Endomyocardial biopsy: safety and prognostic utility in paediatric and adult myocarditis in the European Society of Cardiology EURObservational Research Programme Cardiomyopathy and Myocarditis Long-Term Registry.

BACKGROUND AND AIMS: Contemporary multicentre data on clinical and diagnostic spectrum and outcome in myocarditis are limited. Study aims were to describe baseline features, 1-year follow-up, and baseline predictors of outcome in clinically suspected or biopsy-proven myocarditis (2013 European Society of Cardiology criteria) in adult and paediatric patients from the EURObservational Research Programme Cardiomyopathy and Myocarditis Long-Term Registry. METHODS: Five hundred eighty-one (68.0% male) patients, 493 adults, median age 38 (27-52) years, and 88 children, aged 8 (3-13) years, were divided into 3 groups: Group 1 (n = 233), clinically suspected myocarditis with abnormal cardiac magnetic resonance; Group 2 (n = 222), biopsy-proven myocarditis; and Group 3 (n = 126) clinically suspected myocarditis with normal or inconclusive or no cardiac magnetic resonance. Baseline features were analysed overall, in adults vs. children, and among groups. One-year outcome events included death/heart transplantation, ventricular assist device (VAD) or implantable cardioverter defibrillator (ICD) implantation, and hospitalization for cardiac causes. RESULTS: Endomyocardial biopsy, mainly right ventricular, had a similarly low complication rate in children and adults (4.7% vs. 4.9%, P = NS), with no procedure-related death. A classical myocarditis pattern on cardiac magnetic resonance was found in 31.3% of children and in 57.9% of adults with biopsy-proven myocarditis (P < .001). At 1-year follow-up, 11/410 patients (2.7%) died, 7 (1.7%) received a heart transplant, 3 underwent VAD (0.7%), and 16 (3.9%) underwent ICD implantation. Independent predictors at diagnosis of death or heart transplantation or hospitalization or VAD implantation or ICD implantation at 1-year follow-up were lower left ventricular ejection fraction and the need for immunosuppressants for new myocarditis diagnosis refractory to non-aetiology-driven therapy. CONCLUSIONS: Endomyocardial biopsy was safe, and cardiac magnetic resonance using Lake Louise criteria was less sensitive, particularly in children. Virus-negative lymphocytic myocarditis was predominant both in children and adults, and use of immunosuppressive treatments was low. Lower left ventricular ejection fraction and the need for immunosuppressants at diagnosis were independent predictors of unfavourable outcome events at 1 year.

Performance of the PRIMaCY sudden death risk prediction model for childhood hypertrophic cardiomyopathy: implications for implantable cardioverter-defibrillator decision-making.

AIMS: The validated HCM Risk-Kids model provides accurate individualized estimates of sudden cardiac death risk in children with hypertrophic cardiomyopathy (HCM). A second validated model, PRIMaCY, also provides individualized estimates of risk, but its performance and clinical impact has not been independently investigated. The aim of this study was to investigate the clinical impact of using the PRIMaCY sudden cardiac death (SCD) risk model in childhood HCM. METHODS AND RESULTS: The estimated 5-year SCD risk was calculated for children meeting diagnostic criteria for HCM in a large single-centre cohort using PRIMaCY (clinical and genetic) and HCM Risk-Kids model, and model performance was assessed. Three hundred one patients [median age 10 (interquartile range 4-14)] were followed up for an average of 4.9 (±3.8) years, during which 30 (10.0%) reached the SCD or equivalent event endpoint. Harrell's C-statistic for the clinical and genetic models was 0.66 [95% confidence interval (CI) 0.52-0.8] and 0.66 (95% CI 0.54-0.80) with a calibration slope of 0.19 (95% CI 0.04-0.54) and 0.26 (95% CI -0.03-0.62), respectively. The number needed to treat to potentially treat one life-threatening arrhythmia for the PRIMaCY clinical, PRIMaCY genetic, and HCM Risk-Kids models was 13.7, 14.5, and 9.4, respectively. CONCLUSION: Although PRIMaCY has a similar discriminatory ability to that reported for HCM Risk-Kids, estimated risk estimates did not correlate well with observed risk. A higher proportion of patients met implantable cardioverter-defibrillator thresholds using PRIMaCY model compared with HCM Risk-Kids. This has important clinical implications as these patients will be exposed to a lifetime risk of complications and inappropriate therapies.

Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry.

AIMS: Calmodulinopathy due to mutations in any of the three CALM genes (CALM1-3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. METHODS AND RESULTS: The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5-19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. CONCLUSION: Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter-defibrillator.

Proinflammatory and cardiovascular biomarkers are associated with echocardiographic abnormalities in children with HIV taking antiretroviral therapy.

OBJECTIVES: Children with perinatally acquired HIV (PHIV) and taking antiretroviral therapy (ART) have a high prevalence of subclinical cardiac disease. We hypothesized that cardiac disease may be a consequence of dysregulated systemic immune activation driven by HIV infection. We examined cardiovascular and proinflammatory biomarkers and their association with echocardiographic abnormalities in children with PHIV. DESIGN: Cross-sectional analysis of soluble biomarkers from a prospective cohort of children aged 6-16 years with PHIV and age-matched HIV-uninfected comparison group. METHODS: Cryopreserved plasma samples were used to measure seven soluble biomarkers using multiplex bead assay (Luminex). Multivariable logistic regression assessed how biomarker levels related to cardiac abnormalities. RESULTS: A total of 406 children participated in this study (195 PHIV and 211 HIV-uninfected). Mean [standard deviation (SD)] ages of PHIV and HIV-uninfected participants were 10.7 (2.6) and 10.8 (2.8) years, respectively. Plasma levels of CRP, TNF-α, ST2, VCAM-1 and GDF-15 were significantly higher in the PHIV group compared with uninfected control ( P  < 0.001). Among children with PHIV, with one-unit representing one SD in biomarker level, a one-unit increase in CRP and GDF-15, was associated with increased odds of having left ventricular (LV) diastolic dysfunction [adjusted odds ratio (aOR), 1.49 (1.02-2.18; P  < 0.040)] and [aOR 1.71 (1.18-2.53; P  = 0.006)], respectively. Each one unit increase in GDF-15 was associated with increased odds of LV hypertrophy [aOR 1.84 (95% CI 1.10-3.10; P  < 0.021)]. CONCLUSION: Children with PHIV had higher levels of proinflammatory and cardiovascular biomarkers compared with HIV-uninfected children. Increased CRP and GDF-15 were associated with cardiac abnormalities in children with PHIV.

Association between common cardiovascular risk factors and clinical phenotype in patients with hypertrophic cardiomyopathy from the European Society of Cardiology (ESC) EurObservational Research Programme (EORP) Cardiomyopathy/Myocarditis registry.

AIMS: The interaction between common cardiovascular risk factors (CVRF) and hypertrophic cardiomyopathy (HCM) is poorly studied. We sought to explore the relation between CVRF and the clinical characteristics of patients with HCM enrolled in the EURObservational Research Programme (EORP) Cardiomyopathy registry. METHODS AND RESULTS: 1739 patients with HCM were studied. The relation between hypertension (HT), diabetes (DM), body mass index (BMI), and clinical traits was analysed. Analyses were stratified according to the presence or absence of a pathogenic variant in a sarcomere gene. The prevalence of HT, DM, and obesity (Ob) was 37, 10, and 21%, respectively. HT, DM, and Ob were associated with older age (P<0.001), less family history of HCM (HT and DM P<0.001), higher New York Heart Association (NYHA) class (P<0.001), atrial fibrillation (HT and DM P<0.001; Ob p = 0.03) and LV (left ventricular) diastolic dysfunction (HT and Ob P<0.001; DM P = 0.003). Stroke was more frequent in HT (P<0.001) and mutation-positive patients with DM (P = 0.02). HT and Ob were associated with higher provocable LV outflow tract gradients (HT P<0.001, Ob P = 0.036). LV hypertrophy was more severe in Ob (P = 0.018). HT and Ob were independently associated with NYHA class (OR 1.419, P = 0.017 and OR 1.584, P = 0.004, respectively). Other associations, including a higher proportion of females in HT and of systolic dysfunction in HT and Ob, were observed only in mutation-positive patients. CONCLUSION: Common CVRF are associated with a more severe HCM phenotype, suggesting a proactive management of CVRF should be promoted. An interaction between genotype and CVRF was observed for some traits.

External validation of the HCM Risk-Kids model for predicting sudden cardiac death in childhood hypertrophic cardiomyopathy.

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.

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.

Prospective follow-up in various subtypes of cardiomyopathies: insights from the ESC EORP Cardiomyopathy Registry.

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 < 0.05 for each). Additional invasive procedures were performed: prophylactic implantation of implantable cardioverter-defibrillator (ICD) (5.2%), pacemaker (1.2%), heart transplant (1.1%), ablation for atrial or ventricular arrhythmia (0.5% and 0.1%). Patients with atrial fibrillation increased from 28.7% to 32.2% of the cohort. Ventricular arrhythmias (VF/ventricular tachycardias) in ICD carriers (primary prevention) at 1 year were more frequent in ARVC, then in DCM, HCM, and RCM (10.3%, 8.2%, 7.5%, and 0%, respectively). Major cardiovascular events (MACE) occurred in 29.3% of RCM, 10.5% of DCM, 5.3% of HCM, and 3.9% of ARVC (P < 0.001). MACE were more frequent in index patients compared to relatives (10.8% vs. 4.4%, P < 0.001), more frequent in East Europe centres (13.1%) and least common in South Europe (5.3%) (P < 0.001). Subtype of cardiomyopathy, geographical region, and proband were predictors of MACE on multivariable analysis. 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.

Atypical cardiac defects in patients with RASopathies: Updated data on CARNET study.

BACKGROUND: RASopathies are a set of relatively common autosomal dominant clinically and genetically heterogeneous disorders. Cardiac outcomes in terms of mortality and morbidity for common heart defects (such as pulmonary valve stenosis and hypertrophic cardiomyopathy) have been reported. Nevertheless, also Atypical Cardiac Defects (ACDs) are described. The aim of the present study was to report both prevalence and cardiac outcome of ACDs in patients with RASopathies. METHODS: A retrospective, multicentric observational study (CArdiac Rasopathy NETwork-CARNET study) was carried out. Clinical, surgical, and genetic data of the patients who were followed until December 2019 were collected. RESULTS: Forty-five patients out of 440 followed in CARNET centers had ACDs. Noonan Syndrome (NS), NS Multiple Lentigines (NSML) and CardioFacioCutaneous Syndrome (CFCS) were present in 36, 5 and 4 patients, respectively. Median age at last follow-up was 20.1 years (range 6.9-47 years). Different ACDs were reported, including mitral and aortic valve dysfunction, ascending and descending aortic arch anomalies, coronary arteries dilation, enlargement of left atrial appendage and isolated pulmonary branches diseases. Five patients (11%) underwent cardiac surgery and one of them underwent a second intervention for mitral valve replacement and severe pericardial effusion. No patients died in our cohort until December 2019. CONCLUSIONS: Patients with RASopathies present a distinct CHD spectrum. Present data suggest that also ACDs must be carefully investigated for their possible impact on the clinical outcome. A careful longitudinal follow up until the individuals reach an adult age is recommended.

Development of a Novel Risk Prediction Model for Sudden Cardiac Death in Childhood Hypertrophic Cardiomyopathy (HCM Risk-Kids).

Importance: Sudden cardiac death (SCD) is the most common mode of death in childhood hypertrophic cardiomyopathy (HCM), but there is no validated algorithm to identify those at highest risk. Objective: To develop and validate an SCD risk prediction model that provides individualized risk estimates. Design, Setting, and Participants: A prognostic model was developed from a retrospective, multicenter, longitudinal cohort study of 1024 consecutively evaluated patients aged 16 years or younger with HCM. The study was conducted from January 1, 1970, to December 31, 2017. Exposures: The model was developed using preselected predictor variables (unexplained syncope, maximal left-ventricular wall thickness, left atrial diameter, left-ventricular outflow tract gradient, and nonsustained ventricular tachycardia) identified from the literature and internally validated using bootstrapping. Main Outcomes and Measures: A composite outcome of SCD or an equivalent event (aborted cardiac arrest, appropriate implantable cardioverter defibrillator therapy, or sustained ventricular tachycardia associated with hemodynamic compromise). Results: Of the 1024 patients included in the study, 699 were boys (68.3%); mean (interquartile range [IQR]) age was 11 (7-14) years. Over a median follow-up of 5.3 years (IQR, 2.6-8.3; total patient years, 5984), 89 patients (8.7%) died suddenly or had an equivalent event (annual event rate, 1.49; 95% CI, 1.15-1.92). The pediatric model was developed using preselected variables to predict the risk of SCD. The model's ability to predict risk at 5 years was validated; the C statistic was 0.69 (95% CI, 0.66-0.72), and the calibration slope was 0.98 (95% CI, 0.59-1.38). For every 10 implantable cardioverter defibrillators implanted in patients with 6% or more of a 5-year SCD risk, 1 patient may potentially be saved from SCD at 5 years. Conclusions and Relevance: This new, validated risk stratification model for SCD in childhood HCM may provide individualized estimates of risk at 5 years using readily obtained clinical risk factors. External validation studies are required to demonstrate the accuracy of this model's predictions in diverse patient populations.

Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry.

AIMS: Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1-3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome. METHODS AND RESULTS: A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1-5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0-8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively. CONCLUSION: Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.

High prevalence of echocardiographic abnormalities in older HIV-infected children taking antiretroviral therapy.

BACKGROUND: Antiretroviral therapy (ART) has decreased mortality so that increasing numbers of children with HIV are reaching adolescence. However, longstanding HIV infection and/or its treatment in children is associated with noninfectious complications including cardiac disease. We investigated the prevalence, spectrum and risk factors for echocardiographic abnormalities among children established on ART. METHODS: HIV-infected children aged 6-16 years, on ART at least 6 months were enrolled into a cross-sectional study from a public-sector paediatric HIV clinic in Harare, Zimbabwe. A standardized examination including transthoracic echocardiography was performed. Local echocardiographic reference ranges were used to define cardiac abnormalities. Logistic regression was used to examine the association between cardiac abnormalities and risk factors. RESULTS: Of the 201participants recruited, 92 (46%) were girls and median age was 11 (IQR 9-12) years; CD4+ cell count was 727 cells/µl (IQR 473-935) and 154 (78%) had viral load less than 400 copies/ml. Echocardiographic abnormalities were found in 83 (42%); left ventricular (LV) diastolic dysfunction was the most common abnormality 45 (23%) and LV hypertrophy in 22 (11%). LV and left atrial dilatation were found in 9 (5%) and 16 (8%), respectively. Right ventricular dilatation and systolic dysfunction were found in 13 (7%) and 4 (2%), respectively, of whom 60% had concurrent left heart abnormalities. Current use of nevirapine was associated with LVH [aOR 3.14 (1.13-8.72; P = 0.03)] and hypertension was associated with LV diastolic dysfunction [aOR 3.12 (1.48-6.57; P < 0.01)]. CONCLUSION: HIV-infected children established on ART have a high burden of echocardiographic abnormalities. Right heart disease was predominantly associated with left heart abnormalities and may be part of a global cardiomyopathic process. Further studies are needed to investigate the natural history, aetiology, and pathogenesis of these abnormalities, so that appropriate monitoring and treatment strategies can be developed.

Racial Variation in Echocardiographic Reference Ranges for Left Chamber Dimensions in Children and Adolescents: A Systematic Review.

Echocardiography plays a critical role in the assessment of cardiac disease. Important differences in echocardiographically derived cardiac chamber dimensions have been previously highlighted in different population groups in adult studies, but this has not been systematically studied in children, whose body size changes throughout childhood. The aim of this study was to review the distribution of available reference ranges for the left cardiac chamber dimensions in older children and adolescents. The following electronic data bases were searched: Medline, Embase and Web of Science were searched to identify studies which have established echocardiographic reference ranges of left heart parameters in children and adolescents from 1975 to December 2017. There was no geographical limitation. All results were imported into Endnote. Retrieved articles were screened and data extracted by two independent reviewers. A total of 4398 studies were retrieved, with 36 studies finally included in this review. 29 (81%) references were from North America and European (Caucasians) populations, with only one study each from Africa and South America. Two-dimensional and M-mode techniques were the most commonly used echocardiography techniques. There were methodological variations in techniques and normalisation of references. Comparison of selected cardiac measures showed significant differences for interventricular septal thickness among Black African, Indian, German and US American children. Available echocardiographic references cannot be generalised to all settings and therefore, there is need for locally relevant reference ranges. Africa and South America are particularly under-represented. Future studies should focus on developing comprehensive echocardiographic reference ranges for children from different racial backgrounds and should use standardised techniques.

Data on cardiac defects, morbidity and mortality in patients affected by RASopathies. CARNET study results.

A comprehensive description of morbidity and mortality in patients affected by mutations in genes encoding for signal transducers of the RAS-MAPK cascade (RASopathies) was performed in our study recently published in the International Journal of Cardiology. Seven European cardiac centres participating to the CArdiac Rasopathy NETwork (CARNET), collaborated in this multicentric, observational, retrospective data analysis and collection. In this study, clinical records of 371 patients with confirmed molecular diagnosis of RASopathy were reviewed. Cardiac defects, crude mortality, survival rate of patients with 1) hypertrophic cardiomyopathy (HCM) and age <2 years or young adults; 2) individuals with Noonan syndrome and pulmonary stenosis carrying PTPN11 mutations; 3) biventricular obstruction and PTPN11 mutations; 4) Costello syndrome or cardiofaciocutaneous syndrome were analysed. Mortality was described as crude mortality, cumulative survival and restricted estimated mean survival. In particular, with this Data In Brief (DIB) paper, the authors aim to report specific statistic highlights of the multivariable regression analysis that was used to assess the impact of mutated genes on number of interventions and overall prognosis.

Cardiac defects, morbidity and mortality in patients affected by RASopathies. CARNET study results.

BACKGROUND: RASopathies are developmental disease caused by mutations in genes encoding for signal transducers of the RAS-MAPK cascade. The aim of the present study was to provide a comprehensive description of morbidity and mortality in patients with molecularly confirmed RASopathy. METHODS: A multicentric, observational, retrospective study was conducted in seven European cardiac centres participating to the CArdiac Rasopathy NETwork (CARNET). Clinical records of 371 patients with confirmed molecular diagnosis of RASopathy were reviewed. Mortality was described as crude mortality, cumulative survival and restricted estimated mean survival. Multivariable regression analysis was used to assess the impact of mutated genes on number of interventions and overall prognosis. RESULTS: Cardiac defects occurred in 80.3% of cases, almost half of them underwent at least one intervention. Overall, crude mortality was 0.29/100 patients-year. Cumulative survival was 98.8%, 98.2%, 97.7%, 94.3%, at 1, 5, 10, and 20years, respectively. Restricted estimated mean survival at 20years follow-up was 19.6years. Ten patients died (2.7% of the entire cohort; 3.4% of patients with cardiac defect). Patients with hypertrophic cardiomyopathy (HCM) and age <2years or young adults, as well as subjects with biventricular obstruction and PTPN11 mutations had a higher risk of cardiac death. CONCLUSIONS: The risk of intervention was higher in individuals with Noonan syndrome and pulmonary stenosis carrying PTPN11 mutations. Overall, mortality was relatively low, even though the specific association between HCM, biventricular outflow tract obstructions and PTPN11 mutations appeared to be associated with early mortality, including immediate post-operative events and sudden death.

Echocardiographic reference ranges in older children and adolescents in sub-Saharan Africa.

BACKGROUND: Echocardiographic reference ranges are important to identify abnormalities of cardiac dimensions. Reference ranges for children in sub-Saharan Africa have not been established. The aim of this study was to establish echocardiographic z-score references for Black children in sub-Saharan Africa. METHODS: 282 healthy subjects aged 6-16years (143 [51%] males) with no known history of cardiac disease were enrolled in the study in Harare, Zimbabwe between 2014 and 2016. Standard M-mode echocardiography was performed and nine cardiac chamber dimensions were obtained. Two non-linear statistical models (gamma weighted model and cubic polynomial model) were tested on the data and the best fitting model was used to calculate z-scores of these cardiac chamber measures. The reference ranges are presented on scatter plots against BSA. RESULTS: Normative data for the following cardiac measures were obtained and z-scores calculated: right ventricular diameter at end diastole (RVEDD); left ventricular diameter at end diastole (LVEDD) and systole (LVESD); interventricular septal wall thickness at end diastole (IVSd) and systole (IVSs); left ventricular posterior wall thickness at end diastole (LVPWd) and systole (LVPWs); left atrium diameter at end systole (LA) and tricuspid annular plane systolic excursion (TAPSE). Girls had higher values for BMI and heart rate than boys (p=0.048 and p=0.001, respectively). Mean interventricular septal and left ventricular posterior walls thickness was higher than published normal values in predominantly Caucasian populations. CONCLUSION: These are the first echocardiographic reference ranges for children from sub Saharan Africa and will allow accurate assessment of cardiac dimensions in clinical practice.

Psychosocial adjustment and quality of life in children undergoing screening in a specialist paediatric hypertrophic cardiomyopathy clinic.

OBJECTIVE: This study aimed to assess the psychological well-being and quality of life in children with hypertrophic cardiomyopathy and the potential psychosocial impact of screening. METHODS: A total of 152 children (aged 3-18 years) attending a specialist paediatric hypertrophic cardiomyopathy clinic, and their parents completed the Generic Core Scales and Cardiac Module of the Paediatric Quality of Life Inventory (PedsQL) questionnaire as well as the Strengths and Difficulties Questionnaire; 21 patients (14%) had hypertrophic cardiomyopathy (group A); 23 children (15%) harboured hypertrophic cardiomyopathy-causing sarcomeric mutations with normal echocardiograms (group G); and 108 children (71%) had a family history of hypertrophic cardiomyopathy with normal investigations and attended for clinical cardiological screening (group S). RESULTS: In group A, mean PedsQLTM total scores reported by children and parents were lower than those reported by unaffected children (p<0.001). There was no significant difference between unaffected and gene-positive patients. Mean Cardiac module PedsQLTM total scores by children and parents were lower in children with hypertrophic cardiomyopathy compared with unaffected patients [mean child-reported total score 86.4 in group S versus 72.3 in group A (p<0.001) and 80.2 in group G (p=0.25); mean parent-reported total score 91.6 in group S versus 71.4 in group A (p<0.001) and 87 in group G (p=0.4)]. There was no significant difference between group S and group G on any of the scales, or between the three groups of patients in the mean Strengths and Difficulties Questionnaire scores. CONCLUSIONS: Children with hypertrophic cardiomyopathy have a significantly reduced quality of life. Importantly, Quality-of-Life scores among unaffected children attending for screening were not different compared with scores from a normative UK population.

Nomenclature and systems of classification for cardiomyopathy in children.

There has been a progressive evolution in systems of classification for cardiomyopathy, driven by advances in imaging modalities, disease recognition, and genetics, following initial clinical descriptions in the 1960s. A pathophysiological classification emerged and was endorsed by World Health Organisation Task Forces in 1980 and 1995: dilated, hypertrophic, restrictive, and arrhythmogenic right ventricular cardiomyopathies; subdivided into idiopathic and disease-specific cardiomyopathies. Genetic advances have increasingly linked "idiopathic" phenotypes to specific mutations, although most linkages exhibit highly variable or little genotype-phenotype correlation, confounded by age-dependent changes and varying penetrance. The following two dominant classification systems are currently in use, with advocates in both continents. First, American Heart Association (2006): "A heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually exhibit inappropriate ventricular hypertrophy or dilatation due to a variety of causes that frequently are genetic". These are subdivided to those predominantly involving the heart - primary - due to genetic mutation, including ion channelopathies, acquired disease, or mixed; and those with systemic involvement in other organ systems - secondary. Second, European Society of Cardiology (2008): "A myocardial disorder in which heart muscle is structurally and functionally abnormal… sufficient to cause the observed myocardial abnormality", with subdivision to familial and non-familial, excluding ion channelopathies, and split to specific disease subtypes and idiopathic. Further differences exist in the definitions for hypertrophic cardiomyopathy; however, whichever high-level classification is used, the clinical reality remains phenotype driven. Clinical evaluation and diagnostic imaging dominate initial patient contact, revealing diagnostic red flags that determine further specific tests. Genetic testing is undertaken early. A recent attempt to harmonise these competing systems named the MOGE(S) system, based on descriptive logical nosology, currently remains unproven as a fully practical solution.