Natural history and outcomes in paediatric RASopathy-associated hypertrophic cardiomyopathy.

AIMS: This study aimed to describe the natural history and predictors of all-cause mortality and sudden cardiac death (SCD)/equivalent events in children with a RASopathy syndrome and hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: This is a retrospective cohort study from 14 paediatric cardiology centres in the United Kingdom and Ireland. We included children <18 years with HCM and a clinical and/or genetic diagnosis of a RASopathy syndrome [Noonan syndrome (NS), NS with multiple lentigines (NSML), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFCS), and NS with loose anagen hair (NS-LAH)]. One hundred forty-nine patients were recruited [111 (74.5%) NS, 12 (8.05%) NSML, 6 (4.03%) CS, 6 (4.03%) CFCS, 11 (7.4%) Noonan-like syndrome, and 3 (2%) NS-LAH]. NSML patients had higher left ventricular outflow tract (LVOT) gradient values [60 (36-80) mmHg, P = 0.004]. Over a median follow-up of 197.5 [inter-quartile range (IQR) 93.58-370] months, 23 patients (15.43%) died at a median age of 24.1 (IQR 5.6-175.9) months. Survival was 96.45% [95% confidence interval (CI) 91.69-98.51], 90.42% (95% CI 84.04-94.33), and 84.12% (95% CI 75.42-89.94) at 1, 5, and 10 years, respectively, but this varied by RASopathy syndrome. RASopathy syndrome, symptoms at baseline, congestive cardiac failure (CCF), non-sustained ventricular tachycardia (NSVT), and maximal left ventricular wall thickness were identified as predictors of all-cause mortality on univariate analysis, and CCF, NSVT, and LVOT gradient were predictors for SCD or equivalent event. CONCLUSIONS: These findings highlight a distinct category of patients with Noonan-like syndrome with a milder HCM phenotype but significantly worse survival and identify potential predictors of adverse outcome in patients with RASopathy-related HCM.

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.

Sudden cardiac death in childhood RASopathy-associated hypertrophic cardiomyopathy: Validation of the HCM risk-kids model and predictors of events.

BACKGROUND: RASopathies account for nearly 20% of cases of childhood hypertrophic cardiomyopathy (HCM). Sudden cardiac death (SCD) occurs in patients with RASopathy-associated HCM, but the risk factors for SCD have not been systematically evaluated. AIM: To validate the HCM Risk-Kids SCD risk prediction model in children with RASopathy-associated HCM and investigate potential specific SCD predictors in this population. METHODS: Validation of HCM Risk-Kids was performed in a retrospective cohort of 169 patients with a RASopathy-associated HCM from 15 international paediatric cardiology centres. Multiple imputation by chained equations was used for missing values related to the HCM Risk-Kids parameters. RESULTS: Eleven patients (6.5%) experienced a SCD or equivalent event at a median age of 12.5 months (IQR 7.7-28.64). The calculated SCD/equivalent event incidence was 0.78 (95% CI 0.43-1.41) per 100 patient years. Six patients (54.54%) with an event were in the low-risk category according to the HCM Risk-Kids model. Harrell's C index was 0.60, with a sensitivity of 9.09%, specificity of 63.92%, positive predictive value of 1.72%, and negative predictive value of 91%; with a poor distinction between the different risk groups. Unexplained syncope (HR 42.17, 95% CI 10.49-169.56, p < 0.001) and non-sustained ventricular tachycardia (HR 5.48, 95% CI 1.58-19.03, p < 0.007) were predictors of SCD on univariate analysis. CONCLUSION: Unexplained syncope and the presence of NSVT emerge as predictors for SCD in children with RASopathy-associated HCM. The HCM Risk-Kids model may not be appropriate to use in this population, but larger multicentre collaborative studies are required to investigate this further.

Genetic Insights from Consanguineous Cardiomyopathy Families.

Inherited cardiomyopathies are a prevalent cause of heart failure and sudden cardiac death. Both hypertrophic (HCM) and dilated cardiomyopathy (DCM) are genetically heterogeneous and typically present with an autosomal dominant mode of transmission. Whole exome sequencing and autozygosity mapping was carried out in eight un-related probands from consanguineous Middle Eastern families presenting with HCM/DCM followed by bioinformatic and co-segregation analysis to predict the potential pathogenicity of candidate variants. We identified homozygous missense variants in TNNI3K, DSP, and RBCK1 linked with a dilated phenotype, in NRAP linked with a mixed phenotype of dilated/hypertrophic, and in KLHL24 linked with a mixed phenotype of dilated/hypertrophic and non-compaction features. Co-segregation analysis in family members confirmed autosomal recessive inheritance presenting in early childhood/early adulthood. Our findings add to the mutational spectrum of recessive cardiomyopathies, supporting inclusion of KLHL24, NRAP and RBCK1 as disease-causing genes. We also provide evidence for novel (recessive) modes of inheritance of a well-established gene TNNI3K and expand our knowledge of the clinical heterogeneity of cardiomyopathies. A greater understanding of the genetic causes of recessive cardiomyopathies has major implications for diagnosis and screening, particularly in underrepresented populations, such as those of the Middle East.

Disopyramide is a safe and effective treatment for children with obstructive hypertrophic cardiomyopathy.

BACKGROUND: Left ventricular outflow tract obstruction (LVOTO) is present in 1/3 of children with Hypertrophic Cardiomyopathy (HCM). Disopyramide improves symptoms associated with LVOTO and delays surgical intervention in adults, but it is not licensed in children. AIM: To describe a single-centre thirty-year experience of using disopyramide to treat LVOTO-related symptoms in a paediatric HCM cohort. METHODS: Clinical data were collected for all patients meeting diagnostic criteria for HCM (<18 years) at the time of initiation, 6 months after, and last follow-up or end of disopyramide treatment. It included demographics, clinical history, 12­lead electrocardiography, and echocardiography. Comparisons between baseline and 6 month follow up, and end of follow up respectively were performed. RESULTS: Fifty-one patients with HCM were started on disopyramide at a mean age 10.2±5.3 years. At 6 months, of those previously symptomatic, 33(86.8%) reported an improvement of symptoms and 12(31.6%) were asymptomatic. PR interval, corrected QT interval and maximal LVOT gradient had not significantly changed, but fewer participants were noted to have systolic anterior motion of the mitral valve 31 (72.1%) vs. 26 (57.80%). Patients were followed up for a median of 1.9 years (IQR 0.83-4.5). Nine patients (17.6%) reported side effects, and eleven patients (33.3%) with initial improvement in symptoms reported a return or worsening of symptoms requiring a change in medication (n = 4, 12.1%) or left ventricular septal myomectomy (n = 7, 21.2%) during follow up. CONCLUSION: Disopyramide is a safe and effective treatment for LVOTO-related symptoms in childhood obstructive HCM. Any delay in the need for invasive intervention, particularly during childhood, is of clear clinical benefit.

Clinical Features and Natural History of Preadolescent Nonsyndromic Hypertrophic Cardiomyopathy.

BACKGROUND: Up to one-half of childhood sarcomeric hypertrophic cardiomyopathy (HCM) presents before the age of 12 years, but this patient group has not been systematically characterized. OBJECTIVES: The aim of this study was to describe the clinical presentation and natural history of patients presenting with nonsyndromic HCM before the age of 12 years. METHODS: Data from the International Paediatric Hypertrophic Cardiomyopathy Consortium on 639 children diagnosed with HCM younger than 12 years were collected and compared with those from 568 children diagnosed between 12 and 16 years. RESULTS: At baseline, 339 patients (53.6%) had family histories of HCM, 132 (20.9%) had heart failure symptoms, and 250 (39.2%) were prescribed cardiac medications. The median maximal left ventricular wall thickness z-score was 8.7 (IQR: 5.3-14.4), and 145 patients (27.2%) had left ventricular outflow tract obstruction. Over a median follow-up period of 5.6 years (IQR: 2.3-10.0 years), 42 patients (6.6%) died, 21 (3.3%) underwent cardiac transplantation, and 69 (10.8%) had life-threatening arrhythmic events. Compared with those presenting after 12 years, a higher proportion of younger patients underwent myectomy (10.5% vs 7.2%; P = 0.045), but fewer received primary prevention implantable cardioverter-defibrillators (18.9% vs 30.1%; P = 0.041). The incidence of mortality or life-threatening arrhythmic events did not differ, but events occurred at a younger age. CONCLUSIONS: Early-onset childhood HCM is associated with a comparable symptom burden and cardiac phenotype as in patients presenting later in childhood. Long-term outcomes including mortality did not differ by age of presentation, but patients presenting at younger than 12 years experienced adverse events at younger ages.

Pregnancy in a Patient With Tetralogy of Fallot and Borderline Pulmonary Arterial Hypertension.

Management of pregnancy in patients with complex congenital heart disease and pulmonary arterial hypertension has always been a challenge. We are presenting a patient with complex congenital heart disease and borderline pulmonary arterial hypertension who complicated with pulmonary embolism during pregnancy. (Level of Difficulty: Beginner.).

Association between fractional flow reserve, instantaneous wave-free ratio and dobutamine stress echocardiography in patients with stable coronary artery disease.

AIMS: The association between fractional flow reserve (FFR) and dobutamine stress echocardiography (DSE) in real-world stable angina patients is scant and controversial whereas no such comparison exists with instantaneous wave-free ratio (iFR). The current retrospective study aimed to investigate the associations among these modalities in patients with stable coronary artery disease (CAD) and intermediate coronary lesions. METHODS AND RESULTS: We studied 62 consecutive stable angina patients who underwent DSE and subsequently coronary angiography with FFR (in all 62) and iFR (in 46/62 patients) assessment of intermediate single-vessel lesions between 2014 and 2015. Using receiver operating characteristic (ROC) curves we sought to identify the optimal FFR and iFR cut-off points with the highest discriminative power to predict the DSE result. The kappa coefficient was used to assess the agreement between FFR, iFR and DSE. The mean age of the study cohort was 63.5±12 years and 35 (56.5%) were males. Thirteen (21%) lesions were adjudicated as causing reversible ischaemia on DSE. Using ROC (FFR predicting DSE result), the area under the curve was 0.952 (95% CI: 0.902 to 1), whereas for iFR it was 0.743 (95% CI: 0.560 to 0.927), pAUC comparison=0.03. The optimal FFR cut-off point predicting positive DSE was 0.80. There was strong agreement between DSE and FFR (kappa 0.682, p<0.001). There was only modest agreement between iFR and DSE (kappa 0.258, p=0.068) using a cut-off value of 0.9. CONCLUSIONS: In patients referred for evaluation of stable CAD, there was good agreement between DSE and FFR (87%) but less so with iFR (71.7%).

Clinical and laboratory evaluation of new immigrant and refugee children arriving in Greece.

BACKGROUND: Migrant children are a population at risk for various health problems. Despite the increased inflow of migrants in Greece, data regarding their health assessment are lacking. This study aims to describe the clinical and certain laboratory characteristics and identify possible associations in a group of new immigrant (I) and refugee (R) children, arriving in Athens, Greece. METHODS: A prospective, cross- sectional study was performed in a migrant outpatient clinic of a tertiary Children's hospital. All immigrant and refugee children, examined to obtain a health certificate, within 3 months of their arrival in the country, were enrolled. Clinical and laboratory information was collected in a pre- designed form. We applied multiple logistic regression models to investigate the association between the child's status (immigrant vs refugee) and health indicators controlling for possible confounding effects, mainly of age and area of origin. RESULTS: From 2010 to 2013, a total of 300 children (I/R:138/162) with a mean age of 7.08 (range 1-14) years were included. Overall, 79.3% presented unknown vaccination status, 21.3% dental and 7.3% additional clinical problems. Latent tuberculosis was identified in 2.7%, while anemia, low serum ferritin and eosinophilia were found in 13.7%, 17.3%, and 22.7% of subjects, respectively. 57.7% had protective antibodies to hepatitis B surface antigen (anti-HBs ≥ 10 IU/L) and 30.6% elevated blood lead levels (EBLLs). Immigrants had less likely unknown immunization (OR = 0.25, p < 0.001), but had increased odds of low ferritin (OR = 1.97, p = 0.043), EBLLs (OR = 2.97, p = 0.001) and protective anti-HBs (OR = 1.79, p = 0.03). Age was inversely associated with anemia (OR = 0.0.89, p = 0.017), low ferritin (OR = 0.91, p = 0.027), EBLLs (OR = 0.86, p = 0.001) or positive anti-HBs (OR = 0.92, p = 0.025). Children from Europe or Africa presented decreased probability of EBLLs (OR = 0.31, p = 0.001, and OR = 0.15, p = 0.005, respectively) compared to those from Asia. CONCLUSIONS: New immigrant and refugee children presented distinct clinical problems and certain laboratory abnormalities. Some of these health issues differed according to their migration status, age and geographic area of origin. These findings provide evidence that may assist the optimal approach of this vulnerable population.