Sudden cardiac death in childhood hypertrophic cardiomyopathy is best predicted by a combination of electrocardiogram risk-score and HCMRisk-Kids score.

AIM: To compare risk algorithms (HCMRisk-Kids, ECG Risk-score) in hypertrophic cardiomyopathy (HCM) without syndrome association (ns-HCM) and with Noonan-like syndromes (RAS-HCM). METHODS: A national paediatric HCM cohort (n = 151), presenting <19 years of age, mean follow-up 13.3 years, from all Swedish centres of Paediatric Cardiology (presenting 1972-2015), with 41 RAS-HCM patients (61% males), and 110 ns-HCM patients (68% familial; 65% males). The end-point was a composite of sudden cardiac death and resuscitated cardiac arrest (SCD/CA). Risk-factors were studied with Cox-hazard regression, and receiver operating characteristic curve analysis (C-statistic). RESULTS: There were 33 SCD/CA, 27/110 in ns-HCM and 6/41 in RAS-HCM (p = 0.27). In ns-HCM HCMRisk-Kids ≥6% at diagnosis had C-statistic of 0.69 for predicting SCD/CA during first 5 years of follow-up and positive predictive value (PPV) of 22%. After 7 years of age (HCMRisk-Kids7plus), C-statistic was 0.76. ECG Risk-score ≥6 at diagnosis had C-statistic 0.87 and PPV of 31%. Independent risk factors for SCD/CA were HCMRisk-Kids7plus score (p = 0.005) and ECG risk-score (p < 0.001), whereas early beta-blocker dose (p = 0.001) and myectomy (p = 0.004) reduced risk. The sum of HCMRisk-Kids7yplus and ECG Risk-score7yplus ≥14 best predicted SCD/CA within 5 years in ns-HCM with C-statistic of 0.90 [0.83-0.96], sensitivity 100% and PPV 38%. CONCLUSION: Combining the ECG Risk-score with HCMRisk-Kids improves risk stratification in ns-HCM and shows promise in RAS-HCM.

High ECG Risk-Scores Predict Late Gadolinium Enhancement on Magnetic Resonance Imaging in HCM in the Young.

An ECG risk-score has been described that predicts high risk of subsequent cardiac arrest in young patients with hypertrophic cardiomyopathy (HCM). Myocardial fibrosis measured by cardiac magnetic resonance (CMR) late gadolinium enhancement (LGE) also affects prognosis. We assessed whether an ECG risk-score could be used as an indicator of myocardial fibrosis or perfusion deficit on CMR in HCM. In total 42 individuals (7-31 years); 26 HCM patients, seven genotype-positive, phenotype-negative individuals at risk of HCM (first-degree relatives) and nine healthy volunteers, underwent CMR to identify, and grade extent of, myocardial fibrosis and perfusion defect. 12-lead ECG was used for calculating the ECG risk-score (grading 0-14p). High-risk ECG (risk-score > 5p) occurred only in the HCM group (9/26), and the proportion was significantly higher vs mutation carriers combined with healthy volunteers (0/16, p = 0.008). Extent of LGE correlated to the ECG-score (R2 = 0.47, p = 0.001) in sarcomeric mutations. In low-risk ECG-score patients (0-2p), median percent of myocardium showing LGE (LGE%LVM) were: 0% [interquartile range, IQR, 0-0%], in intermediate-risk (3-5p): 5.4% [IQR 0-13.5%] and in high-risk (6-14p): 10.9% [IQR 4.2-12.3%]. ECG-score > 2p had a sensitivity and specificity of 79% and 84% to detect positive LGE on CMR and 77% vs. 75% to detect perfusion defects in sarcomeric mutations carriers. In patients with myocardial fibrosis as identified by LGE, median ECG risk-score was 8p [range 3-10p]. In conclusions, ECG risk-score > 2 p could be used as a cut-off for screening of myocardial fibrosis. Thus ECG risk-score is an inexpensive complementary tool in risk stratification of HCM in the young.

Novel Genetic Variants in BAG3 and TNNT2 in a Swedish Family with a History of Dilated Cardiomyopathy and Sudden Cardiac Death.

Familial dilated cardiomyopathy is a rare cause of dilated cardiomyopathy (DCM), especially in childhood. Our aim was to describe the clinical course and the genetic variants in a family where the proband was a four-month-old infant presenting with respiratory problems due to DCM. In the family, there was a strong family history of DCM and sudden cardiac death in four generations. DNA was analyzed initially from the deceased girl using next-generation sequencing including 50 genes involved in cardiomyopathy. A cascade family screening was performed in the family after identification of the TNNT2 and the BAG3 variants in the proband. The first-degree relatives underwent clinical examination including biochemistry panel, cardiac ultrasound, Holter ECG, exercise stress test, and targeted genetic testing. The index patient presented with advanced DCM. After a severe clinical course, the baby had external left ventricular assist as a bridge to heart transplantation. 1.5 months after transplantation, the baby suffered sudden cardiac death (SCD) despite maximal treatment in the pediatric intensive care unit. The patient was shown to carry two heterozygous genetic variants in the TNNT2 gene [TNNT2 c.518G>A(p.Arg173Gln)] and BAG3 [BAG3 c.785C>T(p.Ala262Val)]. Two of the screened individuals (two females) appeared to carry both the familial variants. All the individuals carrying the TNNT2 variant presented with DCM, the two adult patients had mild or moderate symptoms of heart failure and reported palpitations but no syncope or presyncopal attacks prior to the genetic diagnosis. The female carriers of TNNT2 and BAG3 variants had more advanced DCM. In the family history, there were three additional cases of SCD due to DCM, diagnosed by autopsy, but no genetic analysis was possible in these cases. Our findings suggest that the variants in TNNT2 and BAG3 are associated with a high propensity to life-threatening cardiomyopathy presenting from childhood and young adulthood.

Respiratory Tract Infection and Risk of Hospitalization in Children with Congenital Heart Defects During Season and Off-Season: A Swedish National Study.

Respiratory tract infections (RTI) are common among young children, and congenital heart defect (CHD) is a risk factor for severe illness and hospitalization. This study aims to assess the relative risk of hospitalization due to RTI in winter and summer seasons for different types of CHD. All children born in Sweden and under the age of two, in 2006-2011, were included. Heart defects were grouped according to type. Hospitalization rates for respiratory syncytial virus (RSV) infection and RTI in general were retrieved from the national inpatient registry. The relative risk of hospitalization was calculated by comparing each subgroup to other types of CHD and otherwise healthy children. The relative risk of hospitalization was increased for all CHD subgroups, and there was a greater increase in risk in summer for the most severe CHD. This included RSV infection, as well as RTI in general. The risk of hospitalization due to RTI is greater for CHD children. Prophylactic treatment with palivizumab, given to prevent severe RSV illness, is only recommended during winter. We argue that information to healthcare staff and parents should include how the risk of severe infectious respiratory tract illnesses, RSV and others, is present all year round for children with CHD.

Peripheral microvascular function is altered in young individuals at risk for hypertrophic cardiomyopathy and correlates with myocardial diastolic function.

Hypertrophic cardiomyopathy (HCM) is a major cause of sudden cardiac death in the young. Based on previous reports of functional abnormalities in not only coronary but also peripheral vessels in adults with HCM, we aimed to assess both peripheral vascular and myocardial diastolic function in young individuals with an early stage of HCM and in individuals at risk for HCM. Children, adolescents, and young adults (mean age: 12 yr) with a family history of HCM who either had (HCM group; n = 36) or did not have (HCM-risk group; n = 30) echocardiography-documented left ventricular (LV) hypertrophy as well as healthy matched controls (n = 85) and healthy young athletes (n = 12) were included in the study. All underwent assessment with 12-lead electrocardiography, two-dimensional echocardiography, tissue Doppler imaging and laser Doppler with transdermal iontophoresis of ACh and sodium nitroprusside. LV thickness and mass were increased in HCM and athlete groups compared with control and HCM-risk groups. The mitral E-to-e' ratio, measured via tissue Doppler, was increased in HCM (P < 0.0001) and HCM-risk (P < 0.01) groups compared with control and athlete groups, as were microvascular responses to ACh (HCM group: P = 0.045 and HCM-risk group: P = 0.02). Responses to ACh correlated with the E-to-e' ratio (r = 0.5, P = 0.001). Microvascular responses to sodium nitroprusside were similar in all groups (P > 0.2). HCM-causing mutations or its familial history are associated with changes in cardiac diastolic function and peripheral microvascular function even before the onset of myocardial hypertrophy. Tissue Doppler can be used to differentiate HCM from physiological LV hypertrophy in young athletes.

Regional Stress-Induced Ischemia in Non-fibrotic Hypertrophied Myocardium in Young HCM Patients.

The relationship between hypertrophy, perfusion abnormalities and fibrosis is unknown in young patients with hypertrophic cardiomyopathy (HCM). Since mounting evidence suggests causal relationship between myocardial ischemia and major adverse cardiac events, we sought to investigate whether (1) regional myocardial perfusion is decreased in young HCM patients and in individuals at risk of HCM, and (2) hypoperfused areas are larger than areas with fibrosis. HCM patients (n = 12), HCM-risk subjects (n = 15) and controls (n = 9) were imaged on a 1.5 T MRI scanner. Myocardial hypertrophy was assessed on cine images. Perfusion images were acquired during adenosine hyperemia and at rest. Maximum upslope ratios of perfusion (stress/rest) were used for semiquantitative analysis. Fibrosis was assessed by late gadolinium enhancement (LGE). Results are presented as median and range. Perfusion in HCM-risk subjects and in non-hypertrophied segments in HCM patients showed no difference compared to controls (P = ns). Hypertrophic segments in HCM patients without LGE showed decreased perfusion compared to segments without hypertrophy [1.5 (1.1-2.3) vs. 2.0 (1.8-2.6), P < 0.001], and hypertrophic segments with LGE showed even lower perfusion using a segmental analysis [0.9 (0.6-1.8), P < 0.05]. The extent of hypoperfused myocardium in HCM patients during adenosine exceeded the extent of fibrosis on LGE [20 (0-48) vs. 4 (0-7) % slice area, P < 0.05] and hypoperfused areas at rest (P < 0.001). Regional perfusion is decreased in hypertrophied compared to non-hypertrophied myocardium and is lowest in fibrotic myocardium in young HCM patients but does not discriminate HCM-risk subjects from controls. The stress-induced hypoperfused regions exceed regions with LGE, indicating that hypoperfusion precedes fibrosis and may be a more sensitive marker of diseased myocardium in HCM.

Evaluating national guidelines for the prophylactic treatment of respiratory syncytial virus in children with congenital heart disease.

AIM: This is the first study to evaluate compliance with the 2003 Swedish national guidelines for prophylactic treatment of respiratory syncytial virus (RSV) in children with congenital heart disease (CHD). We estimated the relative risk (RR) of children with CHD being hospitalised with a RSV infection, studied the extent to which RSV prophylactic treatment with palivizumab corresponded to the guidelines and determined the morbidity of children with CHD who developed RSV infection despite prophylaxis. METHODS: This national observational study comprised prospectively registered data on 219 children with CHD treated with palivizumab, medical records on RSV cases and information on hospitalisation rates of children with CHD and RSV infection. RESULTS: The calculated RR of children with CHD being hospitalised with RSV infection was 2.06 (95% CI 1.6-2.6; p < 0.0001) compared with children without CHD. Approximately half of the patients (49%) born before the RSV season and 25% born during the RSV season did not start treatment as recommended by the guidelines. CONCLUSION: Having CHD increased the rate and estimated RR of children being hospitalised with RSV infection. The guidelines were not followed for about half of the children born before a RSV season and a quarter of the children born during a RSV season and need updating.

Biomarkers and Proteomics in Sarcomeric Hypertrophic Cardiomyopathy in the Young-FGF-21 Highly Associated with Overt Disease.

Background: Any difference in biomarkers between genotype-positive individuals with overt hypertrophic cardiomyopathy (HCM), and genotype-positive but phenotype-negative individuals (G+P-) in HCM-associated pathways might shed light on pathophysiological mechanisms. We studied this in young HCM patients. Methods: 29 HCM patients, 17 G+P--individuals, and age- and sex-matched controls were prospectively included. We analyzed 184 cardiovascular disease-associated proteins by two proximity extension assays, categorized into biological pathways, and analyzed with multivariate logistic regression analysis. Significant proteins were dichotomized into groups above/below median concentration in control group. Results: Dichotomized values of significant proteins showed high odds ratio (OR) in overt HCMphenotype for Fibroblast growth factor-21 (FGF-21) 10 (p = 0.001), P-selectin glycoprotein ligand-1 (PSGL-1) OR 8.6 (p = 0.005), and Galectin-9 (Gal-9) OR 5.91 (p = 0.004). For G+P-, however, angiopoietin-1 receptor (TIE2) was notably raised, OR 65.5 (p = 0.004), whereas metalloproteinase inhibitor 4 (TIMP4) involved in proteolysis, in contrast, had reduced OR 0.06 (p = 0.013). Conclusions: This study is one of the first in young HCM patients and G+P- individuals. We found significantly increased OR for HCM in FGF-21 involved in RAS-MAPK pathway, associated with cardiomyocyte hypertrophy. Upregulation of FGF-21 indicates involvement of the RAS-MAPK pathway in HCM regardless of genetic background, which is a novel finding.

Effectiveness of the STEPSTONES Transition Program for Adolescents With Congenital Heart Disease-A Randomized Controlled Trial.

PURPOSE: Adolescents with congenital heart disease transition from childhood to adulthood and transfer from pediatric-oriented to adult-oriented care. High-level empirical evidence on the effectiveness of transitional care is scarce. This study investigated the empowering effect (primary outcome) of a structured person-centered transition program for adolescents with congenital heart disease and studied its effectiveness on transition readiness, patient-reported health, quality of life, health behaviors, disease-related knowledge, and parental outcomes e.g., parental uncertainty, readiness for transition as perceived by the parents (secondary outcomes). METHODS: The STEPSTONES-trial comprised a hybrid experimental design whereby a randomized controlled trial was embedded in a longitudinal observational study. The trial was conducted in seven centers in Sweden. Two centers were allocated to the randomized controlled trial-arm, randomizing participants to intervention or control group. The other five centers were intervention-naïve centers and served as contamination check control group. Outcomes were measured at the age of 16 years (baseline), 17 years, and 18.5 years. RESULTS: The change in empowerment from 16 years to 18.5 years differed significantly between the intervention group and control group (mean difference = 3.44; 95% confidence interval = 0.27-6.65; p = .036) in favor of intervention group. For the secondary outcomes, significant differences in change over time were found in parental involvement (p = .008), disease-related knowledge (p = .0002), and satisfaction with physical appearance (p = .039). No differences in primary or secondary outcomes were detected between the control group and contamination check control group, indicating that there was no contamination in the control group. DISCUSSION: The STEPSTONES transition program was effective in increasing patient empowerment, reducing parental involvement, improving satisfaction with physical appearance, and increasing disease-related knowledge.

Development of heart block in children of SSA/SSB-autoantibody-positive women is associated with maternal age and displays a season-of-birth pattern.

OBJECTIVE: Congenital heart block may develop in the fetuses of Ro/SSA-positive and La/SSB-positive mothers. Recurrence rates of only 10-20% despite persisting maternal antibodies indicate that additional factors are critical for the establishment of heart block. The authors investigated the influence of other maternal and fetal factors on heart block development in a Swedish population-based cohort. METHODS: The influence of fetal gender, maternal age, parity and time of birth on heart block development was analysed in 145 families, including Ro/La-positive (n=190) and Ro/La-negative (n=165) pregnancies. RESULTS: There was a recurrence rate of 12.1% in Ro/La-positive women, and no recurrence in Ro/La-negative women. Fetal gender and parity did not influence the development of heart block in either group. Maternal age in Ro/La-positive pregnancies with a child affected by heart block was, however, significantly higher than in pregnancies resulting in babies without heart block (p<0.05).Seasonal timing of pregnancy influenced the outcome. Gestational susceptibility weeks 18-24 occurring during January-March correlated with a higher proportion of children with heart block and lower vitamin D levels during the same period in a representative sample of Swedish women and a corresponding higher proportion of children with heart block born in the summer (p<0.02). Maternal age or seasonal timing of pregnancy did not affect the outcome in Ro/La-negative pregnancies. CONCLUSION: This study identifies maternal age and seasonal timing of pregnancy as novel risk factors for heart block development in children of Ro/La-positive women. These observations may be useful for counselling when pregnancy is considered.

Screening of congenital heart disease patients using multiplex ligation-dependent probe amplification: early diagnosis of syndromic patients.

Recurrent copy number variants (CNVs) are found in a significant proportion of patients with congenital heart disease (CHD) and some of these CNVs are associated with other developmental defects. In some syndromic patients, CHD may be the first presenting symptom, thus screening of patients with CHD for CNVs in specific genomic regions may lead to early diagnosis and awareness of extracardiac symptoms. We designed a multiplex ligation-dependent probe amplification (MLPA) assay specifically for screening of CHD patients. The MLPA assay allows for simultaneous analysis of CNVs in 25 genomic regions previously associated with CHD. We screened blood samples from 402 CHD patients and identified 14 rare CNVs in 13 (3.2%) patients. Five CNVs were de novo and six where inherited from a healthy parent. The MLPA screen led to early syndrome diagnosis in two of these patients. We conclude that the MLPA assay detects clinically relevant CNVs and suggest that it could be used within pediatric cardiology as a first tier screen to detect clinically relevant CNVs and identify syndromic patients at an early stage.

The longitudinal association between patient empowerment and patient-reported outcomes: What is the direction of effect?

BACKGROUND: Theoretical literature and cross-sectional studies suggest empowerment is associated with other patient-reported outcomes (PROs). However, it is not known if patient empowerment is leading to improvements in other PROs or vice versa. AIMS: The present study aimed to examine the direction of effects between patient empowerment and PROs in young persons with congenital heart disease (CHD). METHODS: As part of the STEPSTONES-CHD trial, adolescents with CHD from seven pediatric cardiology centers in Sweden were included in a longitudinal observational study (n = 132). Data were collected when patients were 16 (T0), 17 (T1) and 18 ½ years old (T2). The Gothenburg Young Persons Empowerment Scale (GYPES) was used to measure patient empowerment. Random intercepts cross-lagged panel models between patient empowerment and PROs (communication skills; patient-reported health; quality of life; and transition readiness) were undertaken. RESULTS: We found a significant cross-lagged effect of transition readiness over patient empowerment between T1 and T2, signifying that a higher level of transition readiness predicted a higher level of patient empowerment. No other significant cross-lagged relationships were found. CONCLUSION: Feeling confident before the transition to adult care is necessary before young persons with CHD can feel in control to manage their health and their lives. Clinicians interested in improving patient empowerment during the transitional period should consider targeting transition readiness.

Hereditary Hypertrophic Cardiomyopathy in Children and Young Adults-The Value of Reevaluating and Expanding Gene Panel Analyses.

INTRODUCTION: Sudden cardiac death (SCD) and early onset cardiomyopathy (CM) in the young will always lead to suspicion of an underlying genetic disorder. Incited by the rapid advances in genetic testing for disease we have revisited families, which previously tested "gene-negative" for familial predominantly pediatric CM, in hopes of finding a causative gene variant. METHODS: 10 different families with non-syndromic pediatric CM or hypertrophic cardiomyopathy (HCM) with severe disease progression and/or heredity for HCM/CM related SCD with "gene-negative" results were included. The index patient underwent genetic testing with a recently updated gene panel for CM and SCD. In case of failure to detect a pathogenic variant in a relevant gene, the index patient and both parents underwent clinical (i.e., partial) exome sequencing (trio-exome) in order to catch pathogenic variants linked to the disease in genes that were not included in the CM panel. RESULTS: The mean age at clinical presentation of the 10 index cases was 12.5 years (boys 13.4 years, n = 8; girls 9 years, n = 2) and the family history burden was 33 HCM/CM cases including 9 HCM-related SCD and one heart transplantation. In 5 (50%) families we identified a genetic variant classified as pathogenic or likely pathogenic, in accordance with the American College of Medical Genetics and Genomics (ACMG) criteria, in MYH7 (n = 2), RBM20, ALPK3, and PGM1, respectively, and genetic variants of unknown significance (VUS) segregating with the disease in an additional 3 (30%) families, in MYBPC3, ABCC9, and FLNC, respectively. CONCLUSION: Our results show the importance of renewed thorough clinical assessment and the necessity to challenge previous genetic test results with more comprehensive updated gene panels or exome sequencing if the initial test failed to identify a causative gene for early onset CM or SCD in children. In pediatric cardiomyopathy cases when the gene panel still fails to detect a causative variant, a trio exome sequencing strategy might resolve some unexplained cases, especially if a multisystemic condition is clinically missed.

Monozygotic twins with myocarditis and a novel likely pathogenic desmoplakin gene variant.

Myocarditis most often affects otherwise healthy athletes and is one of the leading causes of sudden death in children and young adults. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined heart muscle disorder with increased risk for paroxysmal ventricular arrhythmias and sudden cardiac death. The clinical picture of myocarditis and ARVC may overlap during the early stages of cardiomyopathy, which may lead to misdiagnosis. In the literature, we found several cases that presented with episodes of myocarditis and ended up with a diagnosis of arrhythmogenic cardiomyopathy, mostly of the left predominant type. The aim of this case presentation is to shed light upon a possible link between myocarditis, a desmoplakin (DSP) gene variant, and ARVC by describing a case of male monozygotic twins who presented with symptoms and signs of myocarditis at 17 and 18 years of age, respectively. One of them also had a recurrent episode of myocarditis. The twins and their family were extensively examined including electrocardiograms (ECG), biochemistry, multimodal cardiac imaging, myocardial biopsy, genetic analysis, repeated cardiac magnetic resonance (CMR) and echocardiography over time. Both twins presented with chest pain, ECG with slight ST-T elevation, and increased troponin T levels. CMR demonstrated an affected left ventricle with comprehensive inflammatory, subepicardial changes consistent with myocarditis. The right ventricle did not appear to have any abnormalities. Genotype analysis revealed a nonsense heterozygous variant in the desmoplakin (DSP) gene [NM_004415.2:c.2521_2522del (p.Gln841Aspfs*9)] that is considered likely pathogenic and presumably ARVC related. There was no previous family history of heart disease. There might be a common pathophysiology of ARVC, associated with desmosomal dysfunction, and myocarditis. In our case, both twins have an affected left ventricle without any right ventricular involvement, and they are carriers of a novel DSP variant that is likely associated with ARVC. The extensive inflammation of the LV that was apparent in the CMR may or may not be the primary event of ARVC. Nevertheless, our data suggest that irrespective of a possible link here to ARVC, genetic testing for arrhythmogenic cardiomyopathy might be advisable for patients with recurrent myocarditis associated with a family history of myocarditis.

Outpatient volumes and medical staffing resources as predictors for continuity of follow-up care during transfer of adolescents with congenital heart disease.

BACKGROUND: Providing continuous follow-up care to patients with congenital heart disease (CHD) remains a challenge in many settings. Previous studies highlight that patients with CHD experience discontinuation of follow-up care, but mainly describe a single-centre perspective, neglecting inter-institutional variations. Hospital-related factors above and beyond patient-related factors are believed to affect continuity of care. The present multicentre study therefore investigated (i) proportion of "no follow-up care"; (ii) transfer destinations after leaving paediatric cardiology; (iii) variation in proportions of no follow-up between centres; (iv) the association between no follow-up and outpatient volumes, and (v) its relationship with staffing resources at outpatient clinics. METHODS: An observational, multicentre study was conducted in seven university hospitals. In total, 654 adolescents with CHD, born between 1991 and 1993, with paediatric outpatient visit at age 14-18 years were included. Transfer status was determined 5 years after the intended transfer to adult care (23y), based on medical files, self-reports and registries. RESULTS: Overall, 89.7% of patients were receiving adult follow-up care after transfer; 6.6% had no follow-up; and 3.7% were untraceable. Among patients in follow-up care, only one remained in paediatric care and the majority received specialist adult CHD care. Significant variability in proportions of no follow-up were identified across centres. Higher outpatient volumes at paediatric outpatient clinics were associated with better continued follow-up care after transfer (OR = 1.061; 95% CI = 1.001 - 1.124). Medical staffing resources were not found predictive. CONCLUSION: Our findings support the theory of hospital-related factors influencing continuity of care, above and beyond patient-related characteristics.

The congenital disorder of glycosylation in PGM1 (PGM1-CDG) can cause severe cardiomyopathy and unexpected sudden cardiac death in childhood.

INTRODUCTION: Sudden cardiac death (SCD) in the young is rare and should always lead to suspicion of a genetic cardiac disorder. We describe a family, in which the proband was a girl deceased by sudden cardiac death in the playground at thirteen years of age. The index-patient had short stature, cleft palate but no previous cardiac symptoms. We found an uncommon cause of cardiomyopathy, due to a congenital disorder of glycosylation (CDG), previously described to cause a variable range of usually mild symptoms, and not previously found to cause SCD as the first symptom of the condition. METHODS: The index patient underwent postmortem genetic testing/molecular autopsy for genes known to cause SCD, without a detection of causative agent, why two siblings of similar phenotype as the deceased sister underwent clinical-exome genetic sequencing (next generation sequencing). All first-degree relatives underwent clinical examination including cardiac ultrasound, Holter-ECG, exercise stress test and biochemistry panel. RESULTS: A genetic variant in the gene for phosphoglucomutase 1 (PGM1) was identified in the index patient and her two brothers, all were found to be homozygous for the genetic variant (G230E) NM_002633.2:c.689 G > A in PGM1. This variant has been linked to a congenital disorder of glycosylation (PGM1-CDG), explaining the clinical picture of short stature, cleft palate, liver engagement and cardiomyopathy. During follow-up one of the brothers died unexpectedly after physical exertion during daily life at the age of twelve years. The other brother fainted during similar circumstances at the age of thirteen years. Both parents and three other siblings were found to be heterozygous gene carriers without risk for the disease. CONCLUSION: Our findings suggest that there is a need of multidisciplinary discussion and genetic testing after unexpected cardiac death in the young. We have to be more flexible in our evaluation of diseases and to consider even uncommon diseases including rare recessive inherited disorders. Our findings also suggest that the autosomal recessive PGM1-CDG might be highly associated with life-threatening cardiomyopathy with arrhythmia or sudden cardiac death as the first symptom presenting from childhood and adolescence.

Predictors of risk for sudden death in childhood hypertrophic cardiomyopathy: the importance of the ECG risk score.

Objective: To establish which risk factors are predictive for sudden death in hypertrophic cardiomyopathy (HCM) diagnosed in childhood. Methods: A Swedish national cohort of patients with HCM diagnosed <19 years of age was collected between 1972 and 2014, consisting of 155 patients with available ECGs, with average follow-up of 10.9±(SD 9.0) years, out of whom 32 had suffered sudden death or cardiac arrest (SD/CA group). Previously proposed risk factors and clinical features, ECG and ultrasound measures were compared between SD/CA group and patients surviving >2 years (n=100), and features significantly more common in SD/CA group were further analysed with univariate and multivariate Cox hazard regression in the total cohort. Results: Ranked according to relative risk (RR) the ECG risk score >5 points had an RR of 46.5 (95% CI 6.6 to 331), sensitivity of 97% (83% to 100%) and specificity of 80% (71% to 88%) (p<0.0001), and was the best ECG predictor, predicting a 5-year risk of SD/CA of 30.6%. The following are other features with importantly raised RR: Detroit wall thickness Z-score >4.5: 9.9 (3.1 to 31.2); septal thickness ≥190% of upper limit of normal for age (septum in % of 95th centile for age (SEPPER) ≥190%): 7.9 (3.2 to 19.4); ventricular tachycardia: 9.1 (3.6 to 22.8); ventricular ectopics on exercise testing: 7.4 (2.7 to 20.2); and left ventricular outflow gradient (left ventricular outflow tract obstruction (LVOTO)) >50 mm Hg: 6.6 (4.0 to 11.0). Family history was non-significant. Multivariate Cox hazard analysis gives the following as early predictors: limb-lead QRS amplitude sum (p=0.020), SEPPER ≥190% (p<0.001) and LVOTO at rest (p=0.054); and for late predictors: last ECG risk score (p=0.002) and last Detroit Z-score (p=0.001). Both early (p=0.028) and late (p=0.037) beta-blocker doses reduced risk in the models. Conclusions: ECG phenotype as assessed by ECG risk score is important for risk of sudden death and should be considered for inclusion in risk stratification of paediatric patients with HCM.

Young patients with hypertrophic cardiomyopathy, but not subjects at risk, show decreased myocardial perfusion reserve quantified with CMR.

AIMS: To determine if myocardial perfusion (MP) during hyperaemia is decreased in young patients with hypertrophic cardiomyopathy (HCM). Also, to determine if an MP decrease is associated with diastolic dysfunction, and to investigate if young subjects at risk of HCM show differences in MP compared with controls. METHODS AND RESULTS: This study included 10 HCM patients (age 22.3 ± 6.4 years), 14 subjects at risk for HCM 'HCM risk' (age 18.9 ± 3.8 years), and 12 controls (age 22.8 ± 4.5 years). HCM patients were examined at rest and during hyperaemia (adenosine 140 µg/kg/min) with cardiovascular magnetic resonance (CMR) and echocardiography. MP was calculated as the ratio of coronary sinus flow and left ventricular mass (LVM) from CMR. Myocardial fibrosis was assessed using late gadolinium enhancement. Diastolic function was quantified with both echocardiography and CMR. At rest, MP (mL/min/g) was similar in the control, HCM risk, and HCM patients (0.8 ± 0.1, 1.0 ± 0.1, and 0.9 ± 0.1, respectively, P = ns). During adenosine, MP was lower in HCM patients (2.5 ± 0.4, P < 0.05) compared with both HCM risk (5.0 ± 0.5) and controls (3.9 ± 0.3). Subjects at HCM risk showed no significant difference in MP during adenosine compared with controls. One HCM patient showed mild diastolic dysfunction. Neither controls nor HCM risk individuals showed any sign of myocardial fibrosis, whereas 7/10 HCM patients had fibrosis (5 ± 1% of the total LVM). CONCLUSION: Young individuals with HCM, but not those at risk, show decreased MP during hyperaemia compared with controls even in the absence of diastolic dysfunction or LV outflow obstruction. These results may suggest that microvascular disease contributes to the decreased MP in the investigated population.