Mutations in calmodulin cause ventricular tachycardia and sudden cardiac death.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a devastating inherited disorder characterized by episodic syncope and/or sudden cardiac arrest during exercise or acute emotion in individuals without structural cardiac abnormalities. Although rare, CPVT is suspected to cause a substantial part of sudden cardiac deaths in young individuals. Mutations in RYR2, encoding the cardiac sarcoplasmic calcium channel, have been identified as causative in approximately half of all dominantly inherited CPVT cases. Applying a genome-wide linkage analysis in a large Swedish family with a severe dominantly inherited form of CPVT-like arrhythmias, we mapped the disease locus to chromosome 14q31-32. Sequencing CALM1 encoding calmodulin revealed a heterozygous missense mutation (c.161A>T [p.Asn53Ile]) segregating with the disease. A second, de novo, missense mutation (c.293A>G [p.Asn97Ser]) was subsequently identified in an individual of Iraqi origin; this individual was diagnosed with CPVT from a screening of 61 arrhythmia samples with no identified RYR2 mutations. Both CALM1 substitutions demonstrated compromised calcium binding, and p.Asn97Ser displayed an aberrant interaction with the RYR2 calmodulin-binding-domain peptide at low calcium concentrations. We conclude that calmodulin mutations can cause severe cardiac arrhythmia and that the calmodulin genes are candidates for genetic screening of individual cases and families with idiopathic ventricular tachycardia and unexplained sudden cardiac death.

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.

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.

Third trimester fetal heart rate predicts phenotype and mutation burden in the type 1 long QT syndrome.

BACKGROUND: 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. METHODS AND RESULTS: This retrospective study includes 184 fetuses from 2 LQT1 founder populations segregating p.Y111C and p.R518X (74 noncarriers and 110 KCNQ1 mutation carriers, whereof 13 double mutation carriers). Pedigree-based measured genotype analysis revealed significant associations between fetal heart rate, genotype, and phenotype; mean third trimester prelabor fetal heart rates obtained from obstetric records (gestational week 29-41) were lower per added mutation (no mutation, 143±5 beats per minute; single mutation, 134±8 beats per minute; double mutations, 111±6 beats per minute; P<0.0001), and lower in symptomatic versus asymptomatic mutation carriers (122±10 versus 137±9 beats per minute; P<0.0001). Strong correlations between fetal heart rate and neonatal heart rate (r=0.700; P<0.001), and postnatal QTc (r=-0.762; P<0.001) were found. In a multivariable model, fetal genotype explained the majority of variance in fetal heart rate (-10 beats per minute per added mutation; P<1.0×10(-23)). Arrhythmia symptoms and intrauterine ß-blocker exposure each predicted -7 beats per minute, P<0.0001. CONCLUSIONS: In this study including 184 fetuses from 2 LQT1 founder populations, third trimester fetal heart rate discriminated between fetal genotypes and correlated with severity of postnatal cardiac phenotype. This finding strengthens the role of fetal heart rate in the early detection and risk stratification of LQTS, particularly for fetuses with double mutations, at high risk of early life-threatening arrhythmias.

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.

Nitric oxide in neonatal transposition of the great arteries.

UNLABELLED: Three newborn infants with transposition of the great arteries (TGA) and intact ventricular septum (IVS) developed postnatal persistent pulmonary hypertension of the newborn (PPHN) and were successfully treated with inhaled nitric oxide (iNO). Intervention with balloon atrial septostomy (BAS) was performed in two of the infants before the iNO treatment, but they continued to be severely hypoxic with metabolic acidosis. However, the iNO immediately improved oxygenation and the clinical condition. The third neonate had a moderately large atrial communication and echocardiographic signs of PPHN. He received iNO before BAS with dramatic clinical improvement, which therefore postponed BAS. CONCLUSION: Early diagnosis of PPHN and treatment with iNO may improve final outcome in neonates with TGA and IVS. In the presence of moderately large atrial communication and PPHN, treatment with iNO might be considered before BAS.

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 190% 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 91%, specificity of 78%, positive predictive value of 50%, 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%.