38 research outputs found

    Early Cardiovascular Changes of Familial Hypertrophic Cardiomyopathy in the Young

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    Familial hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease, transmitted in an autosomal dominant fashion, i.e. 50% risk for transmission of the disease-causing mutation to each child of the affected family. Previous studies reveal a high risk for HCM related cardiac events including sudden cardiac death (SCD) during childhood, with a peak incidence of up to 10% during the first two decades of life. HCM remains the most common cause of sudden cardiac death in young people and athletes, probably due to fatal arrhythmias mainly caused by structural and functional changes in the myocardium leading to increased risk for major cardiac events. In young athletes, the distinction between physiological and pathological hypertrophy is often very challenging. The diagnosis of HCM in childhood is more difficult in its early phases, due to the progressive nature of the disease and the lack of HCM symptoms. The increasing population with HCM genotype with little or no detectable myocardial hypertrophy along with the increased risk for cardiac events even in these individuals are important aspects that emphasize the stringent need to improve early diagnosis of HCM in the young. In these studies, we sought to investigate indices of early cardiovascular changes in young individuals with or without myocardial hypertrophy on echocardiography. Study I showed altered diastolic function both in HCM and HCM-risk individuals vs. controls and young athletes. There were altered microvascular responses to acetylcholine, indicating an early endothelial dysfunction present in both the HCM-risk and HCM patients, measured by laser Doppler of peripheral circulation. These microvascular changes were associated with abnormalities in diastolic myocardial function measured by TDI. Study II demonstrated decreased myocardial perfusion (MP) during adenosine induced hyperemia in non-fibrotic myocardium even without diastolic dysfunction in young HCM patients, but not subjects at risk or controls, indicating that microvascular disease can be the cause of MP decrease. Study III showed decreased regional perfusion in hypertrophied compared to non-hypertrophied myocardium and even lower perfusion in areas of fibrotic, hypertrophied myocardium in young HCM patients. The adenosine stress-induced hypoperfused areas were found larger than regions with LGE (fibrosis), indicating that hypoperfusion may be a more sensitive marker of diseased myocardium. Study IV suggests adverse changes of circulating biomarkers reflecting myocardial matrix remodeling, microfibrosis and vascular endotheliopathy in the early stage of hypertrophic cardiomyopathy in the young. Study V showed the superiority of the 2-parameter 12-lead A-ECG score, which is significantly more sensitive and specific than pooled, age-specific conventional ECG criteria for detecting MYBPC3-HCM and in distinguishing such patients from healthy controls, including endurance-trained athletes

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

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    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

    Early repolarization in children with unexplained syncope

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    Introduction: It has traditionally been believed that early repolarization (ER) is benign. Significant association between ER and sudden cardiac arrest due to idiopathic ventricular fibrillation was recently found in a large cohort of adult survivors of sudden cardiac arrest. In some prior studies, unexplained syncope has been linked to risk of sudden death, but the mechanisms remain speculative.We assessed herein the prevalence of ER in children referred to our center for unexplained syncope. Methods: We evaluated retrospectively electrocardiograms from such children (n = 29; mean age, 12.1 years; range, 7-18 years) for presence of ER, which was defined as an elevation of the QRS-ST junction (J-point) in at least 2 leads of at least 1 mm (0.1 mV) above the baseline level. The anterior precordial leads (V1-V3) were excluded from the analysis to avoid inclusion of patients with right ventricular dysplasia or Brugada syndrome. Agematched children (n = 33; mean age, 12.3 years; range, 7-16 years) with noncardiac chest pain were included as controls. Results: Early repolarization was detected in 45% (13/29) of children with unexplained syncope vs 24% (8/33) in the chest pain group. Among children with syncope, ER was far more frequent in males than in females (8/12 vs 5/ 17, respectively). Echocardiography showed normal functional and structural findings in all children. Conclusion: In this relatively small-scale retrospective study of children with unexplained syncope with otherwise normal cardiac findings, we found particularly among those of male gender a greater prevalence of ER than in controls (noncardiac chest pain).With view to earlier findings of Haisaguerre et al (NEJM 2008), this intriguing association warrants further prospective studies addressing its precise clinical implication and underlying mechanisms

    Novel Mutation in the KCNJ2 Gene Is Associated with a Malignant Arrhythmic Phenotype of Andersen-Tawil Syndrome.

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    Andersen-Tawil syndrome (ATS) is a rare inherited multisystem disorder associated with mutations in KCNJ2 and low prevalence of life-threatening ventricular arrhythmias. Our aim was to describe the clinical course of ATS in a family, in which the proband survived aborted cardiac arrest (ACA) and genetic screening revealed a previously unknown mutation (c.271_282del12[p.Ala91_Leu94del]) in the KCNJ2 gene

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

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    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 (950/0 Cl 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

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

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    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 &lt;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 &gt;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 &gt;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&lt;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 &gt;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)) &gt;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&lt;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

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

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    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

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

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    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 &amp;lt;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 &amp;gt;= 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 &amp;gt;= 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 &amp;lt; 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 &amp;gt;= 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.Funding Agencies|Swedish Heart-and Lung FoundationSwedish Heart-Lung Foundation [20080510]; Swedish government; ALF agreement [ALFgbg-544981]; Region Ostergotland (ALF); Strategic Research Area in Forensic Science; FORSS (Medical Research Council of Southeast Sweden)</p
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