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.

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.

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.

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.