Pediatric Hypertrophic Cardiomyopathy Research Articles

Myosin inhibitor reverses hypertrophic cardiomyopathy in genotypically diverse pediatric iPSC-cardiomyocytes to mirror variant correction

Pathogenic variants in MYH7 and MYBPC3 account for the majority of hypertrophic cardiomyopathy (HCM). Targeted drugs like myosin ATPase inhibitors have not been evaluated in children. We generate patient and variant-corrected iPSC-cardiomyocytes (CMs) from pediatric HCM patients harboring single variants in MYH7 (V606M; R453C), MYBPC3 (G148R) or digenic variants (MYBPC3 P955fs, TNNI3 A157V). We also generate CMs harboring MYBPC3 mono- and biallelic variants using CRISPR editing of a healthy control. Compared with isogenic and healthy controls, variant-positive CMs show sarcomere disorganization, higher contractility, calcium transients, and ATPase activity. However, only MYH7 and biallelic MYBPC3 variant-positive CMs show stronger myosin-actin binding. Targeted myosin ATPase inhibitors show complete rescue of the phenotype in variant-positive CMs and in cardiac Biowires to mirror isogenic controls. The response is superior to verapamil or metoprolol. Myosin inhibitors can be effective in genotypically diverse HCM highlighting the need for myosin inhibitor drug trials in pediatric HCM.

Pediatric hypertrophic cardiomyopathy caused by a novel TNNI3 variant

TNNI3 is a gene that causes hypertrophic cardiomyopathy (HCM). A 14-year-old girl who was diagnosed with nonobstructive HCM presented with cardiopulmonary arrest due to ventricular fibrillation. Genetic testing revealed a novel de novo heterozygous missense variant in TNNI3, NM_000363.5:c.583A>T (p.Ile195Phe), which was determined to be the pathogenic variant. The patient exhibited progressive myocardial fibrosis, left ventricular remodeling, and life-threatening arrhythmias. Genetic testing within families is useful for risk stratification in pediatric HCM patients.

Prevalence and clinical significance of late gadolinium enhancement in children and adolescents with hypertrophic cardiomyopathy: a systematic review and meta-analysis.

Hypertrophic cardiomyopathy is the leading cause of sudden cardiac death among the paediatric population. The aim of this study is to investigate the prevalence and clinical significance of late gadolinium enhancement, as assessed by cardiac MRI, in paediatric hypertrophic cardiomyopathy. A systematic literature search was conducted in PubMed, SCOPUS, and Ovid SP to identify relevant studies. Pooled estimates with a 95% confidence interval were calculated using the random-effects generic inverse variance model. Statistical analysis was performed using Review Manager v5.4 and R programming. Seventeen studies were included in this meta-analysis, encompassing a total of 778 patients. Late gadolinium enhancement was highly prevalent in paediatric hypertrophic cardiomyopathy, with a pooled prevalence of 51% (95% confidence interval, 40-62%). The estimated extent of focal fibrosis expressed as a percentage of left ventricular mass was 4.70% (95% confidence interval, 2.11-7.30%). The presence of late gadolinium enhancement was associated with an increased risk of adverse cardiac events (pooled odds ratio 3.49, 95% confidence interval 1.10-11.09). The left ventricular mass index of late gadolinium enhancement-positive group was higher than the negative group, with a standardised mean difference of 0.91 (95% confidence interval, 0.42-1.41). This meta-analysis demonstrates that prevalence of late gadolinium enhancement in paediatric hypertrophic cardiomyopathy is similar to that in the adult population. The presence and extent of late gadolinium enhancement are independent predictors of adverse cardiac events, underscoring their prognostic significance among the paediatric population.

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.

Contemporary review on pediatric hypertrophic cardiomyopathy: insights into detection and management.

Hypertrophic cardiomyopathy is the most common genetic cardiac disorder and is defined by the presence of left ventricular (LV) hypertrophy in the absence of a condition capable of producing such a magnitude of hypertrophy. Over the past decade, guidelines on the screening, diagnostic, and management protocols of pediatric primary (i.e., sarcomeric) HCM have undergone significant revisions. Important revisions include changes to the appropriate screening age, the role of cardiac MRI (CMR) in HCM diagnosis, and the introduction of individualized pediatric SCD risk assessment models like HCM Risk-kids and PRIMaCY. This review explores open uncertainties in pediatric HCM that merit further attention, such as the divergent American and European recommendations on CMR use in HCM screening and diagnosis, the need for incorporating key genetic and imaging parameters into HCM-Risk Kids and PRIMaCY, the best method of quantifying myocardial fibrosis and its prognostic utility in SCD prediction for pediatric HCM, devising appropriate genotype- and phenotype-based exercise recommendations, and use of heart failure medications that can reverse cardiac remodeling in pediatric HCM.

Risk stratification in pediatric hypertrophic cardiomyopathy

Risk stratification in pediatric hypertrophic cardiomyopathy

Modeling the Relationship Between Diastolic Phenotype and Outcomes in Pediatric Hypertrophic Cardiomyopathy

Pediatric hypertrophic cardiomyopathy (HCM) is associated with adverse events. The contribution of diastolic dysfunction to adverse events is poorly understood. The aim of this study was to explore the association between diastolic phenotype and outcomes in pediatric patients with HCM. Children <18years of age with diagnosed with HCM were included. Diastolic function parameters were measured from the first echocardiogram at the time of diagnosis, including Doppler flow velocities, tissue Doppler velocities, and left atrial volume and function. Using principal-component analysis, key features in echocardiographic parameters were identified. The principal components were regressed to freedom from major adverse cardiac events (MACE), defined as implantable cardioverter-defibrillator insertion, myectomy, aborted sudden cardiac death, transplantation, need for mechanical circulatory support, and death. Variables that estimate left ventricular filling pressures were highly collinear and associated with MACE (hazard ratio, 0.86; 95% CI, 0.75-1.00), though this was no longer significant after controlling for left ventricular thickness and genetic variation. Left atrial size parameters adjusted for body surface area were independently associated with outcomes in the covariate-adjusted model (hazard ratio, 0.69; 95% CI, 0.5-0.94). The covariate-adjusted model had an Akaike information criterion of 213, an adjusted R2 value of 0.78, and a concordance index of 0.82 for association with MACE. Echocardiographic parameters of diastolic dysfunction were associated with MACE in this population study, in combination with the severity of left ventricular hypertrophy and genetic variation. Left atrial size parameters adjusted for body surface area were independently associated with adverse events. Additional study of diastolic function parameters adjusted for patient size could facilitate the prediction of adverse events in pediatric patients with HCM.

Effect of beta-blockers and exercise restriction on the prevention of sudden cardiac death in pediatric hypertrophic cardiomyopathy

BackgroundRisk assessment tools and effective prevention strategies for sudden cardiac death (SCD) in pediatric patients with hypertrophic cardiomyopathy (HCM) have not been established. This study aimed to evaluate the efficacy of beta-blockers and exercise restriction for SCD prevention in this population. MethodsWe retrospectively reviewed the medical records of patients aged <18 years who were diagnosed with HCM at our center between January 1996 and December 2021. SCD and aborted SCD were defined as SCD equivalents. We divided patients based on whether they were prescribed beta-blockers or exercise restriction and compared the outcomes among the groups. The primary outcome was the overall survival (OS), and the secondary outcome was the cumulative SCD equivalent rate. Outcomes were analyzed using Kaplan–Meier curves and Cox proportional hazard analysis. We also compared patients according to the occurrence of SCD equivalents to identify SCD risk predictors. ResultsAmong the 43 included patients [mean age, 7.7 (1.6–12.1) years; 23 male individuals], SCD equivalents occurred in 13 patients over 11.2 (4.5–15.6) years of follow-up, among whom 12 were resuscitated and 1 died. The OS rate was significantly higher in the beta-blocker and exercise restriction groups than in the non-beta-blocker and non-exercise restriction groups (81.3 % vs. 19.1 %, p < 0.01 and 57.4 % vs. 12.7 %, p < 0.01, respectively). Among the 13 patients with SCD equivalents, 5 had 9 recurrent SCD equivalents. A significant difference was observed between the SCD equivalent and non-SCD equivalent groups in the history of suspected arrhythmogenic syncope (p < 0.01) in the univariable but not in the multivariable analysis. ConclusionsBeta-blockers and exercise restriction may decrease the risk of SCD in pediatric patients with HCM and should be considered for SCD prevention in this population, particularly because predicting SCD in these patients remains challenging.

Abstract 17362: Left Atrial Stiffness is Increased in Pediatric Hypertrophic Cardiomyopathy and May Be of Incremental Value in Predicting Major Adverse Cardiac Events in This Group

Background: Determining risk factors by echocardiography to prevent major adverse cardiac events (MACE) is crucial in pediatric patients with hypertrophic cardiomyopathy (HCM). Recent studies have shown that LA stiffness and strain may serve as surrogate markers in children, to differentiate elevated pulmonary capillary wedge pressure from normal and predict COVID-19 related myocardial injury. Hypothesis: LA stiffness may predict MACE in pediatric patients with HCM. Methods: We retrospectively enrolled 201 pediatric patients with HCM diagnosed by echocardiography. They were divided into two groups: MACE (n=61) and non-MACE (n=140) groups. LV systolic function, and LA strain were evaluated by conventional 2D and speckle tracking echocardiography. Noninvasive LA stiffness was calculated as the ratio of E/e’ to LA strain as depicted in the following equation: LA Stiffness= E/e ' ratio / LA Peak Strain (% -1 ). The primary outcome was a composite endpoint of MACE (including ICD placement, myomectomy, heart transplant or death) during follow-up. Results: The MACE group showed significantly decreased LV global longitudinal strain (GLS) compared to non-MACE group (GLS - 16.76 ± 5.05% vs. - 20.25 ± 3.40%, p &lt; 0.001), even though LV ejection fraction showed no significant difference between the two groups. LA peak strain was significantly reduced (21.96 ± 7.24% vs. 30.80 ± 7.10%, p &lt; 0.001), whereas, noninvasive LA stiffness was significantly increased (0.72 ± 0.48 % -1 vs. 0.34 ± 0.16 % -1 , p &lt; 0.001) in the MACE group. Among the LV diastolic indices, LA stiffness was the superior-most index for predicting MACE (see Table 1, Figure 1) (AUC: 0.814, cut off value: 0.49% -1 ). Also, LA stiffness was independently associated with increased risk of the composite endpoint of MACE (HR: 3.26 [95% CI: 1.77 -5.99]; P &lt; 0.001, see Table 2). Conclusion: LA stiffness is a newly described index in children, that may be of incremental value in predicting risk of MACE in pediatric HCM patients.

Patterns of Electrocardiographic Abnormalities in Children with Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM), a common cardiomyopathy in children, is an important cause of morbidity and mortality. Early recognition and appropriate management are important. An electrocardiogram (ECG) is often used as a screening tool in children to detect heart disease. The ECG patterns in children with HCM are not well described.ECGs collected from an international cohort of children, and adolescents (≤ 21years) with HCM were reviewed. 482 ECGs met inclusion criteria. Age ranged from 1day to 21years, median 13years. Of the 482 ECGs, 57 (12%) were normal. The most common abnormalities noted were left ventricular hypertrophy (LVH) in 108/482 (22%) and biventricular hypertrophy (BVH) in 116/482 (24%) Of the patients with LVH/BVH (n = 224), 135 (60%) also had a strain pattern (LVH in 83, BVH in 52). Isolated strain pattern (in the absence of criteria for hypertrophy) was seen in 43/482 (9%). Isolated pathologic Q waves were seen in 71/482 (15%). Pediatric HCM, 88% have an abnormal ECG. The most common ECG abnormalities were LVH or BVH with or without strain. Strain pattern without hypertrophy and a pathologic Q wave were present in a significant proportion (24%) of patients. Thus, a significant number of children with HCM have ECG abnormalities that are not typical for "hypertrophy". The presence of the ECG abnormalities described above in a child should prompt further examination with an echocardiogram to rule out HCM.

Clinical profile and outcomes of pediatric hypertrophic cardiomyopathy in a South Indian tertiary care cardiac center: a three decade experience

IntroductionAlthough much research has been done on adult hypertrophic cardiomyopathy, data on pediatric hypertrophic cardiomyopathy is still limited.Methods and resultsThe study enrolled all patients with cardiomyopathy who presented to us between 1990 to 2020 and were younger than 18 yrs. During the thirty-year study period, we identified 233 cases of pediatric cardiomyopathy. Sixty-three cases (27%) had hypertrophic cardiomyopathy. Out of the 63 HCM cases, 12% presented in the neonatal period and 37% presented in the first year of life. The median age of presentation was 7 yrs (Range 0.1–18 yrs). Sixteen patients had proven syndromic, metabolic, or genetic disease (25%). LV outflow obstruction was present in 30 patients (47%). Noonan syndrome was present in 9 of the 63 patients (14%). Dyspnea on exertion was the most common mode of presentation. Cardiac MRI was done in 28 patients, out of which 17 had late gadolinium enhancement (LGE). Mid myocardial enhancement was the most common pattern. Four patients had LGE of more than 15%. Over a mean follow-up period of 5.6 years (0.1–30 years), twenty-one were lost to follow-up (33%). Among the patients whose outcome was known, eleven died (26%), and thirty-one (73%) were alive. The 5-year survival rate of HCM patients was 82%, and the 10-year survival rate was 78%. Seven died of sudden cardiac death, three from heart failure, and one from ventricular arrhythmias. Sustained ventricular arrhythmias were seen in three patients and atrial arrhythmias in two. First-degree AV block was seen in 10 patients (15%) and bundle branch blocks (BBB) in five (8%). Eight patients required ICD or transplant (12.7%). Two patients underwent ICD for primary prevention, and one underwent PPI for distal AV conduction disease. Among the various clinical, echocardiographic, and radiological risk factors studied, only consanguinity showed a trend towards higher events of death or ventricular arrhythmias (P-value 0.08).ConclusionMore than one-third of our HCM cohort presented in infancy. LV outflow tract obstruction is common (47%). Mid myocardial enhancement was the most common pattern of late gadolinium enhancement. SCD was the most common cause of death. The outcome in our HCM cohort is good and similar to other population cohorts. Only Consanguinity showed a trend towards higher events of death or ventricular arrhythmias.

LV and LA mechanics in pediatric HCM : a CMR study of phenotype-genotype correlation

Abstract Funding Acknowledgements Type of funding sources: None. Background Paediatric hypertrophic cardiomyopathy (HCM) is a leading cause of sudden death. The relationship between the genotype variation and phenotype expression has not been fully elucidated, with some studies showing association with an increased hypertrophy and MYH7 or multiple genetic variations. In HCM fibrosis and hypertrophy contribute to left ventricular (LV) mechanics’ alteration resulting in subendocardial dysfunction. The latter is associated with a decreased global longitudinal and radial strains (GLS, GRS), whereas epicardial thickening leads to preserved global circumferential strain (GCS) and LV twist. Children with HCM have reduced LA function, measurable by both volumetric and strain analysis and reduced LA mechanics are associated with poor exercise capacity. Feature tracking –cardiac magnetic resonance (FT-CMR) has enhanced the non-invasive assessment of myocardial deformation in HCM. The main aim of our study was to assess differences of LV and LA mechanics features on CMR between patients harbouring multiple pathogenic or likely pathogenic variants (MGv, n=16) or single genetic variations (SGv, n=35). Methods Our retrospective CMR study included 51 patients (1.7–18.8 years ago). CMR data were: LV and LA’s morphological values, late gadolinium enhancement (LGE) of LA and LV walls, LV feature tracking (FT) derived strain and LV twist (LVT). LV twist was calculated as the difference between basal and apical rotation. The LA feature FT derived strain, LA conduit function, reservoir function and pump function were computed. Results In MGv group, the indexed LV mass 108.8 +/-53.0 vs 74.3+/- 22.2 in SGv (p = 0.03). LGE was present in 51% patients of the whole cohort, with LGE in 64 % of MGv group. LV FT derived strain values and LA function were not statistically significant different between groups (MGv vs SGv: GLS −15.8+/−5.3 vs −18.7+/−4.8, GCS −27.8+/8 vs −31.1+/−8.6, GRS 44.7+/−24.6 vs 62.3+/−32). LVT was reduced in MGv group (0.04+/−7.6) vs (7.4+/−7.4) in SGv (p = 0.003). LA contractile function did not differ between the groups (MGv vs SGv: GLS LA 25.1+/−14.2 vs 27.6+/−13.5). LA reservoir, conduction and pump function did not differ between the groups. LVT was significantly correlated with the LA contractile function. An increased of LVT was associated with an increased LA GLS and EF (p = 0.011; p = 0.004). Conclusions Patients with multiple genetic variants have a greater LV mass and altered LV mechanics with reduced LV twist. This study gives insights in phenotype- genotype correlation in paediatric HCM and warrants larger longitudinal studies to assess its clinical significance.

LV and LA mechanics in pediatric HCM: A CMR study of phenotype-genotype correlation

The relationship between the genotype variation and phenotype expression in paediatric hypertrophic cardiomyopathy (HCM) has not been fully elucidated. In HCM, fibrosis and hypertrophy contribute to left ventricular (LV) mechanics with a decreased global longitudinal and radial strains (GLS, GRS). The epicardial thickening leads to preserved global circumferential strain (GCS) and LV twist. Feature tracking – cardiac magnetic resonance (FT-CMR) has enhanced the non-invasive assessment of myocardial deformation in HCM. The aim of our study was to assess differences of LV and LA mechanics features on CMR between patients harbouring multiple pathogenic or likely pathogenic variants (MGv, n = 16) or single genetic variations (SGv, n = 35). Our retrospective CMR study included 51 patients (1.7–18.8 years ago). CMR data were: LV and LA's morphological values, late gadolinium enhancement (LGE) of LA and LV walls, LV feature tracking (FT) derived strain and LV twist (LVT). LV twist was calculated as the difference between basal and apical rotation. The LA feature FT derived strain and function's parameters were computed. In MGv group, the indexed LV mass 108.8–53.0 vs. 74.3 ± 22.2 in SGv (P = 0.03). LGE was present in 51% patients of the whole cohort, with LGE in 64% of MGv group. LV FT derived strain values were not statistically significant different between groups (MGv vs. SGv: GLS −15.8 ± 5.3 vs. −18.7 ± 4.8, GCS −27.8 ± 8 vs. −31.1 ± 8.6, GRS 44.7 ± 24.6 vs. 62.3 ± 32). LVT was reduced in MGv group (0.04 ± 7.6) vs. (7.4 ± 7.4) in SGv (P = 0.003). LA contractile function did not differ between the groups. Patients with multiple genetic variants have a greater LV mass and altered LV mechanics with reduced LV twist. This study gives insights in phenotype-genotype correlation in paediatric HCM and warrants larger longitudinal studies to assess its clinical significance (Fig. 1).

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.

Septal Myectomy Outcomes in Children and Adolescents With Obstructive Hypertrophic Cardiomyopathy

BackgroundLittle data exist regarding characteristics and outcomes of pediatric patients undergoing septal myectomy. We evaluated this in a large referral population. MethodsSeptal myectomy was performed in 199 consecutive patients aged ≤18 years with obstructive hypertrophic cardiomyopathy from January 1, 1976, to June 30, 2021. ResultsMedian age was 13 years (interquartile range [IQR], 8-15 years). Left ventricular myectomy approaches included transaortic (163 of 198 [82%]), transapical (16 of 198 [8%]), and combined (19 of 198 [10%]). Right ventricular interventions included myectomy (13 of 199 [7%]) and patch reconstruction of the outflow tract (15 of 199 [8%]). Maximum left ventricular outflow tract gradients decreased after myectomy (prebypass: 50 mm Hg [IQR, 31-73 mm Hg] vs postbypass: 4 mm Hg [IQR, 0-9 mm Hg], P < .001), and this was sustained long-term (5 mm Hg [IQR, 5-10 mm Hg] at 10 years). Iatrogenic aortic and mitral valve injuries occurred in 13 of 199 (7%) and 1 of 199 (1%), respectively; however, all were successfully repaired. Operative mortality was 2 of 199 (1%). The cumulative incidence of redo myectomy was low, at 5.8% at 5 and 8.3% at 10 years. Redo myectomy patients had higher maximum left ventricular outflow tract gradients on echocardiography at predischarge and 1 year and were younger at the index operation (8 years [IQR, 2.5-10 years] vs 13 years [IQR, 9-16 years], P < .001). Overall survival at 10 years was 90%, relative to 47% in a previously reported pediatric nonoperative cohort. ConclusionsPediatric septal myectomy provides safe, effective, and durable relief of ventricular outflow tract obstruction. Iatrogenic valve injury remains a low but nonnegligible risk. Recurrent obstruction requiring redo myectomy is infrequent and can be identified early. Long-term survival in this pediatric septal myectomy cohort appears to fare better than pediatric hypertrophic cardiomyopathy cohorts managed nonoperatively.

Rare Case of Pediatric Hypertrophic Obstructive Cardiomyopathy (HOCM) in A 6-year-old Boy: How to Recognize, Assess, and Manage the Risk?

Highlights: It discusses pediatric HCM which is usually caused by autosomal dominant traits caused by mutation in cardiac sarcomere protein genes. It explains how to recognize the cardiac risk Abstract: Hypertrophic Obstructive Cardiomyopathy (HOCM) is a disease characterized by increased left ventricular (LV) wall thickness and accompanied by obstructive physiology measured by increased LV outflow tract gradient. It is mainly inherited in autosomal dominant traits caused by a mutation in cardiac sarcomere protein genes. In pediatrics, HOCM is rare and comprises a different diagnosis and management approach compared to adults. The risk of sudden cardiac death (SCD) is also higher in the pediatric population. Case Summary. This report is about a case of HOCM found incidentally in a 6-year-old boy and a discussion based on the latest literature review. The patient first came for evaluation for cardiac murmur and abnormality in ECG and chest x-ray. Diagnosis of HOCM was made through echocardiography assessment. Discussion. ICD implantation for primary prevention of SCD was considered based on individualized 5-year SCD risk assessment which is around 7%. Optimal pharmacological therapy with beta-blocker, careful planning of ICD implantation with balanced benefit and risk, and septal reduction surgery when indicated should extend the life expectancy and quality of life of pediatric HOCM. It is both essential and interesting to recognize pediatric HOCM diagnostic findings and to pursue further research about therapies of this rare disease.

The Prevalence of Pathologic Q Waves on Electrocardiograms of Pediatric Patients with Confirmed Hypertrophic Cardiomyopathy: A Systematic Review of the Literature

Objectives The electrocardiogram (ECG) of patients with hypertrophic cardiomyopathy (HCM) ranges from normal to exhibiting evidence of ventricular hypertrophy, including pathologic Q waves and ST-T wave changes. Deep Q waves in the inferior and lateral leads are one of the classic ECG findings associated with HCM. The prevalence or frequency of this finding in pediatric HCM patients, however, is not well-established. Furthermore, other pediatric health conditions have also been associated with pathologic and non-pathologic Q waves and an awareness of those conditions is important to consider when Q waves are observed. The primary goal of this systematic review of the literature is to describe the prevalence of pathologic Q waves in the ECGs of pediatric patients with echocardiogram proven HCM. A secondary goal is to review other pediatric conditions that can present with pathologic and non-pathologic Q waves. Methods The databases PubMed, Web of Science, Scopus and cumulative index to nursing and allied health literature (CINAHL) were searched utilizing the preferred reporting items for systematic reviews and meta-analyses (PRISMA) format. The Rayyan systemic review software was used to screen articles for final review. The initial search (Search 1) consisted of the following terms: “dagger Q wave”, “dagger-like Q waves”, “dagger shape Q waves”. Subsequently, a broader search (Search 2) was conducted to determine if viable articles were omitted in the first search. This broader search strategy eliminated the term “HCM”. The authors then performed detailed review of the articles these two searches yielded, as well as a review of the references of these articles to find other relevant articles as well as produce a list of other pediatric conditions that may be associated with pathologic or nonpathologic Q waves. Results Of the articles found via the three searches, a total of nine English language articles that specifically addressed the prevalence of pathological Q waves in pediatric HCM patients were ultimately included in our systematic review. These nine articles described a total of 845 pediatric patients with HCM. Of these, 258 (30.5%) demonstrated pathological Q waves on their electrocardiograms. The range of percentages reported for pathological Q waves was 12.5 to 66.7%. Additionally, our review found fifteen different pediatric conditions reported to be associated with pathologic or non-pathologic Q waves. Conclusion Our systematic review confirmed that pathologic Q waves are a common and early electrocardiographic finding in children with HCM and may, in fact, be the only ECG finding. In addition, our review provided an extensive list of other pediatric diseases and conditions associated with pathologic or non-pathologic Q waves on the electrocardiogram.

Abstract 12104: Pediatric Hypertrophic Cardiomyopathy With Left Ventricular Systolic Dysfunction: Insights From the Sarcomeric Human Cardiomyopathy Registry (SHaRe)

Introduction: Left ventricular systolic dysfunction (LVSD, LV ejection fraction (LVEF) &lt;50), occurs in ~8% of adults with hypertrophic cardiomyopathy (HCM) and is associated with poor prognosis. However, the incidence and prognosis of LVSD in pediatric patients with HCM (&lt;18 years old) is poorly understood. Methods: Patients in SHaRe with pediatric HCM were included. Time-to-event analyses were performed to estimate 1) cumulative incidence of LVSD in pediatric vs adult HCM (Kaplan Meier), 2) predictors of incident LVSD in pediatric HCM (Cox-proportional hazards) and 3) a composite outcome of all-cause mortality, heart transplant and left ventricular assist device implant in pediatric HCM. Results: In total, 1296 pediatric HCM patients (34% females, median 12.2 years at diagnosis, median 8.3 years follow-up) were included. LVSD occurred in 155 (12%) of patients with 29% (n=45) having LVSD at the first SHaRe visit and 22% (n=34) developing LVSD &lt;18 years old. At 5-year follow-up, the cumulative incidence of LVSD was 9% [8-11%]. Predictors of incident pediatric LVSD included HCM before age 12 (HR 2.0 [1.3-3.0]), female sex (HR 0.49 [0.32-0.77]), P/LP variants in thick filament genes (HR 2.6 [1.1-4.2], multiple P/LP variants (HR 9.1 [CI 2.9-29.1]) and baseline LVEF (HR 0.63 [0.58-0.68], per 5 %-points increase). Pediatric HCM was associated with higher rate of LVSD compared to adult-onset HCM (n=6428, median HCM at age 49 years, median follow-up of 7.1 years), p=0.05 (Figure 1). The composite endpoint occurred in 41% (n= 63/155) of children with HCM and subsequent LVSD. In patients with LVSD, female sex (HR 2.44 [1.41-4.17]) and baseline LVEF &lt;35% (HR 4.0 [2.4-6.9]) were independently associated with the composite outcome. Conclusion: Females were less likely to develop LVSD but more likely to have adverse outcomes once they do. Clinical outcomes are adverse, and greater recognition of and surveillance for LVSD in pediatric HCM are warranted.

Abstract 11055: Outcomes and Progression of Rasopathy-Associated Hypertrophic Cardiomyopathy

Background: RASopathy associated hypertrophic cardiomyopathy (HCM) is a frequent cause of pediatric onset HCM. RAS pathway inhibitors are a precision therapeutic option for RASopathy associated HCM. However, limited understanding of HCM progression and correlation with clinical outcomes currently restrict use to a compassionate basis, primarily in infancy. We hypothesize review of RASopathy associated HCM progression and outcomes will demonstrate burden of disease throughout childhood with the goal to identify high risk populations who may benefit from targeted therapies. Methods: A single-center retrospective review identified 59 patients with a diagnosis of HCM and a RASopathy. Echocardiographic, clinical, and molecular data were collected through chart review with echocardiographic measurements at set time points from neonate to young adult. Results: There was high overall mortality in our cohort (20.3%, n = 12). Cardiac arrest, transplant, or death was significantly higher in patients with heart failure in infancy (defined by need for diuretic use) (p&lt;0.001) (Fig 1A). There were no differences by syndrome or genotype. Pulmonary valve (PV) intervention was 16.9% (n = 10) and largely limited to infancy with median age 0.79 years (IQR 0.34-1.63) at first intervention. Incidence of atrial arrhythmias was 13.6% (n = 8) with median age of onset 0.44 years (IQR 0.35-0.88). Rates of septal myectomy were high (23.7%, n = 14). Myectomies, however, were not limited to infancy with median age at first myectomy 3.10 years (IQR 1.09-10.49) (Fig 1B). 21.4% (n = 3) required repeat myectomy. Conclusions: In contrast to previous research, our data suggest there is significant continued HCM growth outside of infancy as evidenced by high incidence of myectomy throughout childhood and young adulthood with frequent need for repeat myectomy. These suggest potential use of targeted therapies outside of infancy with further study needed to identify high-risk populations.

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.