Hypertrophic Cardiomyopathy In Children Research Articles

Genetic variations in PTPN11 lead to a recurrent Left Ventricular Outflow Tract Obstruction phenotype in childhood hypertrophic cardiomyopathy

ObjectiveLeft ventricular septal myotomy provides a favorable prognosis for children with hypertrophic obstructive cardiomyopathy (HOCM). However, some children still suffer from recurrent left ventricular outflow tract obstruction (LVOTO) after surgery. Poor prognosis exists for HOCM caused by PTPN11 mutation. Therefore, the aim of this study was to determine the clinical features of recurrent obstruction in children with HOCM caused by pathogenic mutations in the PTPN11 gene. MethodsA total of 56 children were diagnosed with HOCM underwent septal myectomies. Whole exome sequencing of 49 pediatric cardiomyopathies associated genes (including PTPN11) were performed. We performed hematoxylin-eosin(H&E), Masson, and wheat germ agglutinin (WGA)staining of tissues positive for PTPN11 and those negative for PTPN11 were conducted. ResultsWhole exome sequencing results showed 11 PTPN11 mutation (19.6%) children. In long-term follow-up (median 37 months, maximum 9 years), children with PTPN11 mutation had 6(54.5%) recurrent LVOTO compared with other groups (P=.015), but similar survival rates(P=.514). The mean postoperative time to recurrent obstruction was 22±27 months. Children with PTPN11 mutation were 9-fold more likely to experience the risk associated with recurrent obstruction (95% CI = 1.77-45.81, P<.001). H&E, Masson and WGA staining also revealed more cardiomyocyte hypertrophy in PTPN11 mutation tissues. See Figure 4 for a graphical abstract of the study. ConclusionChildren with PTPN11 mutation-associated hypertrophic cardiomyopathy have a higher risk of recurrent LVOTO.

Mitochondrial cardiomyopathy: a puzzle for the final diagnosis.

Hypertrophic cardiomyopathy in children has diverse causes. Mitochondrial diseases, a rare aetiology leading to cardiomyopathy in 20-40% of affected children, predominantly present as hypertrophic cardiomyopathy. Diagnosis is challenging due to inconsistent genotype-phenotype correlation, resulting in various clinical presentations. We present a case of a one-month-old infant with severe hypertrophic cardiomyopathy and cardiac tamponade. Genetic diagnosis revealed a Valyl-tRNA synthetase 2 (VARS2) gene mutation, linking it to mitochondrial encephalopathy-cardiomyopathy. This case highlights novel variants and expands the understanding of hypertrophic cardiomyopathy aetiology in infants.

Evaluation of new predictive scores for sudden cardiac death in childhood hypertrophic cardiomyopathy in a French cohort

BackgroundHypertrophic cardiomyopathy (HCM) is rare in children, and sudden cardiac death (SCD) is difficult to predict. Two prognostic scores – HCM Risk-Kids and Precision Medicine for Cardiomyopathy (PRIMaCY) – were developed to assess the risk of SCD in the next 5 years in children with HCM. AimsTo test the ability of these scores to predict SCD in children with HCM. Also, to identify factors associated with a severe cardiac rhythmic event (SCRE) (ventricular fibrillation, sustained ventricular tachycardia, heart transplant for rhythmic reasons or SCD). MethodsRetrospective, multicentre, observational study at 10 medical centres in the Nord-Pas-de-Calais region, France. ResultsThis study included 72 paediatric patients with HCM during 2009–2019 who were followed for a median (interquartile range [IQR]) of 8.5 (5.0–16.2) years. Eleven patients (15.3%) presented with SCRE. HCM Risk-Kids was high, with a median (IQR) score of 6.2% (2.1–12.8%; significant threshold≥6.0%) and the PRIMaCY median (IQR) score was 7.1% (2.6–15.0%; significant threshold≥8.3%). The positive predictive value was only 27.1% (95% confidence interval [CI] 21.5–32.5%) for HCM Risk-Kids (with a threshold of≥6.0%) and 33.2% (95% CI 27.1–38.9%) for the PRIMaCY score (with a threshold of≥8.3%). The negative predictive values were 95.4% (95% CI 92.3–97.7%) and 93.0% (95% CI 89.8–96.2%), respectively. Three of 28 patients with an implantable cardioverter defibrillator (ICD) experienced complications (including inappropriate shocks). ConclusionHCM Risk-Kids and the PRIMaCY score have low positive predictive values to predict SCD in paediatric patients. If used alone, they could increase the rate of ICD implantation and thus ICD complications. Therefore, the scores should be used in combination with other data (genetic and magnetic resonance imaging results).

Cardiac MRI in diagnosis, prognosis, and follow-up of hypertrophic cardiomyopathy in children: current perspectives.

Hypertrophic Cardiomyopathy (HCM) is an inherited myocardial disease characterised by left ventricular hypertrophy, which carries an increased risk of life-threatening arrhythmias and sudden cardiac death. The age of presentation and the underlying aetiology have a significant impact on the prognosis and quality of life of children with HCM, as childhood-onset HCM is associated with high mortality risk and poor long-term outcomes. Accurate cardiac assessment and identification of the HCM phenotype are therefore crucial to determine the diagnosis, prognostic stratification, and follow-up. Cardiac magnetic resonance (CMR) is a comprehensive evaluation tool capable of providing information on cardiac morphology and function, flow, perfusion, and tissue characterisation. CMR allows to detect subtle abnormalities in the myocardial composition and characterise the heterogeneous phenotypic expression of HCM. In particular, the detection of the degree and extent of myocardial fibrosis, using late-gadolinium enhanced sequences or parametric mapping, is unique for CMR and is of additional value in the clinical assessment and prognostic stratification of paediatric HCM patients. Additionally, childhood HCM can be progressive over time. The rate, timing, and degree of disease progression vary from one patient to the other, so close cardiac monitoring and serial follow-up throughout the life of the diagnosed patients is of paramount importance. In this review, an update of the use of CMR in childhood HCM is provided, focussing on its clinical role in diagnosis, prognosis, and serial follow-up.

Indications and management of implantable cardioverter-defibrillator therapy in childhood hypertrophic cardiomyopathy: A position statement from the AEPC Working Group on Basic Science, Genetics and Myocardial Disease and the AEPC Working Group on Cardiac Dysrhythmias and Electrophysiology - ERRATUM.

Indications and management of implantable cardioverter-defibrillator therapy in childhood hypertrophic cardiomyopathy: A position statement from the AEPC Working Group on Basic Science, Genetics and Myocardial Disease and the AEPC Working Group on Cardiac Dysrhythmias and Electrophysiology - ERRATUM.

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

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. 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. 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

BackgroundRASopathies 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. AimTo validate the HCM Risk-Kids SCD risk prediction model in children with RASopathy-associated HCM and investigate potential specific SCD predictors in this population. MethodsValidation 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. ResultsEleven 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. ConclusionUnexplained 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.

Historical and modern aspects of surgical treatment of hypertrophic cardiomyopathy in children (literature review)

Hypertrophic cardiomyopathy (HCM) is a common, genetically determined myocardial pathology that can manifest itself at any age. The manifestation of this pathology in childhood always means a high risk of sudden cardiac death and the rapid progression of symptoms. The annual mortality in asymptomatic patients over 1 year is 1%. There are many recommendations for the management of patients with obstructive cardiomyopathy, but they are all written for the adult population. Drug treatment of symptomatic patients with this pathology is effective only in 70% of patients. The remaining 30% should be given preference to surgical treatment. It is important for a cardiac surgeon to know the main methods of HCM correction, their advantages and disadvantages. The literature review shows the evolution of methods of surgical correction of obstructive HCM from the middle of the 20th century until now. The main surgical methods for treating left ventricular outflow tract obstruction, correcting SAM-syndrome (systolic anterior motion syndrome) and mitral insufficiency, which have had a great influence on the development of HCM surgery, are presented. A clinical experience of treating left ventricular outflow tract obstruction in children is presented. The most promising method today is “transaortic extended septal myectomy”. Thus, there is a need to evaluate and modify existing methods for correcting obstructive HCM and their complications. Works aimed at their improvement and elimination of shortcomings are promising.

Childhood Hypertrophic Cardiomyopathy Caused by Beta-Myosin Heavy Chain Variants Is Associated With a More Obstructive but Less Arrhythmogenic Phenotype Than Myosin-Binding Protein C Disease.

Childhood Hypertrophic Cardiomyopathy Caused by Beta-Myosin Heavy Chain Variants Is Associated With a More Obstructive but Less Arrhythmogenic Phenotype Than Myosin-Binding Protein C Disease.

PO-03-125 VENTRICULAR PREEXCITATION AND PEDIATRIC HYPERTROPHIC CARDIOMYOPATHY: ETIOLOGY AND ACCESSORY PATHWAY CHARACTERISTICS

The etiology of pediatric hypertrophic cardiomyopathy (HCM) is varied. Ventricular preexcitation (VPe) is well recognized, yet little is known regarding the specific etiology, and accessory pathways (AP) characteristics. Define the etiology of HCM in patients with VPe and the characteristics of the responsible APs. Retrospective cohort study of patients <21 years of age with HCM/VPe from 2000-22. The etiology was defined as sarcomeric/non-sarcomeric (isolated HCM), storage disorder, metabolic disease, or genetic syndrome. AP were designated as atrioventricular (AV) or fasciculoventricular fibers (FVF) using standard invasive EP study criteria when available. AV APs were defined as high risk if any of the following were <250 ms: shortest preexcited RR interval in AF, shortest paced preexcited cycle length, or APERP. ECG characteristics were compared in patients with VPe exclusively secondary to an FVF to those with anteroseptal AP-mediated VPe. From a total of 345 patients with HCM, 28 (8%) had VPe and proportion with VPe varied significantly between etiologic groups: isolated HCM 10/220 (5%), storage 8/17 (47%), metabolic 5/19 (26%), genetic syndrome 5/89 (6%), p < 0.001. Six (21%) had clinical AF (1 with SPPRI <250 ms, 4 with storage disease). Invasive EP study was performed in 22, identifying 39 APs (23 AV AP, 16 FVF; fig 1). VPe resulted exclusively from an FVF in 8 (36%) patients. Multiple AV APs were seen in 8 (36%) and AV AP plus FVF in 10 (45%). Five (23%) patients had AV APs with high-risk conduction properties (≥1 in each etiologic group). Ablation was acutely successful in 13/14 patients with recurrence in 3. The only complication was a single case of heart block after ablation of a high-risk midseptal AP. Patients with storage disease had larger QRS amplitudes (median 42.3 v. 23.0 mm, p < 0.01). The delta wave amplitude did not discriminate between anteroseptal AP and FVF (median 4.3 v. 4.1 mm, p = 0.92). VPe and high risk or multiple AP may be associated with any etiology of childhood HCM. This is most common in storage disorders associated with high QRS amplitudes and clinical AF, with important implications for prognosis and management.

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.

Recent research on childhood hypertrophic cardiomyopathy caused by MYH7 gene mutations

Hypertrophic cardiomyopathy (HCM) is the most common monogenic inherited myocardial disease in children, and mutations in sarcomere genes (such as MYH7 and MYBPC3) are the most common genetic etiology of HCM, among which mutations in the MYH7 gene are the most common and account for 30%-50%. MYH7 gene mutations have the characteristics of being affected by environmental factors, coexisting with multiple genetic variations, and age-dependent penetrance, which leads to different or overlapping clinical phenotypes in children, including various cardiomyopathies and skeletal myopathies. At present, the pathogenesis, course, and prognosis of HCM caused by MYH7 gene mutations in children remain unclear. This article summarizes the possible pathogenesis, clinical phenotype, and treatment of HCM caused by MYH7 gene mutations, in order to facilitate the accurate prognostic evaluation and individualized management and treatment of the children with this disorder.

Sudden cardiac death in childhood hypertrophic cardiomyopathy

The most prevalent cause of mortality in children with hypertrophic cardiomyopathy (HCM) is sudden cardiac death (SCD), which happens more frequently than in adult patients. Risk stratification tactics have generally been drawn from adult practice, however emerging data has revealed significant disparities between children and adult cohorts, implying the need for pediatric-specific risk stratification methodologies. We conducted an all-language literature search on Medline, Cochrane, Embase, and Google Scholar until October 2021. The following search strings and Medical Subject Heading (MeSH) terms were used: "HCM," "SCD," "Sudden Cardiac Death," and "Childhood Onset HCM." We explored the literature on the risk of SCD in HCM for its epidemiology, pathophysiology, the role of various genes and their influence, associated complications leading to SCD and preventive and treatment modalities. Childhood-onset HCM is linked to significant life-long morbidity and mortality, including a higher SCD rate in children than in adults. The present focus is on symptom relief and avoiding illness-related consequences, but the prospect of future disease-modifying medicines offers an intriguing opportunity to alter disease expression and outcomes in these young individuals. Current preventive recommendations promote implantable cardioverter defibrillator placement based on cumulative risk factor thresholds, although they have been demonstrated to have weak discriminating capacity. This article addresses questions and discusses the etiology, risk factors, and method to risk stratification for SCD in children with HCM.

Conflicting results on the role of ECG in risk-stratification for sudden cardiac death in childhood hypertrophic cardiomyopathy.

The research group at University College London introduced the concept of standardizing the quantification of risk by assessing risk of sudden death or equivalent malignant arrhythmia event occurring during the subsequent 5 years of follow-up after diagnosis. While the aims in the recent article by Norrish et al.1 published in this journal are laudable, it is imperative to highlight the methodological shortcomings underlying their analysis. The authors aim to assess the ability of the electrocardiogram (ECG) risk-score and other aspects of the 12-lead ECG to predict ‘major arrhythmic cardiac event’. They selected a subset (356/1029) of the multi-centre cohort of paediatric patients with hypertrophic cardiomyopathy (HCM) used to construct the HCM Risk-Kids algorithm, where ECGs had been archived. This subset however consisted mainly of recently recruited patients, and so median follow-up was only 3.9 years (interquartile range Q1–Q3 2.0–7.7).1 A major concern is that Norrish et al. did not restrict their analysis to include only those survivors who had reached 5 years of follow-up (n = 77 + 68 = 145), and the patients who had a ‘major arrhythmic cardiac event’ within 5 years of follow-up (n = 17). Instead they compared all patients without events, even if 25% of them had <2 years follow-up, with all patients who had major arrhythmic cardiac event, even if 8 of them had an event later than 5 years of follow-up. Thus, in fact, only 17 (patients with major arrhythmic cardiac event within 5 years) + 145 (patients with ≥5 years follow-up without event) = 162 of the patients are actually statistically informative about the end-point of major arrhythmic cardiac event within 5 years.1 This constitutes only 46% of the total ECG group analysed. The other 194 actually confuse the results as patients with high-risk ECG features and short follow-up might have had a major arrhythmic cardiac event later on within the 5-year span. Similarly, the ECGs of patients with major arrhythmic cardiac event after >5 years of follow-up might have evolved more ECG changes closer to the event as shown in other studies.2 Thus including these late major arrhythmic cardiac events will underestimate the sensitivity of the method.

Myocardial Tissue Characterization in Danon Disease.

HomeRadiologyVol. 307, No. 2 PreviousNext Reviews and CommentaryFree AccessImages in RadiologyMyocardial Tissue Characterization in Danon DiseaseFei Chen, Mao Chen Fei Chen, Mao Chen Author AffiliationsFrom the Department of Cardiology, Laboratory of Heart Valve Disease, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu 610041, PR China.Address correspondence to M.C. (email: [email protected]).Fei ChenMao Chen Published Online:Jan 17 2023https://doi.org/10.1148/radiol.222333MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In A 14-year-old boy was referred for cardiac MRI, which showed mild left ventricular (LV) wall thickening to 13 mm (Figure, A). No edema signal or late gadolinium enhancement (LGE) was observed (Figure, A, B). Native myocardial T1 was elevated (1331 msec; reference, 1114–1290 msec), but extracellular volume (ECV) fraction (25%) and myocardial T2 (38 msec) were normal (Figure, C–E). LV hypertrophy associated with storage disorders was suspected.Baseline and follow-up cardiac MRI scans in a young boy with Danon disease. (A–E) Cardiac MRI scans at age 14 years show (A) mild left ventricular (LV) hypertrophy (maximum thickness, 13 mm; LV mass index, 93 g/m2) with no edema, (B) late gadolinium enhancement (LGE), (C) abnormal global native T1 value of 1331 msec (reference, 1114–1290 msec), (D) normal global extracellular volume (ECV) fraction of 25% (reference, 21%–33%), and (E) normal global T2 value of 38 msec (reference, 33–44 msec). (F–J) Cardiac MRI scans at age 19 years show (F) extreme LV hypertrophy (maximum thickness, 43 mm; LV mass index, 476 g/m2) with extensive midwall-dominant edema, (G) LGE, and (H-J) increased global tissue characterization metrics ([H] native T1 value [1478 msec], [I] extracellular volume fraction [44%], and [J] T2 value [51 msec]). CE-bSSFP = contrast-enhanced balanced steady-state free precession.Download as PowerPointOpen in Image Viewer At age 19 years, a repeated cardiac MRI showed a marked increase in LV wall thickness to 43 mm (Figure, F). LGE manifested in a nonischemic pattern of midwall-dominant involvement, sparing the basal septum, and with a base-to-apex increasing tendency (Figure, G). Myocardial T1 had increased (1478 msec) since the last examination, as had ECV fraction (44%) (Figure, H, I). T2 imaging showed myocardium edema signals and increased myocardial T2 (51 msec) (Figure, F, J).Genetic testing was indicated and identified a pathogenic mutation in the lysosome-associated membrane protein 2 (LAMP2) gene (c.190_191delGT), suggesting the diagnosis of Danon disease (1). Danon disease, or LAMP2 deficiency (glycogen type 2b storage disease), predominantly affects cardiac and skeletal muscles and also includes neurologic manifestations. It may be underrecognized as a cause of hypertrophic cardiomyopathy in childhood and early adulthood (2,3). Cardiac MRI could reveal cardiomyocyte injury, edema, and fibrosis in the progression of Danon disease, as well as isolated intracellular autophagic vacuoles accumulation during the early stage.Disclosures of conflicts of interest: F.C. No relevant relationships. M.C. No relevant relationships.

Abstract 11615: The Prevalence and Association of Exercise Test Abnormalities With Sudden Cardiac Death and Transplant-Free Survival in Childhood Hypertrophic Cardiomyopathy

Introduction: Hypertrophic cardiomyopathy (HCM) can be associated with an abnormal exercise response. In adults with HCM, an abnormal exercise stress test (EST) is predictive of heart failure outcomes. Our goal was to determine if an abnormal exercise response is associated with adverse outcomes in pediatric HCM patients. Methods: : In an international cohort study with 20 centers (PRIMaCY), children &lt;18 years with primary HCM were included. Abnormal EST was defined as an abnormal heart rate or blood pressure response, arrhythmias and/or ischemic ECG changes on exercise. Sudden cardiac death (SCD) events were defined as a composite of SCD and aborted SCD including appropriate implantable cardioverter defibrillator discharges. Using Kaplan-Meier survival analyses, we analyzed the association of abnormal EST with SCD and transplant-free survival. Results: Of 724 eligible patients, 604 underwent at least one EST on follow-up. There were no differences in clinical characteristics between those with or without an EST. The median age at EST was 13.8yrs (IQR 11.0-15.7yrs), 76% were male, 55% were on beta-blockers. 299 (49.5%) had an abnormal EST. Patients with an abnormal EST had more severe septal hypertrophy, higher left atrial diameter z-scores, higher resting LV outflow gradient at first evaluation, and a higher proportion were genotype-positive (p&lt;0.05) compared to those with a normal EST. An abnormal EST was associated with lower 5-year transplant-free survival (99% vs. 95%, p=0.0082) and lower 5-year freedom from SCD events (96% vs. 92%, p=0.025) (Figure 1). Conclusions: Exercise abnormalities are common in childhood HCM. An abnormal EST in children with HCM was associated with lower transplant-free survival and more SCD events. Further analysis will determine if the inclusion of EST results can increase the predictive accuracy of current pediatric SCD risk prediction models.

The Prevalence and Association of Exercise Test Abnormalities With Sudden Cardiac Death and Transplant-Free Survival in Childhood Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) can be associated with an abnormal exercise response. In adults with HCM, abnormal results on exercise stress testing are predictive of heart failure outcomes. Our goal was to determine whether an abnormal exercise response is associated with adverse outcomes in pediatric patients with HCM. In an international cohort study including 20 centers, phenotype-positive patients with primary HCM who were <18 years of age at diagnosis were included. Abnormal exercise response was defined as a blunted blood pressure response and new or worsened ST- or T-wave segment changes or complex ventricular ectopy. Sudden cardiac death (SCD) events were defined as a composite of SCD and aborted sudden cardiac arrest. Using Kaplan-Meier survival, competing outcomes, and Cox regression analyses, we analyzed the association of abnormal exercise test results with transplant and SCD event-free survival. Of 724 eligible patients, 630 underwent at least 1 exercise test. There were no major differences in clinical characteristics between those with or without an exercise test. The median age at exercise testing was 13.8 years (interquartile range, 4.7 years); 78% were male and 39% were receiving beta-blockers. A total of 175 (28%) had abnormal test results. Patients with abnormal test results had more severe septal hypertrophy, higher left atrial diameter z scores, higher resting left ventricular outflow tract gradient, and higher frequency of myectomy compared with participants with normal test results (P<0.05). Compared with normal test results, abnormal test results were independently associated with lower 5-year transplant-free survival (97% versus 88%, respectively; P=0.005). Patients with exercise-induced ischemia were most likely to experience all-cause death or transplant (hazard ratio, 4.86 [95% CI, 1.69-13.99]), followed by those with an abnormal blood pressure response (hazard ratio, 3.19 [95% CI, 1.32-7.71]). Exercise-induced ischemia was also independently associated with lower SCD event-free survival (hazard ratio, 3.32 [95% CI, 1.27-8.70]). Exercise-induced ectopy was not associated with survival. Exercise abnormalities are common in childhood HCM. An abnormal exercise test result was independently associated with lower transplant-free survival, especially in those with an ischemic or abnormal blood pressure response with exercise. Exercise-induced ischemia was also independently associated with SCD events. These findings argue for routine exercise testing in childhood HCM as part of ongoing risk assessment.

Prognostic factors in hypertrophic cardiomyopathy in children: An MRI based study

BackgroundClinical and prognostic role of cardiac magnetic resonance (CMR) in adult population with hypertrophic cardiomyopathy (HCM) have been largely assessed.We sought to investigate the role of CMR for predicting cardiovascular events in children with HCM. MethodsCMR was performed in 116 patients with HCM (37 sarcomeric mutations, 31 other mutations, mean age 10.4 ± 4.3 yrs). CMR protocol included cine imaging for evaluation of morphology and function and late gadolinium enhancement (LGE). Hard cardiac events (sustained VT, resuscitated cardiac arrest, sudden cardiac death, end-stage heart failure, heart transplant and appropriate ICD intervention) were recorded through a median follow-up of 4 (1–7) years. ResultsDuring follow-up 21 heart cardiac events occurred. At maximal-rank statistic the optimal cut-point for LGE extent for predicting events was ≥2%. Syncope, non-sustained ventricular tachycardia (NSVT) and LGE extent ≥2% were independent predictors of events. At Harrel's C statistic combination of LGE extent ≥2% and syncope was the strongest model for predicting events. HR of patients with LGE extent ≥2% and no history of syncope was 3.6 (1.1–12.2) that increased to 37.6 (5.4–161) in those with LGE extent ≥2% and syncope. The median time dependent AUC of LGE extent (0.88, 95% CI 0.86–0.89) was significantly higher than that of syncope (0.63, 95% CI 0.61–0.66, p < 0.0001) and NSVT (0.52, 95% CI 0.50–0.53, p < 0.0001). ConclusionsIn children with HCM, LGE and syncope were independent predictors of hard cardiac events at follow-up.

Surgical treatment of obstructive hypertrophic cardiomyopathy in children with Noonan syndrome

About 80-90% of patients with Noonan syndrome have changes in the cardiovascular system, 30% of which include cardiomyopathy, hypertrophic phenotype in particular. The treatment of cardiomyopathy patients with Noonan syndrome is carried out according to the clinical recommendations for the treatment of chronic heart failure (CHF) and cardiomyopathy. Surgical treatment of progressive nature of heart failure with left ventricular outflow tract obstruction and mitral regurgitation can be one of the possible methods. The review presents our experience with septal myectomy (SM) in children suffered from hypertrophic obstructive cardiomyopathy with Noonan syndrome. Objective. To assess the efficiency of septal myectomy in children suffered from hypertrophic obstructive cardiomyopathy with Noonan syndrome. Materials and methods. Clinical examination (family history, patient examination), lab tests (NT-proBNP level), echocardiography, electrocardiography, Holter monitoring, Chest X-rays and molecular genetic methods using mass parallel sequencing (NGS) and direct automatic Sanger sequencing. The indications for the SM were determined according to the clinical guidelines for the diagnostic and treatment of hypertrophic cardiomyopathy. Results. 7 patients out of 48 with Noonan syndrome underwent SM and 1 with Noonan syndrome with multiple lentigo (LEOPARD). Two of them required the removal of obstruction of the outflow tracts of both ventricles, followed by plastic removal of the right ventricle and pulmonary artery valve. Related surgical interventions included aortic (n = 1) and mitral valves (n = 2), permanent pacemaker (n = 1) in the early postoperative period. After a year, all children recorded a decline of NT-proBNP from the average of 16,198 to 3,865 pg/ml, a significant improvement in health, disappearance of shortness of breath, increased physical activity tolerance, improved physical (weight, growth) and speech development. When assessing the dynamics of the Echo parameters 1 year after the SM, normalization of the size of both atria in 4 cases, reduction of severity of isolated dilation of the left atrium in 2 cases was noted. No cases of repeated obstruction have been reported. Conclusion. Hypertrophic cardiomyopathy (HCM) can be in structure of hereditary syndromes such as Noonan syndrome. Septal myectomy (SM) can now be used in the case of progressive nature of heart failure with left ventricular outflow tract obstruction in children with Noonan syndrome.

Clinical Features and Natural History of Preadolescent Nonsyndromic Hypertrophic Cardiomyopathy

BackgroundUp 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. ObjectivesThe 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. MethodsData 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. ResultsAt 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. ConclusionsEarly-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.