported in non-syndromic childhood HCM, but no patients died suddenly