A homozygous SCN5A mutation in a severe, recessive type of cardiac conduction disease.

Cardiac sodium channels are key players in the generation and propagation of action potentials in the human heart. Heterozygous mutations in the SCN5A gene have been found to be associated with long QT syndrome, Brugada syndrome, and sinus node dysfunction (SND). Recently, overlapping arrhythmia phenotypes have been reported as well. Here we describe a novel recessive SCN5A mutation in a family originating from the German minority in White Russia. Four affected children with a history of early cardiac arrhythmia encompassing SND, conduction disease, and severe ventricular arrhythmias, are homozygous carriers of a novel SCN5A missense mutation (p.I230T) in the channel protein. Interestingly, the heterozygous mutation carriers had neither significant ECG abnormalities nor a history of cardiac events. Heterologous expression of SCN5A(I230T) channels revealed normal protein transport but altered biophysical sodium channel properties. Voltage range of both activation and inactivation were shifted in a way that resulted in decreased sodium current and loss of channel function. In conclusion, we describe a rare clinical condition with a novel SCN5A mutation causing a new type of complex cardiac arrhythmia. Unlike most previously reported sodium channelopathies, this overlap syndrome displays recessive inheritance characteristics and does not seem to follow simple Mendelian rules.

Effect of Carvedilol on QT Duration in Paediatric Patients with Congestive Heart Failure.

OBJECTIVE: To investigate the effect of carvedilol on electrocardiographic parameters in children with congestive heart failure. PATIENTS AND METHODS: 18 children with heart failure (aged 2 months-17 years) were treated with carvedilol (initially 0.09 mg/kg/day, slowly increased up to 0.7 mg/kg/day) in addition to conventional therapy with digoxin, ACE inhibitors and diuretics. Twelve-lead rest electrocardiograms (ECGs) and echocardiography were performed in 16 patients with sinus rhythm at baseline and after 1, 2, 4 (n = 14) and 6 months (n = 14) of therapy. ECGs were analysed for heart rate, QT duration and QT dispersion. Echocardiography was performed for analysis of ejection fraction. RESULTS: After 6 months of therapy the mean ejection fraction increased from 37% to 55% (p < 0.05) and mean heart rate decreased by 14% (p < 0.05). Mean QT duration calculated by Bazett's formula (QT(B)) and Fridericia's formula (QT(F)) decreased from 428 msec (372-507 msec) to 387 msec (323-440 msec [QT(B)]; p < 0.05) and from 381 msec (315-466 msec) to 355 msec (309-435 msec [QT(F)]; p < 0.05) following therapy with carvedilol. In contrast, mean QT dispersion did not change significantly (18 msec; 10-40 msec before to 12 msec; 5-20 msec; p > 0.05). CONCLUSION: In conclusion, carvedilol treatment reduced QT duration but not QT dispersion in paediatric patients with heart failure. The decrease in QT duration reflects stabilisation of the action potential, and this may contribute to the improved prognosis in these patients.

Juvenile spondyloarthritis and severe cardiac involvement in a female patient.

Heart involvement is a recognized complication in 10-20% of all adults with spondyloarthritis. Until now only 8 cases of cardiac involvement in juvenile spondyloarthritis (JS) have been reported, all male patients. We describe the first female patient with JS, in whom progressive cardiac involvement developed, and summarize the pediatric JS cases with cardiac involvement.

Plasma concentrations of N-terminal pro-brain natriuretic peptide in control children from the neonatal to adolescent period and in children with congestive heart failure.

OBJECTIVE: To determine plasma levels of N-terminal pro-brain natriuretic peptide (N-BNP) in control children to establish a normal age-dependent range from the neonatal period to adulthood. In addition, plasma concentrations of N-BNP were measured in children with congestive heart failure (CHF) and correlated with ejection fraction and clinical symptoms of heart failure. METHODS: For establishing a normal age-dependent range of plasma N-BNP, venous blood samples were taken in 133 control patients from the neonatal period to adulthood (10 days-32 years) and in 31 children with CHF. Plasma N-BNP levels were determined by an enzyme immunoassay. In children (1 month-14 years) with CHF, plasma N-BNP levels were correlated to ejection fraction measured by echocardiography and clinical symptoms of heart failure using the Ross Score. RESULTS: N-BNP levels in control children, adolescents, and adults did not show a significant age-related difference. In control children, the normal range was established between 150 (10th percentile) and 430 fmol/mL (90th percentile). Mean plasma N-BNP in control children was 311 fmol/mL (range: 74-654 fmol/mL). In 31 children with CHF, the plasma N-BNP levels were significantly higher (mean: 846; range: 219-2718) than in control children. N-BNP levels showed a negative correlation with the ejection fraction (r = -0.53) and a positive correlation with the clinical heart failure score (r = 0.74). CONCLUSIONS: Plasma N-BNP levels reflect the severity of symptoms of heart failure and the impairment of cardiac function in children with CHF. In the future, determination of plasma N-BNP levels may be used as a helpful adjunct to monitor the effect of various treatments for CHF in children.

Carvedilol therapy in pediatric patients with congestive heart failure: a study investigating clinical and pharmacokinetic parameters.

OBJECTIVE: Our purpose was to evaluate the clinical effect of carvedilol among pediatric patients with congestive heart failure (CHF) who did not respond to standard therapy and to assess the pharmacokinetics of carvedilol among these children. METHODS: In this prospective, open intervention trial with blinded interpretation of selected end points, patients with CHF who did not improve on standard therapy, including digoxin, angiotensin-converting enzyme inhibitors, and diuretics, were treated with oral carvedilol in a ramped dosing scheme. Clinical parameters (ejection fraction, fractional shortening, and modified Ross score) were assessed before initiation of treatment and monthly for 6 months. Pharmacokinetic profiles of carvedilol were determined over the first 12-hour period after the initial dose in study patients, and for comparison, in 9 healthy adult volunteers. RESULTS: Fifteen patients (aged 6 weeks to 19 years) were enrolled in the study, including 10 patients with dilated cardiomyopathy and 5 with CHF secondary to congenital heart disease. All 15 patients tolerated carvedilol for the duration of the trial, and all achieved maximum target dosing. After 6 months of carvedilol therapy, ejection fraction increased (36% vs 54%; P <.05) and modified Ross Score improved (5 +/- 2 vs 3 +/- 3; P <.05). Elimination half-life was about 50% shorter in pediatric CHF patients compared with healthy adult volunteers (2.9 vs 5.2 hours; P <.05). CONCLUSIONS: Pediatric patients with CHF not responding to standard therapy may benefit from oral carvedilol treatment. The observed increased elimination of carvedilol in children suggests that optimal dosing strategies need to be further defined among the pediatric population.