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.

Sudden cardiac death in childhood hypertrophic cardiomyopathy is best predicted by a combination of electrocardiogram risk-score and HCMRisk-Kids score.

AIM: To compare risk algorithms (HCMRisk-Kids, ECG Risk-score) in hypertrophic cardiomyopathy (HCM) without syndrome association (ns-HCM) and with Noonan-like syndromes (RAS-HCM). METHODS: A national paediatric HCM cohort (n = 151), presenting <19 years of age, mean follow-up 13.3 years, from all Swedish centres of Paediatric Cardiology (presenting 1972-2015), with 41 RAS-HCM patients (61% males), and 110 ns-HCM patients (68% familial; 65% males). The end-point was a composite of sudden cardiac death and resuscitated cardiac arrest (SCD/CA). Risk-factors were studied with Cox-hazard regression, and receiver operating characteristic curve analysis (C-statistic). RESULTS: There were 33 SCD/CA, 27/110 in ns-HCM and 6/41 in RAS-HCM (p = 0.27). In ns-HCM HCMRisk-Kids ≥6% at diagnosis had C-statistic of 0.69 for predicting SCD/CA during first 5 years of follow-up and positive predictive value (PPV) of 22%. After 7 years of age (HCMRisk-Kids7plus), C-statistic was 0.76. ECG Risk-score ≥6 at diagnosis had C-statistic 0.87 and PPV of 31%. Independent risk factors for SCD/CA were HCMRisk-Kids7plus score (p = 0.005) and ECG risk-score (p < 0.001), whereas early beta-blocker dose (p = 0.001) and myectomy (p = 0.004) reduced risk. The sum of HCMRisk-Kids7yplus and ECG Risk-score7yplus ≥14 best predicted SCD/CA within 5 years in ns-HCM with C-statistic of 0.90 [0.83-0.96], sensitivity 100% and PPV 38%. CONCLUSION: Combining the ECG Risk-score with HCMRisk-Kids improves risk stratification in ns-HCM and shows promise in RAS-HCM.

High ECG Risk-Scores Predict Late Gadolinium Enhancement on Magnetic Resonance Imaging in HCM in the Young.

An ECG risk-score has been described that predicts high risk of subsequent cardiac arrest in young patients with hypertrophic cardiomyopathy (HCM). Myocardial fibrosis measured by cardiac magnetic resonance (CMR) late gadolinium enhancement (LGE) also affects prognosis. We assessed whether an ECG risk-score could be used as an indicator of myocardial fibrosis or perfusion deficit on CMR in HCM. In total 42 individuals (7-31 years); 26 HCM patients, seven genotype-positive, phenotype-negative individuals at risk of HCM (first-degree relatives) and nine healthy volunteers, underwent CMR to identify, and grade extent of, myocardial fibrosis and perfusion defect. 12-lead ECG was used for calculating the ECG risk-score (grading 0-14p). High-risk ECG (risk-score > 5p) occurred only in the HCM group (9/26), and the proportion was significantly higher vs mutation carriers combined with healthy volunteers (0/16, p = 0.008). Extent of LGE correlated to the ECG-score (R2 = 0.47, p = 0.001) in sarcomeric mutations. In low-risk ECG-score patients (0-2p), median percent of myocardium showing LGE (LGE%LVM) were: 0% [interquartile range, IQR, 0-0%], in intermediate-risk (3-5p): 5.4% [IQR 0-13.5%] and in high-risk (6-14p): 10.9% [IQR 4.2-12.3%]. ECG-score > 2p had a sensitivity and specificity of 79% and 84% to detect positive LGE on CMR and 77% vs. 75% to detect perfusion defects in sarcomeric mutations carriers. In patients with myocardial fibrosis as identified by LGE, median ECG risk-score was 8p [range 3-10p]. In conclusions, ECG risk-score > 2 p could be used as a cut-off for screening of myocardial fibrosis. Thus ECG risk-score is an inexpensive complementary tool in risk stratification of HCM in the young.

Short atrioventricular delay pacing therapy in young and old patients with hypertrophic obstructive cardiomyopathy: good long-term results and a low need for reinterventions.

Aims: Examination of long-term results following different treatments in hypertrophic obstructive cardiomyopathy (HOCM) in a complete geographical cohort. Methods and results: HOCM patients attending during 2002-13 in all 10 hospitals in the West Götaland Region, Sweden, were identified (n = 251), follow-up 14.4 (±8.9) years (mean ± SD), 121 managed medically, 42 treated with myectomy and 88 with short atrioventricular (AV) delay pacing as first interventional procedure. Post-intervention follow-up was 12.9 ± 8.7 years and 12.2 ± 5.0 years, respectively. Both intervention treatments improved New York Heart Association (NYHA) class and outflow gradients significantly. Patients treated with pacing were older (median age 64 vs. 43 years, P < 0.001). Freedom from disease-related death post-procedure at 5, 10, and 20 years were 93%, 80%, 56% vs. 93%, 93%, 57% in pacing and myectomy groups, respectively (log-rank P = 0.43). Survival after diagnosis was not different in patients just treated conservatively (P = 0.51 pacing/conservative; P = 0.39 myectomy/conservative). Reintervention for outflow gradients in patients ≥18 years at procedure occurred in 3.5% in pacing group and 15.6% in myectomy group (P = 0.007). Pacing therapy was equally effective in patients aged 13-64 years (n = 44), as in patients ≥65 years (n = 44): resting gradient pre-procedure and at last follow-up were median (IQR) 65 (71) and 12 (20) mmHg for <65 year-olds (P < 0.001), and 75 (64) and 14 (38) mmHg, respectively, for ≥65 year-olds (P < 0.001). New York Heart Association class improved significantly in both age ranges to 1.6 ± 0.6 and 1.8 ± 0.7, respectively (P < 0.001; P < 0.001). Conclusion: Short AV delay pacing provided lasting satisfactory relief of symptoms and outflow obstruction in the majority of patients, with low risk of requiring reintervention. Our findings support the view that pacing therapy should be considered a valid option to treat patients with HOCM.

Effects of lifestyle changes and high-dose ß-blocker therapy on exercise capacity in children, adolescents, and young adults with hypertrophic cardiomyopathy.

AIM: The use of ß-blocker therapy in asymptomatic patients with hypertrophic cardiomyopathy is controversial. This study evaluates the effect of lifestyle changes and high-dose ß-blocker therapy on their exercise capacity. METHODS AND RESULTS: A total of 29 consecutive newly diagnosed asymptomatic patients with familial hypertrophic cardiomyopathy, median age 15 years (range 7-25), were recruited. In all, 16 patients with risk factors for sudden death were treated with propranolol if no contraindications, or equivalent doses of metoprolol; 13 with no risk factors were randomised to metoprolol or no active treatment. Thus, there were three treatment groups, non-selective ß-blockade (n=10, propranolol 4.0-11.6 mg/kg/day), selective ß-blockade (n=9, metoprolol 2.7-5.9 mg/kg/day), and randomised controls (n=10). All were given recommendations for lifestyle modifications, and reduced energetic exercise significantly (p=0.002). Before study entry, and after 1 year, all underwent bicycle exercise tests with a ramp protocol. There were no differences in exercise capacity between the groups at entry, or follow-up, when median exercise capacity in the groups were virtually identical (2.4, 2.3, and 2.3 watt/kg and 55, 55, and 55 watt/(height in metre) 2 in control, selective, and non-selective groups, respectively. Maximum heart rate decreased in the selective (-29%, p=0.04) and non-selective (-24%, p=0.002) groups. No patient developed a pathological blood-pressure response to exercise because of ß-blocker therapy. Boys were more frequently risk-factor positive than girls (75% versus 33%, p=0.048) and had higher physical activity scores than girls at study-entry (p=0.011). CONCLUSIONS: Neither selective nor non-selective ß-blockade causes significant reductions in exercise capacity in patients with hypertrophic cardiomyopathy above that induced by lifestyle changes.

Differential diagnosis between left ventricular hypertrophy and cardiomyopathy in childhood.

The sensitivity and specificity of the electrocardiogram for the diagnosis of left ventricular hypertrophy of different etiologies are described. The sensitivity of the electrocardiogram for detecting left ventricular pressure overload is substantially lower (<35%) than the sensitivity for detecting evidence of a cardiomyopathy (55% to around 87%). Attention is drawn to the finding that in many differing etiologies of left ventricular hypertrophy ST-T-wave changes commonly referred to as "strain"-pattern are a harbinger of an increased risk of malignant cardiac arrhythmias and sudden death. In the most common pediatric cause of sudden death, hypertrophic cardiomyopathy, a described ECG risk score, which scores both voltage and repolarization abnormalities, is the most powerful predictor hitherto described for predicting the risk of sudden death in this diagnosis. A point score over 5 points gives a relative risk for sudden death of 24.3 with a sensitivity of 96% and a specificity of 78% in childhood.

Biomarkers and Proteomics in Sarcomeric Hypertrophic Cardiomyopathy in the Young-FGF-21 Highly Associated with Overt Disease.

Background: Any difference in biomarkers between genotype-positive individuals with overt hypertrophic cardiomyopathy (HCM), and genotype-positive but phenotype-negative individuals (G+P-) in HCM-associated pathways might shed light on pathophysiological mechanisms. We studied this in young HCM patients. Methods: 29 HCM patients, 17 G+P--individuals, and age- and sex-matched controls were prospectively included. We analyzed 184 cardiovascular disease-associated proteins by two proximity extension assays, categorized into biological pathways, and analyzed with multivariate logistic regression analysis. Significant proteins were dichotomized into groups above/below median concentration in control group. Results: Dichotomized values of significant proteins showed high odds ratio (OR) in overt HCMphenotype for Fibroblast growth factor-21 (FGF-21) 10 (p = 0.001), P-selectin glycoprotein ligand-1 (PSGL-1) OR 8.6 (p = 0.005), and Galectin-9 (Gal-9) OR 5.91 (p = 0.004). For G+P-, however, angiopoietin-1 receptor (TIE2) was notably raised, OR 65.5 (p = 0.004), whereas metalloproteinase inhibitor 4 (TIMP4) involved in proteolysis, in contrast, had reduced OR 0.06 (p = 0.013). Conclusions: This study is one of the first in young HCM patients and G+P- individuals. We found significantly increased OR for HCM in FGF-21 involved in RAS-MAPK pathway, associated with cardiomyocyte hypertrophy. Upregulation of FGF-21 indicates involvement of the RAS-MAPK pathway in HCM regardless of genetic background, which is a novel finding.

Hypertrophic cardiomyopathy: do sudden death prevention strategies in children differ between Europe and North America?

PURPOSE OF REVIEW: Hypertrophic cardiomyopathy (HCM) is the second most common childhood heart muscle disease and is the most common cause of unexpected sudden cardiac death in young people. The purpose of this review is to describe the risk of sudden death, to assess which of the criteria conventionally used as indication for a primary prevention defibrillator placement in adults are applicable in children with HCM, and to review differences in management between Europe and North America. RECENT FINDINGS: There is no uniform 'annual mortality rate' in childhood, and the risk of sudden death is at its highest level between 8 and 16 years. There are no significant differences between sudden death fatality rates in childhood HCM in Europe, North America and Australia when patients presenting with sudden death as the first sign of disease are excluded. The criteria for primary prevention defibrillator placement in adults with HCM are, with the exception of previous cardiac arrest and ventricular tachycardia on Holter monitoring, not predictive of risk in childhood HCM, and further research is required to establish better criteria for primary prevention in children. SUMMARY: Most children diagnosed with HCM have a favorable prognosis with life-style modification with additional medical therapy, surgical therapy, and/or defibrillator placement in selected patients. The challenges inherent in identification of the patients most likely to benefit from invasive therapies and avoidance of these therapies in those least likely to benefit (and most likely to experience harm) exist on both sides of the Atlantic.

Quality of life in asymptomatic children and adolescents before and after diagnosis of hypertrophic cardiomyopathy through family screening.

AIMS AND OBJECTIVES: The aim of this study was to measure quality of life (QoL) in asymptomatic children with hypertrophic cardiomyopathy (HCM) before and after diagnosis. BACKGROUND: Hypertrophic cardiomyopathy is a disease with a 50% risk of inheritance. Children at risk for serious complications can be diagnosed early with family screening, but before embarking on a screening programme, it is important to evaluate the psychosocial consequences of such screening. DESIGN: Prospective case-control study. METHODS: Quality of life was measured using a questionnaire by Lindström incorporating both objective and subjective aspects of the three spheres: external, interpersonal and personal, before and two years after diagnosis. The study group consisted of 13 children/adolescents (11 boys), median age 11 (5-18) years, with HCM diagnosed at family screening. All filled out a questionnaire before diagnosis and at follow-up. 41 healthy children/adolescents (22 boys), median age 11 (2-19) years with a first-degree relative diagnosed with HCM served as controls; 15/41 also completed follow-up data. RESULTS: The total QoL score for all spheres was similar in both groups at baseline and follow-up. In the interpersonal sphere, it was more common that children diagnosed with HCM had no siblings both at baseline (p = 0·002) and follow-up (p = 0·005). The family situation, social support and life events were unchanged from baseline to follow-up. Children with HCM had significantly more psychosomatic symptoms compared with controls at baseline (p < 0·05) but not at follow-up. Self-esteem, peer acceptance and satisfaction with school were unchanged and similar between groups. CONCLUSION: Family screening for HCM does not appear to negatively influence QoL. RELEVANCE TO CLINICAL PRACTICE: This study indicates that family screening of asymptomatic children and adolescents had no significant detrimental effects on QoL. This suggests that the benefits of finding symptomatic individuals at risk for serious complications outweigh concerns about screening asymptomatic individuals.

Screening for Critical Congenital Heart Defects in Sweden.

OBJECTIVES: Early diagnosis of critical congenital heart defects (CCHD) improves survival. We evaluated the relative contributions of prenatal ultrasound, neonatal pulse oximetry screening (POS), and neonatal physical examination (NPE) to the early detection (before discharge) of CCHD in the context of increasing prenatal detection, and POS being a national standard since 2013. METHODS: Retrospective, nationwide population-based study. All full-term live-born infants with CCHD in Sweden between 2014 and 2019 were included. CCHD was defined as a congenital heart defect requiring surgery or catheter-based intervention or resulting in death within 28 days of birth. RESULTS: Of 630 infants, 89% were diagnosed before discharge or death, 42% prenatally, 11% from early symptoms, 23% by POS, and 14% from NPE after a negative POS. Four (0.6%) died undiagnosed before discharge and 64/630 (10%) were discharged undiagnosed, with 24/64 being readmitted with circulatory failure and causing 1 preoperative death. Coarctation was the most prevalent CCHD (N = 184), 25% of whom were detected prenatally (12% by POS and 29% by NPE). Two died undiagnosed before discharge and 30% were discharged undiagnosed. Transposition was the second most common defect (N = 150) and 43% were detected prenatally (33% by POS, 1 by NPE) and 2 died undiagnosed before POS. None was discharged undiagnosed. CONCLUSIONS: POS and NPE remain important for the early detection of CCHD complementing prenatal ultrasound screening. Nevertheless, 1 in 10 with CCHD leaves the hospital without a diagnosis, with coarctation being the predominant lesion. Future research on CCHD screening should have a particular focus on this cardiac defect.

The experience of being diagnosed with hypertrophic cardiomyopathy through family screening in childhood and adolescence.

AIM: To describe the experiences of children and adolescents being screened positive for hypertrophic cardiomyopathy and how this impacts their daily life. BACKGROUND: Hypertrophic cardiomyopathy is a hereditary disease and the most common medical cause of sudden death in childhood and adolescence. This is the reason for recommending screening in children with an affected first-degree relative. A diagnosis of hypertrophic cardiomyopathy implies lifestyle modifications, restrictions that may bring profound changes to the daily life of the affected individual. DESIGN: This is a descriptive qualitative interview study. METHODS: We interviewed 13 asymptomatic children or adolescents diagnosed with hypertrophic cardiomyopathy through family screening 12-24 months after the diagnosis. Analysis was conducted with qualitative content analysis. RESULTS: Children described an involuntary change, which affected their daily life with limitations and restrictions in life, both in the individual and social context. Lifestyle recommendations had the most severe impact on daily life and affected their social context. They tried to navigate in a world with new references, and after reorientation they felt hope and had faith in the future. CONCLUSIONS: Children diagnosed with hypertrophic cardiomyopathy through family screening went through an involuntary change resulting in limitations and restrictions in life. This study indicates that there is a need for support and that healthcare professionals have to consider the specific needs in these families. Our findings thus give guidance in how best to improve support to the patients and their family. Diagnosis in asymptomatic children should be accompanied by ideally multi-professional follow-up, focusing not only on medical issues.

What Aspects of Phenotype Determine Risk for Sudden Cardiac Death in Pediatric Hypertrophic Cardiomyopathy?

Sudden cardiac death due to hypertrophic cardiomyopathy (HCM), is the most common autopsy-proven cause of unexpected medical death in children after infancy. This mode of death is preventable by implantation of an internal cardiac defibrillator (ICD), a procedure that has considerable morbidity in childhood patients, and even mortality. Since HCM is an inheritable disease (usually autosomal dominant, occasionally recessive), family screening may identify subjects at risk. This review summarizes published studies carried out to identify which phenotypic markers are important risk factors in childhood patients with HCM and reviews the performance of existing risk-stratification algorithms (HCM Risk-Kids, PRIMaCY) against those of single phenotypic markers. A significant proportion of HCM-patients diagnosed in childhood are associated with RASopathies such as Noonan syndrome, but a knowledge gap exists over risk stratification in this patient group. In conclusion, pediatric risk-stratification algorithms for sudden cardiac death perform better in children than adult HCM risk-stratification strategies. However, current multivariable algorithms overestimate risk substantially without having high sensitivity, and remain 'a work in progress'. To include additional phenotypic parameters that can be reproducibly measured such as ECG-markers, e.g., ECG risk score (which has high sensitivity and negative predictive value), tissue Doppler diastolic function measurements, and quantification of myocardial scarring on cardiac magnetic resonance imaging, has the potential to improve risk-stratification algorithms. Until that work has been achieved, these are three factors that the clinician can combine with the current algorithm-calculated per cent risk, in order better to assess risk.

Factors associated with excess female mortality in obstructive hypertrophic cardiomyopathy.

BACKGROUND: Several studies have reported excess female mortality in patients with hypertrophic cardiomyopathy, but the cause is unknown. AIMS: To compare risk-factors for disease-related death in both sexes in a geographical cohort of patients with obstructive hypertrophic cardiomyopathy (oHCM). METHODS AND RESULTS: Data-bases in all ten hospitals within West Götaland Region yielded 250 oHCM-patients (123 females, 127 males). Mean follow-up was 18.1 y. Risk-factors for disease-related death were evaluated by Cox-hazard regression and Kaplan-Meier survival-curves, with sex-comparisons of distribution of risk-factors and therapy in total and age-matched (n = 166) groups. At diagnosis females were older, median 62 y vs. 51 y, (P < 0.001), but not different in outflow-gradients and median NYHA-class. However, septal hypertrophy was more advanced: 10.6 [IQR = 3.2] vs. 9.6 [2.5] mm/m2 BSA; P = 0.002. Females had higher disease-related mortality than males (P = <0.001), with annual mortality 2.9% vs. 1.5% in age-matched groups (P = 0.010 log-rank). For each risk-category identified (NYHA-class ≥ III, outflow-gradient ≥50 mmHg), a higher proportion of females died (P = 0.0004; P = 0.001). Calcium-blocker therapy was a risk-factor (P = 0.005) and was used more frequently in females (P = 0.034). A beta-blocker dose above cohort-median reduced risk for disease-related death in both males (HR = 0.32; P = 0.0040) and in females (HR = 0.49; P = 0.020). Excess female deaths occurred in chronic heart-failure (P = 0.001) and acute myocardial infarctions (P = 0.015). Fewer females received beta-blocker therapy after diagnosis (64% vs. 78%, P = 0.018), in a smaller dose (P = 0.007), and less frequently combined with disopyramide (7% vs. 16%, P = 0.048). CONCLUSION: Addressing sex-disparities in the timing of diagnosis and pharmacological therapy has the potential to improve the care of females with oHCM.

Management of growth failure and other endocrine aspects in patients with Noonan syndrome across Europe: A sub-analysis of a European clinical practice survey.

AIM: To date, there is a lack of international guidelines regarding the management of the endocrine features of individuals with Noonan syndrome (NS). The aim was to develop a clinical practice survey to gather information on current treatment and management of these patients across Europe. MATERIALS AND METHODS: A group of 10 experts from three clinical specialities involved in the management of NS patients (clinical geneticists, paediatric endocrinologists, and paediatric cardiologists) developed a 60-question clinical practice survey. The questionnaire was implemented in Survey Monkey and sent to physicians from these three specialities via European/national societies. Contingency tables and the Chi-Squared test for independence were used to examine differences between specialities and countries. RESULTS: In total, responses of 364 specialists (paediatric endocrinologists, 40%; geneticists, 30%; paediatric cardiologists, 30%) from 20 European countries were analysed. While endocrinologists mostly referred to national growth charts for the general population, geneticists mostly referred to NS-specific growth charts. Approximately half of the endocrinologists perform growth hormone (GH) stimulation tests in short patients with low IGF1 levels. Two thirds of endocrinologists begin GH treatment for short patients in early childhood (4-6.9 years), and over half of them selected a threshold of -2 standard deviation score (SDS) according to national growth charts. The main concerns about GH treatment appear to be presence of hypertrophic cardiomyopathy (HCM) (59%), increased risk of malignancy (46%), and limited efficacy (31%). When asked if they consider HCM as a contraindication for GH treatment, one third of respondents skipped this question, and among those who replied, two thirds selected 'cannot answer', suggesting a high level of uncertainty. A total of 21 adverse cardiac responses to GH treatment were reported. Although most respondents had not encountered any malignancy during GH treatment, six malignancies were reported. Finally, about half of the endocrinologists expected a typical final height gain of 1-1.5 SDS with GH treatment. CONCLUSION: This survey describes for the first time the current clinical practice of endocrine aspects of NS across Europe and helps us to identify gaps in the management but also in the knowledge of this genetic disorder.

Management of cardiac aspects in children with Noonan syndrome - results from a European clinical practice survey among paediatric cardiologists.

BACKGROUND: The majority of children with Noonan syndrome (NS) or other diseases from the RASopathy spectrum suffer from congenital heart disease. This study aims to survey cardiac care of this patient cohort within Europe. METHODS: A cross-sectional exploratory survey assessing the treatment and management of patients with NS by paediatric endocrinologists, cardiologists and clinical geneticists was developed. This report details responses of 110 participating paediatric cardiologists from multiple countries. RESULTS: Most paediatric cardiologists responding to the questionnaire were associated with university hospitals, and most treated <10 patients/year with congenital heart disease associated with the NS spectrum. Molecular genetic testing for diagnosis confirmation was initiated by 81%. Half of the respondents reported that patients with NS and congenital heart disease typically present <1y of age, and that a large percentage of affected patients require interventions and pharmacotherapy early in life. A higher proportion of infant presentation and need for pharmacotherapy was reported by respondents from Germany and Sweden than from France and Spain (p = 0.031; p = 0.014; Fisher's exact test). Older age at first presentation was reported more from general hospitals and independent practices than from university hospitals (p = 0.031). The majority of NS patients were followed at specialist centres, but only 37% reported that their institution offered dedicated transition clinic to adult services. Very few NS patients with hypertrophic cardiomyopathy (HCM) were reported to carry implantable cardioverter defibrillators for sudden cardiac death prevention. Uncertainty was evident in regard to growth hormone treatment in patients with NS and co-existing HCM, where 13% considered it not a contra-indication, 24% stated they did not know, but 63% considered HCM either a possible (20%) or definite (15%) contraindication, or a cause for frequent monitoring (28%). Regarding adverse reactions for patients with NS on growth hormone therapy, 5/19 paediatric cardiology respondents reported a total of 12 adverse cardiac events. CONCLUSIONS: Congenital heart disease in patients with NS or other RASopathies is associated with significant morbidity during early life, and specialty centre care is appropriate. More research is needed regarding the use of growth hormone in patients with NS with congenital heart disease, and unmet medical needs have been identified.

European Medical Education Initiative on Noonan syndrome: A clinical practice survey assessing the diagnosis and clinical management of individuals with Noonan syndrome across Europe.

INTRODUCTION: Noonan syndrome (NS) is a rare genetic disorder caused by mutations in genes encoding components of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway. Patients with NS exhibit certain characteristic features, including cardiac defects, short stature, distinctive facial appearance, skeletal abnormalities, cognitive deficits, and predisposition to certain cancers. Here, a clinical practice survey was developed to learn more about differences in the diagnosis and management of this disease across Europe. The aim was to identify gaps in the knowledge and management of this rare disorder. MATERIALS AND METHODS: The European Medical Education Initiative on NS, which comprised a group of 10 experts, developed a 60-question clinical practice survey to gather information from European physicians on the diagnosis and clinical management of patients with diseases in the NS phenotypic spectrum. Physicians from three specialities (clinical genetics, paediatric endocrinology, paediatric cardiology) were invited to complete the survey by several national and European societies. Differences in answers provided by respondents between specialities and countries were analysed using contingency tables and the Chi-Squared test for independence. The Friedman's test was used for related samples. RESULTS: Data were analysed from 364 respondents from 20 European countries. Most respondents came from France (21%), Spain (18%), Germany (16%), Italy (15%), United Kingdom (8%) and the Czech Republic (6%). Respondents were distributed evenly across three specialities: clinical genetics (30%), paediatric endocrinology (40%) and paediatric cardiology (30%). Care practices were generally aligned across the countries participating in the survey. Delayed diagnosis did not emerge as a critical issue, but certain unmet needs were identified, including transition of young patients to adult medical services and awareness of family support groups. CONCLUSION: Data collected from this survey provide a comprehensive summary of the diagnosis and clinical management practices for patients with NS across different European countries.

Electrocardiographic amplitudes: a new risk factor for sudden death in hypertrophic cardiomyopathy.

AIMS: Assessment of ECG-features as predictors of sudden death in adults with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: ECG-amplitude sums were measured in 44 normals, 34 athletes, a hospital-cohort of 87 HCM-patients, and 29 HCM-patients with sudden death or cardiac arrest (HCM-CA). HCM-patients with sudden death or cardiac arrest had substantially higher ECG-amplitudes than the HCM-cohort for limb-lead and 12-lead QRS-amplitude sums, and amplitude-duration products (P = 0.00003-P = 0.000002). Separation of HCM-CA from the HCM-cohort is obtained by limb-lead QRS-amplitude sum >or=7.7 mV (odds ratio 18.8, sensitivity 87%, negative predictive value (NPV) 94%, P < 0.0001), 12-lead amplitude-duration product >or=2.2 mV s (odds ratio 31.0, sensitivity 92%, NPV 97%, P < 0.0001), and limb-lead amplitude-duration product >or=0.70 mV s (odds ratio 31.5, sensitivity 93%, NPV 96%, P < 0.0001). Sensitivity in HCM-patients <40 years is 90, 100, and 100% for those ECG-variables, respectively. Qualitative analysis showed correlation with cardiac arrest for pathological T-wave-inversion (P = 0.0003), ST-depression (P = 0.0010), and dominant S-wave in V(4) (P = 0.0048). A risk score is proposed; a score >or=6 gives a sensitivity of 85% but a higher positive predictive value than above measures. Optimal separation between HCM-CA <40 years and athletes is obtained by a risk score >or=6 (odds ratio 345, sensitivity 85%, specificity 100%, P < 0.0001). CONCLUSION: Twelve-lead ECG is a powerful instrument for risk-stratification in HCM.

Parents' experiences of having an asymptomatic child diagnosed with hypertrophic cardiomyopathy through family screening.

BACKGROUND: Hypertrophic cardiomyopathy is hereditary and the commonest medical cause of sudden death in childhood and adolescence, which is the reason for recommending screening in children with an affected parent. A diagnosis of hypertrophic cardiomyopathy implies lifestyle modifications, restrictions that may bring profound changes to the affected individual and impacts on the whole family. OBJECTIVE: To describe parents' experiences of how the diagnosis of hypertrophic cardiomyopathy in their child affects daily life. METHOD: Twelve parents with asymptomatic children diagnosed with hypertrophic cardiomyopathy through family screening were interviewed 12-24 months after the diagnosis. Analysis was conducted with qualitative content analysis. RESULTS: Parents described the immediate reaction of shock, grief, and injustice but were also grateful that the child was still asymptomatic. The diagnosis caused a significant change in lifestyle for most families due mainly to restrictions of sports activities. Parents had to adapt to the new life and develop strategies to protect their child. Death became a reality causing feelings of vulnerability. Regular medical check-ups and access to the liaison nurse were described as important factors of reassurance. CONCLUSIONS: Parents experienced early diagnosis as positive in a long-term perspective. The main changes perceived were ascribed to lifestyle modifications. Parents with athletic children experienced the lifestyle modifications as more severe. They strived to create a new life where they could feel secure and have faith in the future, and emphasised the need of regular follow-up and support from health care professionals as "mental pain relief", which helped them achieve a new state of normality.

Morbidity and resource usage after myectomy- or pacing-treatment in hypertrophic obstructive cardiomyopathy: A case-control study.

BACKGROUND: Treatment of left ventricular outflow-obstruction (LVOTO) in hypertrophic obstructive cardiomyopathy (HOCM) by short atrio-ventricular delay pacing has long-term hemodynamic results that are not inferior to myectomy, but publications comparing long-term morbidity following those treatments are lacking. METHODS: A search for HOCM-patients attending all ten hospitals in the West Götaland Region, Sweden, from 2002 through 2013, identified 251 patients (42 treated with myectomy, 88 with pacing and 121 conservatively). As the age at procedure was significantly lower in the myectomy-group compared to the pacing-group, morbidity was compared by case-control methodology, matching patients for age, maximal wall thickness and LVOT-gradient. We found 31 pairs who constituted the comparison-groups. Post-intervention median follow-up was 15.4 and 10.4 years in pacing- and myectomy-group, respectively. Post-procedural and long-term complications and re-interventions, length of stay, and cost of hospitalization were documented. RESULTS: Both treatments improved New York Heart Association class and LVOT-gradients significantly. There were fewer peri-procedural complications in the pacing-group compared to myectomy-group (3.2% and 35.5% p < 0.001). During follow-up pacemaker was implanted in 35.5% of myectomy-group for atrio-ventricular block, 9.7% peri-operatively, and 25.8% during late-follow-up. Furthermore, the pacing group had a superior freedom from all re-interventions, 90.3% versus 61.3% in myectomy-group (p = 0.003). Pacing patients had a shorter in-hospital stay (median 4 [IQR = 2] days) compared to myectomy 11 [7] days; P < 0.001). The mean cost of hospitalization was 74,000 ± 16,000 SEK for pacing and 310,000 ± 180,000 SEK for myectomy, p < 0.001. CONCLUSION: Pacing is a simple and reliable treatment for drug-refractory HOCM-patients with low rate of complications and costs.