Echocardiographic and electrocardiographic identification of those children with hypertrophic cardiomyopathy who should be considered at high-risk of dying suddenly

Background., Hypertrophic cardiomyopathy is a common cause of sudden death in children. In this study, we aimed to identify clinical measures for stratification of this risk in childhood. Patients and methods: By means of a retrospective cohort study from six regional centres of paediatric cardiology, we identified 128 patients with hypertrophic cardiomyopathy presenting below 19 years of age, with a mean follow-up of 10.8 years. Of the patients, 31 had died, 16 suddenly, with a median age at sudden death of 13.3 years. Results: Cox regression shows that electrocardiographic voltages, analysed as the sum of the R and S waves in all six limb leads (p equal to 0.001), and septal thickness expressed as proportion of the 95th centile for age (p equal to 0.036), were independent predictors of sudden death. When the sum of the R and S waves is over 10 millivolts, the odds ratio for sudden death was 8.4, with 95% confidence intervals from 2.2 to 33.7 (p equal to 0.0012), and finding a septal thickness over 1.90% of 95th centile for age gives an odds ratio of 6.2, with confidence intervals from 1.5 to 25.1 (p equal to 0.011). Noonan's syndrome, with a p value equal to 0.043, and the ratio of the left ventricular wall to its cavity in diastole, with a p value equal to 0.005, were independent predictors of death in cardiac failure, with a ratio of the mural thickness to the dimension of the cavity over 0.30 giving an odds ratio of 36.0, with confidence limits from 4.2 to 311, and a p value equal to 0.00009. At follow-up, patients deemed to be at a high risk of dying suddenly were identified by the combination of the sum of the R and S waves greater than 10 millivolts and septal thickness over 190%, with a sensitivity of 9.1%, specificity of 78%, positive predictive value of 5096, and a negative predictive value of 97%. Conclusions: Children at high risk of dying suddenly with hypertrophic cardiomyopathy, with a subsequent annual mortality of 6.6%, can be distinguished at the time of diagnosis from those patients having a low risk of sudden death, the latter with an annual mortality of 0.27%

Diagnostic conclusions from the EASI-derived 12-lead electrocardiogram as compared with the standard 12-lead electrocardiogram in children.

Background Fewer electrodes on more easily located places would facilitate electrocardiogram (ECG) recording. To investigate the possibility of simplifying ECG recording in children, we compared the diagnostic conclusions when interpreting standard versus EASI-derived 12-lead ECGs. Our hypothesis was that the variation of the interpretation of standard versus EASI-derived 12-lead ECGs was not greater than the intrareader variation of the interpretation of standard ECGs. Methods The study included 221 children. The 2 lead systems were recorded simultaneously. Two experienced pediatric cardiologists interpreted the ECGs. First, the reader interpreted a set of 221 ECGs with randomly allocated standard and EASI-derived 12-lead ECGs. Next, the reader interpreted the complementary ECG set without having access to the first set. Finally, the reader reinterpreted the standard ECGs from 98 children. Results The variation of the interpretation of standard versus EASI-derived 12-lead ECGs was only slightly larger than the intrareader variation of the interpretation of standard ECGs. Conclusions For most of the electrocardiographic diagnoses, the conclusions from EASI-derived 12-lead ECGs were similar to those from standard ECGs. These findings support the suggestion that the EASI lead system is a potential alternative to the standard ECG in children

Third Trimester Fetal Heart Rate Predicts Phenotype and Mutation Burden in the Type 1 Long QT Syndrome.

-Early diagnosis and risk stratification is of clinical importance in the Long QT Syndrome (LQTS), however little genotype-specific data are available regarding fetal LQTS. We investigate third trimester fetal heart rate, routinely recorded within public maternal health care, as a possible marker for LQT1 genotype and phenotype

Age- and gender-specific mortality rates in childhood hypertrophic cardiomyopathy

Aims Hypertrophic cardiomyopathy (HCM) is the commonest inherited cause of sudden cardiac death in children; current guidelines suggest HCM screening after 12-15 years of age. The study aims to establish the age range at highest risk. Methods and results Cohort study from six regional centres of paediatric cardiology, including children presenting with sudden death; n = 150 (59% = male; 39% familial HCM). Age- and gender-specific mortality was calculated, and compared with rates calculated from the Swedish National Cause of Death Registry. There were 56 deaths within the cohort, 39 were sudden arrhythmia deaths, with 31 at < 19 years of age. Between 9-13.9 years of age annual sudden death mortality averages 7.2%, vs. 1.7% after 16 years of age; P = 0.025, odds ratio for proportions 3.75 [95% confidence intervals (CI) 1.18-11.91], similar in both familial and idiopathic HCM. The risk for sudden death peaks earlier in girls (10-11 years), with male preponderance after the age of 15. National cause of death statistics confirm that the mortality rate from HCM is significantly higher in the 8-16 year olds (0.112 per 100 000 age-specific population) than in the 17-30 year olds (0.055 per 100 000; 95% CI 0.011-0.099). Conclusion In families with HCM, children should be screened at an early age

An individual with a healthy phenotype in spite of a pathogenic LDL receptor mutation (C240F)

Familial hypercholesterolemia (FH) is caused by a defect in the function of the low density lipoprotein (LDL) receptor and inherited in an autosomal, codominant way. In this study we present a 13-year-old girl, compound heterozygote for the LDL receptor mutations C240F and Y167X. Fibroblasts from the patient showed very low cholesterol esterification rate, LDL uptake, and degradation compared to normal fibroblasts (< 2%, 8%, and < 2%, respectively). The C240F mutant was expressed in LDL receptor deficient CHOMldlA7 cells. Analysis of cell extracts by immunoblotting demonstrated delayed processing of the mutated LDL receptor, which was accumulated as a precursor protein of normal size. A high molecular weight form of the receptor was also detectable in these cells, which probably reflects cross-linking through the unpaired cysteine residue in the binding domain. Cells expressing the C240F mutant protein were unable to mediate uptake and degradation of LDL. The two siblings of the index case also carried the C240F mutation, but surprisingly one of them (a 17-year-old brother) showed no signs of hypercholesterolemia. This observation is consistent with the view that there may be cholesterol lowering mechanisms that can be activated, perhaps by mutations in known or hitherto unknown genes

Mutations in the HERG K+-Ion channel: A novel link between long QT syndrome and sudden infant death syndrome

In a 7-week-old infant who experienced sudden infant death syndrome (SIDS), a novel missense mutation was identified in KCNH2, causing a lysine-to-glutamic acid amino acid substitution at position 101 (K101E). KCNH2 codes for the HERG ion channel and mutations in the gene are associated with congenital long-QT syndrome (LQTS), and in the family of this case of SIDS, the mutation was associated with Torsades de pointes tachycardia, making SIDS the most likely outcome of congenital LQTS