Childhood-onset hypertrophic cardiomyopathy caused by thin-filament sarcomeric variants.

Up to 20% of children with sarcomeric hypertrophic cardiomyopathy (HCM) have disease-causing variants in genes coding for thin-filament proteins. However, data on genotype-phenotype correlations for thin-filament disease are limited. This study describes the natural history and outcomes of children with thin-filament-associated HCM and compares it to thick-filament-associated disease.Longitudinal data were collected from 40 children under 18 years with a disease-causing variant in a thin-filament protein from a single quaternary referral centre. Twenty-one (female n=6, 35.5%) were diagnosed with HCM at a median age of 13.0 years (IQR 8.3-14.0). Over a median follow-up of 5.0 years (IQR 4.0-8.5), three (14.3%) experienced one or more major adverse cardiac events (MACE) (two patients had an out-of-hospital arrest and eight appropriate implantable cardiac defibrillator (ICD) therapies in three patients). One gene carrier died suddenly at age 9 years. Compared with those with thick-filament disease, children with thin-filament variants more commonly experienced non-sustained ventricular tachycardia [NSVT; n=6 (28.6%) vs n=14 (10.8%), p=0.024] or underwent ICD insertion (thin, n=13 (61.9%) vs thick, n=50 (38.5%), p=0.040). However, there was no difference in the incidence of MACE (thin 2.47/100 pt years (95% CI 0.80 to 7.66) vs thick 3.63/100 pt years (95% CI 2.25 to 5.84)) or an arrhythmic event (thin 1.65/100 pt years (95% CI 0.41 to 6.58) vs thick 2.55/100 pt years (95% CI 1.45 to 4.48), p value 0.43).This study suggests that adverse events in thin-filament disease are predominantly arrhythmic and may occur in the absence of hypertrophy, but overall short-term outcomes do not differ significantly from thick-filament disease.

Arterial tortuosity in pediatric Loeys-Dietz syndrome patients.

Loeys-Dietz syndrome (LDS) is an autosomal connective tissue disorder commonly presenting with hypertelorism, bifid uvula, aortic aneurysms, and arterial tortuosity. The aim of the present study was to investigate differences in tortuosity index (TI) between genotypes of LDS, possible progression over time and its use as an adjunctive prognostic tool alongside aortic dimensions to aid timely surgical planning in pediatric patients. A retrospective observational study of pediatric LDS patients referred to our center (November 2012-February 2021) was conducted. Using magnetic resonance angiography (MRA) with 3D maximum intensity projection volume-rendered angiogram, arterial TI was measured. Twenty three patients had genetically confirmed LDS with at least one head and neck MRA and 19 had no less than one follow-up MRA available. All patients presented arterial tortuosity. Patients with TGFBR2 variants had greater values of TI compared to patients with TGFB2 variants (p = 0.041). For patients who did not undergo surgery (n = 18), z-scores at the level of the sinus of Valsalva showed a significant correlation with vertebral TI (rs = 0.547). There was one death during follow-up. This study demonstrates that patients with LDS and TGFBR2 variants have greater values of TI than patients with TGFB2 variants and that greatest values of TI are associated with increased aortic root z-scores. Furthermore, as TI decreases over time, less frequent neuroimaging follow-up can be considered. Nevertheless, additional studies are needed to better define more accurate risk stratification and long-term surveillance in these patients.

Insights into adherence to medication and lifestyle recommendations in an international cohort of patients with catecholaminergic polymorphic ventricular tachycardia.

AIMS: In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a rare inherited arrhythmia syndrome, arrhythmic events can be prevented by medication and lifestyle recommendations. In patients who experience breakthrough arrhythmic events, non-adherence plays an essential role. We aimed to investigate the incidence and potential reasons for non-adherence to medication and lifestyle recommendations in a large, international cohort of patients with CPVT. METHODS AND RESULTS: An online multilingual survey was shared with CPVT patients worldwide by their cardiologists, through peer-recruitment, and on social media from November 2022 until July 2023. Self-reported non-adherence was measured using the validated Medication Adherence Rating Scale (MARS) and a newly developed questionnaire about lifestyle. Additionally, validated questionnaires were used to assess potential reasons for medication non-adherence. Two-hundred-and-eighteen patients completed the survey, of whom 200 (92%) were prescribed medication [122 (61%) female; median age 33.5 years (interquartile range: 22-50)]. One-hundred-and-three (52%) were prescribed beta-blocker and flecainide, 85 (43%) beta-blocker, and 11 (6%) flecainide. Thirty-four (17%) patients experienced a syncope, aborted cardiac arrest or appropriate implantable cardioverter defibrillator shock after diagnosis. Nineteen (13.4%) patients were exercising more than recommended. Thirty (15%) patients were non-adherent to medication. Female sex [odds ratio (OR) 3.7, 95% confidence interval (CI) 1.3-12.0, P = 0.019], flecainide monotherapy compared to combination therapy (OR 6.8, 95% CI 1.6-31.0, P = 0.010), and a higher agreement with statements regarding concerns about CPVT medication (OR 1.2, 95% CI 1.1-1.3, P < 0.001) were independently associated with non-adherence. CONCLUSION: The significant rate of non-adherence associated with concerns regarding CPVT-related medication, emphasizes the potential for improving therapy adherence by targeted patient education.

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.

Cardiac myosin binding protein-C variants in paediatric-onset hypertrophic cardiomyopathy: natural history and clinical outcomes.

BACKGROUND: Variants in the cardiac myosin-binding protein C gene (MYBPC3) are a common cause of hypertrophic cardiomyopathy (HCM) in adults and have been associated with late-onset disease, but there are limited data on their role in paediatric-onset HCM. The objective of this study was to describe natural history and clinical outcomes in a large cohort of children with HCM and pathogenic/likely pathogenic (P/LP) MYBPC3 variants. METHODS AND RESULTS: Longitudinal data from 62 consecutive patients diagnosed with HCM under 18 years of age and carrying at least one P/LP MYBPC3 variant were collected from a single specialist referral centre. The primary patient outcome was a major adverse cardiac event (MACE). Median age at diagnosis was 10 (IQR: 2-14) years, with 12 patients (19.4%) diagnosed in infancy. Forty-seven (75%) were boy and 31 (50%) were probands. Median length of follow-up was 3.1 (IQR: 1.6-6.9) years. Nine patients (14.5%) experienced an MACE during follow-up and five (8%) died. Twenty patients (32.3%) had evidence of ventricular arrhythmia, including 6 patients (9.7%) presenting with out-of-hospital cardiac arrest. Five-year freedom from MACE for those with a single or two MYBPC3 variants was 95.2% (95% CI: 78.6% to 98.5%) and 68.4% (95% CI: 40.6% to 88.9%), respectively (HR 4.65, 95% CI: 1.16 to 18.66, p=0.03). CONCLUSIONS: MYBPC3 variants can cause childhood-onset disease, which is frequently associated with life-threatening ventricular arrhythmia. Clinical outcomes in this cohort vary substantially from aetiologically and genetically mixed paediatric HCM cohorts described previously, highlighting the importance of identifying specific genetic subtypes for clinical management of childhood HCM.

Prevalence of Inherited Cardiac Conditions in Pediatric First-Degree Relatives of Patients with Idiopathic Ventricular Fibrillation.

Idiopathic ventricular fibrillation (IVF) is diagnosed in out-of-hospital VF survivors after comprehensive investigations have excluded structural heart disease or inherited channelopathies. Current guidelines recommend clinical screening of first-degree relatives of IVF survivors, but this approach has not been validated in children. This study aimed to assess the yield of clinical cardiac screening in child first-degree relatives of IVF victims. A retrospective observational study was conducted of all consecutive pediatric first-degree relatives of IVF patients referred to our center between December 2007 and April 2020. Patients underwent systematic evaluation including medical and family history; 12-lead resting, signal-averaged, and ambulatory electrocardiogram (ECG); echocardiogram; exercise testing; cardiac magnetic resonance imaging; and ajmaline provocation testing. Sixty child first-degree relatives of 32 IVF survivors were included [median follow-up time of 55 months (IQR 27.0-87.0 months); 30 (50%) females]. Eight patients (13.3%) from 6 families (18.8%) received a cardiac diagnosis: long QT syndrome (n = 4); Brugada syndrome (n = 3); and dilated cardiomyopathy (n = 1). There were no deaths during follow-up. This study demonstrates a high yield of clinical screening for inherited cardiac disease in child first-degree relatives of IVF survivors. These findings highlight the variable expression of inherited cardiac conditions and the importance of comprehensive clinical evaluation in pediatric relatives, even when extensive investigations in the proband have not identified a clear etiology. Moreover, our results support the validity of the investigations proposed by current guidelines in family relatives of IVF survivors.

Analysis of buccal mucosa as a prognostic tool in children with arrhythmogenic cardiomyopathy.

Background: The diagnosis of arrhythmogenic cardiomyopathy (ACM) is challenging especially in children at risk of adverse events. Analysis of cardiac myocyte junctional protein distribution may have diagnostic and prognostic implications, but its utility is limited by the need for a myocardial sample. We previously reported that buccal mucosa cells show junctional protein redistribution similar to that seen in cardiac myocytes of adult patients with ACM. Objectives: We aimed to determine when junctional protein distribution abnormalities first occur in children with ACM variants and whether they correlate with progression of clinically apparent disease. Methods: We analyzed buccal mucosa samples of children and adolescents with a family history of ACM (n = 13) and age-matched controls (n = 13). Samples were immunostained for plakoglobin, desmoplakin, plakophilin-1 and connexin43 and analyzed by confocal microscopy. All participants were swabbed at least twice with an average interval of 12-18 months between samplings. Results: Junctional protein re-localization in buccal mucosa cells did not correlate with the presence of ACM-causing variants but instead occurred with clinical onset of disease. No changes in protein distribution were seen unless and until there was clinical evidence of disease. In addition, progressive shifts in the distribution of key proteins correlated with worsening of the disease phenotype. Finally, we observed restoration of junctional signal for Cx43 in patient with a favorable response to anti-arrhythmic therapy. Conclusions: Due to ethical concerns about obtaining heart biopsies in children with no apparent disease, it has not been possible to analyze molecular changes in cardiac myocytes with the onset/progression of clinical disease. Using buccal smears as a surrogate for the myocardium may facilitate future studies of mechanisms and pathophysiological consequences of junctional protein redistribution in ACM. Buccal cells may also be a safe and inexpensive tool for risk stratification and potentially monitoring response to treatment in children bearing ACM variants.

Clinical outcomes and programming strategies of implantable cardioverter-defibrillator devices in paediatric hypertrophic cardiomyopathy: a UK National Cohort Study.

AIMS: Sudden cardiac death (SCD) is the most common mode of death in paediatric hypertrophic cardiomyopathy (HCM). This study describes the implant and programming strategies with clinical outcomes following implantable cardioverter-defibrillator (ICD) insertion in a well-characterized national paediatric HCM cohort. METHODS AND RESULTS: Data from 90 patients undergoing ICD insertion at a median age 13 (±3.5) for primary (n = 67, 74%) or secondary prevention (n = 23, 26%) were collected from a retrospective, longitudinal multi-centre cohort of children (<16 years) with HCM from the UK. Seventy-six (84%) had an endovascular system [14 (18%) dual coil], 3 (3%) epicardial, and 11 (12%) subcutaneous system. Defibrillation threshold (DFT) testing was performed at implant in 68 (76%). Inadequate DFT in four led to implant adjustment in three patients. Over a median follow-up of 54 months (interquartile range 28-111), 25 (28%) patients had 53 appropriate therapies [ICD shock n = 45, anti-tachycardia pacing (ATP) n = 8], incidence rate 4.7 per 100 patient years (95% CI 2.9-7.6). Eight inappropriate therapies occurred in 7 (8%) patients (ICD shock n = 4, ATP n = 4), incidence rate 1.1/100 patient years (95% CI 0.4-2.5). Three patients (3%) died following arrhythmic events, despite a functioning device. Other device complications were seen in 28 patients (31%), including lead-related complications (n = 15) and infection (n = 10). No clinical, device, or programming characteristics predicted time to inappropriate therapy or lead complication. CONCLUSION: In a large national cohort of paediatric HCM patients with an ICD, device and programming strategies varied widely. No particular strategy was associated with inappropriate therapies, missed/delayed therapies, or lead complications.

Clinical significance of inferolateral early repolarisation and late potentials in children with Brugada Syndrome.

INTRODUCTION: The clinical utility of inferolateral early repolarisation (ER) and late potentials (LP) in children with Brugada Syndrome (BrS) has not been previously evaluated. The aim of this study was to determine the prevalence of electrocardiographic (ECG) abnormalities in children with BrS, and to investigate their relationship with clinical outcomes. METHODS: 43 patients with BrS and 47 controls aged ≤18 undergoing systematic clinical and ECG evaluation, including signal-averaged ECG (SAECG) and pharmacological provocation testing, between 2003 and 2019 were included. RESULTS: Four patients with BrS (9%) presented with a spontaneous type 1 Brugada pattern; the remaining 39 (91%) were diagnosed following ajmaline provocation testing. Twelve BrS patients (28%) had late potentials (LP) on SAECG compared to 1 (2%) in controls (p = 0.001). LP were more common in 5 patients with a high-risk phenotype (60% vs 24%) but this was not statistically significant. Twelve patients with BrS (28%) had inferolateral early repolarisation (ER) and 2 (5%) had fractionated QRS (f-QRS), but there were no statistically-significant differences with controls in these parameters. A significant arrhythmia (non-sustained ventricular tachycardia or atrial fibrillation) was seen in 4 patients (9%). CONCLUSIONS: This study shows a high prevalence of SAECG abnormalities in children with BrS compared with controls, but this was not significantly associated with a high-risk phenotype.

Yield of Clinical Screening for Hypertrophic Cardiomyopathy in Child First-Degree Relatives.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a heritable myocardial disease with age-related penetrance. Current guidelines recommend clinical screening of relatives beginning at 10 years of age, but the clinical value of this approach has not been systematically evaluated. METHODS: Anonymized clinical data were collected from children referred for family screening between 1994 and 2017 after diagnosis of HCM in a first-degree relative. RESULTS: Of 1198 consecutive children (≤18 years of age) from 594 families who underwent serial evaluation (median, 3.5 years; interquartile range, 1.2-7), 32 individuals met diagnostic criteria at baseline (median maximal left ventricular wall thickness, 13 mm; interquartile range, 8-21 mm), and 25 additional patients developed HCM during follow-up. Median age at diagnosis was 10 years (interquartile range, 4-13 years); 44 (72%) were ≤12 years of age. Median age of affected patients at the last follow-up was 14 years (interquartile range, 9.5-18.2 years). A family history of childhood HCM was more common in those patients diagnosed with HCM (n=32 [56%] versus n=257 [23%]; P<0.001). Eighteen patients (32%) were started on medication for symptoms; 2 (4%) underwent a septal myectomy; 14 (25%) received an implantable cardioverter-defibrillator; 1 underwent cardiac transplantation; 2 had a resuscitated cardiac arrest; and 1 died after a cerebrovascular accident. CONCLUSIONS: Almost 5% of first-degree child relatives undergoing screening meet diagnostic criteria for HCM at first or subsequent evaluations, with the majority presenting as preadolescents; a diagnosis in a child first-degree relative is made in 8% of families screened. The phenotype of familial HCM in childhood is varied and includes severe disease, suggesting that clinical screening should begin at a younger age.

Clinical presentation and survival of childhood hypertrophic cardiomyopathy: a retrospective study in United Kingdom.

AIMS: Understanding the spectrum of disease, symptom burden and natural history are essential for the management of children with hypertrophic cardiomyopathy (HCM). The effect of changing screening practices over time has not previously been studied. This study describes the clinical characteristics and outcomes of childhood HCM over four decades in a well-characterized United Kingdom cohort. METHODS AND RESULTS: Six hundred and eighty-seven patients with HCM presented at a median age of 5.2 years (range 0-16). Aetiology was: non-syndromic (n = 433, 63%), RASopathy (n = 126, 18.3%), Friedreich's ataxia (n = 59, 8.6%) or inborn errors of metabolism (IEM) (n = 64, 9%). In infants (n = 159, 23%) underlying aetiology was more commonly a RASopathy (42% vs. 11.2%, P < 0.0001) or IEM (18.9% vs. 6.4% P < 0.0001). In those with familial disease, median age of presentation was higher (11 years vs. 6 years, P < 0.0001), 141 (58%) presented <12 years. Freedom from death or transplantation was 90.6% (87.9-92.7%) at 5 years (1.5 per 100 patient years) with no era effect. Mortality was most frequently sudden cardiac death (SCD) (n = 20, 2.9%). Children diagnosed during infancy or with an IEM had a worse prognosis (5-year survival 80.5% or 66.4%). Arrhythmic events occurred at a rate of 1.2 per 100 patient years and were more likely in non-syndromic patients (n = 51, 88%). CONCLUSION: This national study describes a heterogeneous disease whose outcomes depend on the age of presentation and aetiology. Overall mortality and SCD rates have not changed over time, but they remain higher than in adults with HCM, with events occurring in syndromic and non-syndromic patients.

A validation study of the European Society of Cardiology guidelines for risk stratification of sudden cardiac death in childhood hypertrophic cardiomyopathy.

AIMS: Sudden cardiac death (SCD) is the most common cause of death in children with hypertrophic cardiomyopathy (HCM). The European Society of Cardiology (ESC) recommends consideration of an implantable cardioverter-defibrillator (ICD) if two or more clinical risk factors (RFs) are present, but this approach to risk stratification has not been formally validated. METHODS AND RESULTS: Four hundred and eleven paediatric HCM patients were assessed for four clinical RFs in accordance with current ESC recommendations: severe left ventricular hypertrophy, unexplained syncope, non-sustained ventricular tachycardia, and family history of SCD. The primary endpoint was a composite outcome of SCD or an equivalent event (aborted cardiac arrest, appropriate ICD therapy, or sustained ventricular tachycardia), defined as a major arrhythmic cardiac event (MACE). Over a follow-up period of 2890 patient years (median 5.5 years), MACE occurred in 21 patients (7.5%) with 0 RFs, 19 (16.8%) with 1 RFs, and 3 (18.8%) with 2 or more RFs. Corresponding incidence rates were 1.13 [95% confidence interval (CI) 0.7-1.73], 2.07 (95% CI 1.25-3.23), and 2.52 (95% CI 0.53-7.35) per 100 patient years at risk. Patients with two or more RFs did not have a higher incidence of MACE (log-rank test P = 0.34), with a positive and negative predictive value of 19% and 90%, respectively. The C-statistic was 0.62 (95% CI 0.52-0.72) at 5 years. CONCLUSIONS: The incidence of MACE is higher for patients with increasing numbers of clinical RFs. However, the current ESC guidelines have a low ability to discriminate between high- and low-risk individuals.

High prevalence of early repolarization in the paediatric relatives of sudden arrhythmic death syndrome victims and in normal controls.

AIMS: Elevation of the ECG J-point in the inferior and lateral leads (early repolarization) has been described in survivors of ventricular fibrillation (VF) arrest and occurs in adult first-degree relatives of sudden cardiac death (SCD) probands at a frequency significantly greater than in controls, raising the possibility that this could represent an independent risk factor in the aetiology of SCD. However, data on early repolarization in the paediatric population are lacking. This study aimed to assess the prevalence of early repolarization in paediatric first-degree relatives of sudden arrhythmic death syndrome (SADS) victims. METHODS AND RESULTS: Paediatric relatives (aged <18 years) of SADS probands referred to the Inherited Arrhythmia Clinic at Great Ormond Street Hospital had their initial screening ECG reviewed for evidence of J-point elevation. J-point elevation was defined as QRS-ST slurring or a discrete notch in two or more inferior (II, III, aVF) or lateral (I, aVL, V4, V5, V6) leads with the change beginning >1 mV from baseline. The ECGs of 77 consecutive paediatric first-degree relatives of SADS victims from 46 families were reviewed by two assessors. J-point elevation was present in 24 patients (31%) of this patient group compared with the reported prevalence of 5-13% in the published general paediatric population (P = 0.02) and that of 19% in the internal control group (P = 0.07). Subgroup analysis according to J-point elevation and ST segment morphologies showed a significantly higher prevalence of inferior early repolarization 0.1-0.2 mV in the study group compared with controls (75 vs. 38%; P = 0.02). CONCLUSION: Inferolateral J-point elevation occurs in a substantial proportion of paediatric first-degree relatives of SADS probands with a similar prevalence to that described in adults. This suggests that early repolarization could be an important inherited trait when evaluating relatives of SADS victims. However, prospective follow-up of this group of children is important to establish the implication of this finding in future risk stratification, given the apparently high prevalence in normal individuals.

Electrothermal instability mitigation by using thick dielectric coatings on magnetically imploded conductors.

Recent experiments on Sandia's Z facility have confirmed simulation predictions of dramatically reduced instability growth in solid metallic rods when thick dielectric coatings are used to mitigate density perturbations arising from an electrothermal instability. These results provide further evidence that the inherent surface roughness as a result of target fabrication is not the dominant seed for the growth of magneto-Rayleigh-Taylor instabilities in liners with carefully machined smooth surfaces, but rather electrothermal instabilities that form early in the electrical current pulse as Joule heating melts and vaporizes the liner surface. These results suggest a new technique for substantially reducing the integral magneto-Rayleigh-Taylor instability growth in magnetically driven implosions, such as cylindrical dynamic material experiments and inertial confinement fusion concepts.

Sudden arrhythmic death syndrome: diagnostic yield of comprehensive clinical evaluation of pediatric first-degree relatives.

AIMS: Sudden arrhythmic death syndrome (SADS) is most often caused by heritable cardiac diseases. Studies in adults have identified evidence of inherited cardiovascular diseases in up to 53% of families, but data on the prevalence of familial disease in children are scarce. The aim of this study was to evaluate the yield of clinical screening in pediatric first-degree relatives of victims of SADS using a systematic and comprehensive protocol. METHODS: Patients referred for family screening after sudden cardiac death (SCD) of a family member were, retrospectively, enrolled into the study. Systematic evaluation of the children included clinical examination, family history, electrocardiogram (ECG), echocardiogram, 24-hour tape, and signal-averaged ECG. Older patients also underwent exercise testing, cardiac magnetic resonance imaging, and ajmaline provocation testing. RESULTS: A total of 90 children from 52 consecutive families were included in the study. An inherited cardiac disease was identified in seven first-degree children from seven (13.5%) families (five children were diagnosed with Brugada syndrome, one with long QT syndrome, and one with catecholaminergic polymorphic ventricular tachycardia). Two further children had late potentials on signal-averaged ECGs with no other abnormalities. CONCLUSIONS: These data show a high prevalence of inherited heart disease in pediatric first-degree relatives of SADS victims. The results highlight the importance of a systematic, comprehensive approach and ongoing screening of pediatric family members.

Reactive ion-assisted deposition of e-beam evaporated titanium for high refractive index TiO2 layers and laser damage resistant, broad bandwidth, high-reflection coatings.

High-reflection coatings with broad bandwidth can be achieved by pairing a low refractive index material, such as SiO2, with a high refractive index material, such as TiO2. To achieve high refractive index, low absorption TiO2 films, we optimized the reactive, ion-assisted deposition process (O2 levels, deposition rate, and ion beam settings) using e-beam evaporated Ti. TiO2 high-index layers were then paired with SiO2 low-index layers in a quarter-wave-type coating to achieve a broader high-reflection bandwidth compared to the same coating composed of HfO2/SiO2 layer pairs. However, the improved bandwidth exhibited by the TiO2/SiO2 coating is associated with lower laser damage threshold. To improve the laser damage resistance of the TiO2/SiO2 coating, we also created four coatings where HfO2 replaced some of the outer TiO2 layers. We present the laser damage results of these coatings to understand the trade-offs between good laser damage resistance and high-reflection bandwidth using TiO2 and HfO2.

Utility and acceptability of remote 6-lead electrocardiographic monitoring in children with inherited cardiac conditions.

OBJECTIVE: This pilot study sought to investigate the utility and acceptability of the KardiaMobile 6-lead ECG (KM6LECG) as a tool for remote monitoring in children with inherited cardiac conditions. DESIGN: A single-centre prospective cohort study. Children underwent standard clinical evaluation including a 12-lead ECG and a KM6LECG in the clinic. Participants recorded KM6LECGs monthly at home for 3 months. Families completed a questionnaire on their experience. SETTING: Great Ormond Street Hospital Centre for Inherited Cardiovascular Diseases. PARTICIPANTS: 64 children: 22 with hypertrophic cardiomyopathy (HCM); 22 with long QT syndrome and 20 unaffected siblings (controls). MAIN OUTCOME MEASURES: Comparison of data extracted from the clinic 12-lead ECG and supervised KM6LECG, and the supervised and unsupervised KM6LECG recording. RESULTS: Of 64 children (35% female, mean age 12 years), 58 had a baseline 12-lead ECG and appropriate baseline KM6LECG. In children with HCM, abnormalities in ventricular depolarisation/repolarisation in the limb leads of the 12-lead ECG were reliably reproduced. From the whole cohort, there was a strong positive correlation between the corrected QT interval from the 12-lead ECG and baseline KM6LECG (intraclass correlation coefficient=0.839) and baseline KM6LECG with an unsupervised KM6LECG (intraclass correlation coefficient=0.736). Suspected 'lead' misplacement impacted 18% of unsupervised recordings. Overall, the acceptability of the KM6LECG to families was good. CONCLUSIONS: The KM6LECG provides an accurate tool for assessing some ECG abnormalities associated with paediatric inherited cardiovascular disease and may provide a useful at-home adjunct to face-to-face clinical care of children requiring ECG assessment.

Novel Multiplexed Plasma Biomarker Panel Has Diagnostic and Prognostic Potential in Children With Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is defined clinically by pathological left ventricular hypertrophy. We have previously developed a plasma proteomics biomarker panel that correlates with clinical markers of disease severity and sudden cardiac death risk in adult patients with HCM. The aim of this study was to investigate the utility of adult biomarkers and perform new discoveries in proteomics for childhood-onset HCM. METHODS: Fifty-nine protein biomarkers were identified from an exploratory plasma proteomics screen in children with HCM and augmented into our existing multiplexed targeted liquid chromatography-tandem/mass spectrometry-based assay. The association of these biomarkers with clinical phenotypes and outcomes was prospectively tested in plasma collected from 148 children with HCM and 50 healthy controls. Machine learning techniques were used to develop novel pediatric plasma proteomic biomarker panels. RESULTS: Four previously identified adult HCM markers (aldolase fructose-bisphosphate A, complement C3a, talin-1, and thrombospondin 1) and 3 new markers (glycogen phosphorylase B, lipoprotein a and profilin 1) were elevated in pediatric HCM. Using supervised machine learning applied to training (n=137) and validation cohorts (n=61), this 7-biomarker panel differentiated HCM from healthy controls with an area under the curve of 1.0 in the training data set (sensitivity 100% [95% CI, 95-100]; specificity 100% [95% CI, 96-100]) and 0.82 in the validation data set (sensitivity 75% [95% CI, 59-86]; specificity 88% [95% CI, 75-94]). Reduced circulating levels of 4 other peptides (apolipoprotein L1, complement 5b, immunoglobulin heavy constant epsilon, and serum amyloid A4) found in children with high sudden cardiac death risk provided complete separation from the low and intermediate risk groups and predicted mortality and adverse arrhythmic outcomes (hazard ratio, 2.04 [95% CI, 1.0-4.2]; P=0.044). CONCLUSIONS: In children, a 7-biomarker proteomics panel can distinguish HCM from controls with high sensitivity and specificity, and another 4-biomarker panel identifies those at high risk of adverse arrhythmic outcomes, including sudden cardiac death.

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.

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.