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Idebenone and reduced cardiac hypertrophy in Friedreich's ataxia

Background: Friedreichs ataxia encodes a protein of unknown function, frataxin. The loss of frataxin is caused by a large GAA trinucleotide expansion in the first intron of the gene, resulting in deficiency of a Krebs cycle enzyme, aconitase, and of three mitochondrial respiratory chain complexes (I–III). This causes oxidative stress. Idebenone, a short chain quinone acting as an antioxidant, has been shown to protect heart muscle against oxidative stress in some patients. Objective: To assess the efficiency of idebenone on cardiac hypertrophy in Friedreichs ataxia. Design: Prospective, open trial. Setting: Tertiary care centre. Methods: Idebenone (5 mg/kg/day) was given orally to 38 patients with Friedreichs ataxia aged 4–22 years (20 males, 18 females). Cardiac ultrasound indices were recorded before and after idebenone treatment. Results: After six months, cardiac ultrasound indicated a reduction in left ventricular mass of more than 20% in about half the patients (p < 0.001). The shortening fraction was initially reduced in six of the 38 patients (by between 11–26%) and it improved in five of these. In one patient, the shortening fraction only responded to 10 mg/kg/day of idebenone. No correlation was found between responsiveness to idebenone and age, sex, initial ultrasound indices, or the number of GAA repeats in the frataxin gene. Conclusions: Idebenone is effective at controlling cardiac hypertrophy in Friedreichs ataxia. As the drug has no serious side effects, there is a good case for giving it continuously in a dose of 5–10 mg/kg/day in patients with Friedreichs ataxia at the onset of hypertrophic cardiomyopathy.

Long-term fate of the coronary arteries after the arterial switch operation in newborns with transposition of the great arteries.

OBJECTIVE: Concern continues to be expressed about the long-term impact of coronary artery translocation after the arterial switch operation for transposition of the great arteries. This study was conducted to determine the prevalence of obstructions of the translocated coronary arteries by the use of selective coronary artery angiography. METHODS AND RESULTS: 64 children (mean age 7.6 (SD) 1.5 years) who had survived an arterial switch operation underwent evaluation. They had been operated on by one surgeon and they were followed up by a single hospital. Selective coronary artery angiography was possible in 58 patients. Five patients showed occlusion or stenosis of a coronary artery: one occlusion and two stenoses of the left coronary trunk, two occlusions of the circumflex artery. The prevalence of late coronary artery complications was 7.8 (SD) 6.6% (95% CI 1.2 to -14.4%). The three patients with occlusion of one coronary artery had perioperative ischaemic complications, with associated electrocardiogram evidence of ischaemia and left ventricular dysfunction with mitral valve insufficiency. Both patients with stenosis of the left main coronary artery trunk did not have any evidence of an anomaly before catheterisation. CONCLUSIONS: The prevalence of the late coronary artery complications after an arterial switch operation was low in this series. This accords with the view that the arterial switch operation remains the preferred treatment for such patients. Screening for late coronary artery patency should be done by using selective coronary artery angiography, because even patients who remain symptom free can have coronary artery anomalies.

Quality of life and perceived health status in surviving adults with univentricular heart

OBJECTIVE To evaluate the quality of life in patients with univentricular heart and to determine the impact of sociodemographic and clinical characteristics. DESIGN AND SETTING Retrospective, cross sectional study conducted in a regional paediatric cardiology centre. PATIENTS The health records of 89 survivors with univentricular heart (median age 21 years; range 17–49 years) were reviewed. Sixty seven answered the Duke questionnaire. Sociodemographic and clinical variables were similar in the responders and non-responders. The impact of sociodemographic and clinical variables on individual Dukes measures was assessed. RESULTS The Duke scores of adults with univentricular heart were similar to the normal population. Cyanosis predicted a worse score for physical (p = 0.05) and perceived health measures (p = 0.02). A higher educational level predicted a better score for physical (p = 0.004), mental (p = 0.01), and general health measures (p = 0.02). Orthopaedic problems worsened the social score (p = 0.05). Psychosocial problems worsened the pain score (p = 0.04). In comparison with the other anatomical types, mitral atresia worsened the perceived health score (p = 0.02). Patients younger than 23 years scored better for almost all health and dysfunction measures. CONCLUSIONS Despite repeated interventions and other disease related everyday stresses, a selected group of adults with univentricular heart had a satisfying quality of life.

Relation of genotype 22q11 deletion to phenotype of pulmonary vessels in tetralogy of Fallot and pulmonary atresia–ventricular septal defect

Objective To compare the morphology of the pulmonary vessels in tetralogy of Fallot or pulmonary atresia–ventricular septal defect (PA–VSD) with (del22q) and without 22q11 deletion (non-del22q). Patients 94 consecutive infants (54 with tetralogy of Fallot, 40 with PA–VSD) were studied using ultrasound and catheterisation. Molecular investigations Identification of the 22q deletion was performed either by fluorescent in situ hybridisation or polymerisation chain reaction genotyping. Results 25 patients were del22q (16/40 (40%) PA–VSD v 9/54 (17%) tetralogy of Fallot; p < 0.02). Major aortopulmonary collateral arteries was more common in patients with PA–VSD-del22q (p < 0.03). Such collaterals were identified in 13 patients: 10 del22q and three non-del22q (p < 0.001). The size of the right and left pulmonary arteries expressed as a standard deviation (SD) difference of the normal range was −4.2 (quartiles −5.3 and −2.9) for PA–VSD del22q, and −2.6 (−3.1 and −1.8) for PA–VSD non-del22q (p = 0.02). The mean (SD) difference between the measured and theoretical Nakata index was −373 (94) for PA–VSD del22q v−245 (93) in PA–VSD non-del22q (p = 0.0002). In tetralogy of Fallot patients with and without del22q, the size of the pulmonary arteries was similar (p = 0.6). Conclusions A “specific” phenotype could be defined in patients with deletion: PA–VSD, major aortopulmonary collateral arteries with complex loop morphology, and small central pulmonary arteries. Differences in the morphology of the pulmonary vessels may indicate a different timing of the faulty developmental pathway in patients with and without 22q11 deletion.

Maintaining tricuspid valve competence in double discordance: a challenge for the paediatric cardiologist

Objectives To establish the prevalence of tricuspid valve abnormalities in children with a double discordant heart (or congenitally corrected transposition of the great arteries); to study the influence of the loading conditions induced by various surgical interventions on the right and left ventricle in patients with double discordance and an abnormal tricuspid valve; and to propose a rational surgical approach. Methods Case notes were reviewed of 141 consecutive patients admitted in the first year of life with various types of double discordance (intact ventricular septum (group 1), ventricular septal defect (group 2), ventricular septal defect and pulmonary obstruction (group 3)). A study group of 62 patients with an abnormal tricuspid valve was selected by cross sectional echocardiography. These were followed up through palliative and open heart procedures with grading of tricuspid regurgitation. Results Tricuspid valve abnormalities were more common in groups 1 and 2 (60% and 56%) than in group 3 (31%). Preoperative tricuspid regurgitation was more common in group 2 (90%) than in groups 1 and 3 (38% and 36%). Ten patients in groups 1 and 2 died in the neonatal period with severe tricuspid regurgitation, associated with coarctation of the aorta in 60%. Eight patients in group 1 had no surgery and are doing well, with a competent tricuspid valve. Palliative procedures were undertaken in 28 patients: 14 had pulmonary artery banding, which resulted in a decrease in tricuspid regurgitation, 12 in group 2 by reducing the pulmonary blood flow and two in group 1 by changing the septal geometry; 14 in group 3 had an aortopulmonary shunt, which induced tricuspid regurgitation in two. Twenty patients are still alive after palliation, with stable tricuspid valve function. Repair of the tricuspid valve was unsuccessful in the three patients who underwent conventional surgery, leaving the right ventricle facing the systemic circulation. In two patients with a competent but abnormal tricuspid valve, conventional surgery induced severe tricuspid regurgitation. Of the 15 patients who underwent conventional surgery, only 10 survived (mortality 33%): eight with a tricuspid valve prosthesis and two with severe residual tricuspid regurgitation. However, tricuspid regurgitation decreased after anatomical correction (nine patients), restoring a systemic left ventricle and a subpulmonary right ventricle, even when the tricuspid valve was not repaired (five patients). Eight patients are doing well after anatomical correction (mortality 11%). Conclusions Tricuspid valve function in double discordance with an abnormal tricuspid valve depends on the loading conditions of both ventricles and on the septal geometry. Interventions that increase right ventricular volume or decrease left ventricular pressure are likely to induce tricuspid regurgitation, while those that decrease right ventricular volume or increase left ventricular pressure are likely to improve tricuspid valve function. Repair of the tricuspid valve always failed when the right ventricle was left in a systemic position and always succeeded when the right ventricle was placed in a subpulmonary position. These results should be taken in to account when dealing with patients with double discordance and an abnormal tricuspid valve.

Mechanical properties of the common carotid artery in Williams syndrome

OBJECTIVE To determine whether arterial wall hypertrophy in elastic arteries was associated with alteration in their mechanical properties in young patients with Williams syndrome. METHODS Arterial pressure and intima–media thickness, cross sectional compliance, distensibility, circumferential wall stress, and incremental elastic modulus of the common carotid artery were measured non-invasively in 21 Williams patients (mean (SD) age 8.5 (4) years) and 21 children of similar age. RESULTS Systolic and diastolic blood pressures were higher in Williams patients (125/66v 113/60 mm Hg, p < 0.05). The mean (SD) intima–media thickness was increased in Williams patients, at 0.6 (0.07) v 0.5 (0.03) mm (p < 0.001). Normotensive Williams patients had a lower circumferential wall stress (2.1 (0.5) v 3.0 (0.7) mm Hg, p < 0.01), a higher distensibility (1.1 (0.3) v 0.8 (0.3) mm Hg−1.10−2, p < 0.01), similar cross sectional compliance (0.14 (0.04) v 0.15 (0.05) mm2.mm Hg−1, p > 0.05), and lower incremental elastic modulus (7.4 (2.0) v 14.0 (5.0) mm Hg.102; p < 0.001). CONCLUSIONS The compliance of the large elastic arteries is not modified in Williams syndrome, even though increased intima–media thickness and lower arterial stiffness are consistent features. Therefore systemic hypertension cannot be attributed to impaired compliance of the arterial tree in this condition.

Assessment of the geometric profile of the Amplatzer and Cardioseal septal occluders by three dimensional echocardiography

OBJECTIVE To apply three dimensional echocardiography to describe the geometric profile of the Amplatzer and Cardioseal occluders after deployment for closure of atrial septal defect. METHODS 20 patients (mean (SD) age, 14 (5) years) were enrolled for transcatheter closure of a secundum atrial septal defect with the Amplatzer occluder (10) or with the Cardioseal occluder (10). The two populations were matched for the stretched diameter of the defect (mean 18 (6) mm). The profile of the two occluders was examined. RESULTS Transoesophageal echocardiography did not show any residual shunts after Amplatzer occluder deployment, whereas three patients had a small residual leak after Cardioseal deployment. One patient had transient atrioventricular block with the Amplatzer device. The mean surface area of the Amplatzer occluder was 6.9 (2) cm2, and that of the Cardioseal device 5.4 (3) cm2 (p = 0.03). The mean volume of the Amplatzer occluder was 9.2 (1) cm3, while that of the Cardioseal occluder was 3.5 (1) cm3 (p < 0.0001). From the three dimensional views, the Cardioseal occluder looked like a flat square after deployment whereas the Amplatzer occluder took up a ball shape in the atrial cavity. CONCLUSIONS Three dimensional views by multiplane transoesophageal echocardiography allow a realistic in vivo description of atrial septal occluders. The Amplatzer occluder, with its high geometric profile, allows complete closure of large atrial septal defects but with some risk of mechanical complications. Use of the Cardioseal device, with its small surface coverage and high residual shunt rate, should be limited to transcatheter closure of a patent foramen ovale or small atrial septal defects.

Total cavopulmonary and atriopulmonary connections are associated with reduced heart rate variability

AIM To determine whether cavopulmonary connections are associated with abnormalities of heart rate variability. METHODS Heart rate variability was studied by 24 hour Holter monitoring in 39 patients (mean (SD) age 12.2 (4.1) years) who underwent cavopulmonary connection operations (partial in 12, total in 13, and atriopulmonary in 14). Two control groups were used: 18 healthy children (11.1 (2.5) years) and 16 patients (11.7 (4.3) years) undergoing cardiovascular surgery for biventricular repair of congenital heart disease. All patients were in sinus rhythm and had normal left ventricular function. Four time domain indices were calculated: mean duration of RR intervals (RR), standard deviation of all RR intervals (SD), square root of the mean squared differences of successive RR intervals (r-MSSD), and percentage differences of successive RR intervals of > 50 ms duration (pNN50). Four frequency domain indices were calculated: total power (TP), low frequency (LF), high frequency (HF), and the LF:HF ratio. RESULTS Heart rate variability indices were identical in the two control groups. Significantly reduced heart rate variability was found in patients with total cavopulmonary connections and atriopulmonary connections compared with the two control groups. In patients with partial cavopulmonary connections, heart rate variability was reduced compared with healthy controls. No differences in heart rate variability could be related to clinical status (New York Heart Association functional class), number of surgical interventions, or presence of right atrial enlargement. CONCLUSIONS Patients with cavopulmonary connections have significantly reduced heart rate variability and a particularly low vagal drive.

Pulmonary balloon valvuloplasty in the palliation of complex cyanotic congenital heart disease.

OBJECTIVE: To assess the value of pulmonary balloon valvuloplasty in the interim palliation of complex congenital heart disease and pulmonary stenosis in children, who often require numerous palliative operations before definitive surgical repair. METHODS: Evaluation of pulmonary balloon valvuloplasty procedures performed over a five year period in 18 patients (age 8 days--29 years; mean 5.5 years) with complex cyanotic congenital heart disease. RESULTS: After pulmonary balloon valvuloplasty oxygen saturation increased from a mean (SD) of 69 (7.5)% to 83 (7.0)% (P < 0.001). Mean pulmonary artery pressure increased from a mean (SD) of 11.3 (3.8) mm Hg to 15.7 (3.9) mm Hg (P < 0.001). Transient complete atrioventricular block occurred in one patient. No other complications were encountered. In 5 patients (28%) there was an inadequate improvement in cyanosis compared with pre-procedure values (72 (4.7)% v 66 (8.1)%). Reasons for failure were increasing infundibular stenosis in three and inadequate mixing in one child. In 13 patients (72%) pulmonary balloon valvuloplasty gave adequate interim palliation over a mean follow up of 1.1 (1.3) years. Oxygen saturation was 81 (5.6)% at last follow up compared with 70 (7.3)% before pulmonary balloon valvuloplasty (P < 0.001). CONCLUSION: Pulmonary balloon valvuloplasty is a safe and effective technique in the palliation of patients with complex cyanotic congenital heart disease associated with pulmonary valve stenosis.

Impaired cardiac adrenergic innervation assessed by MIBG imaging as a predictor of treatment response in childhood dilated cardiomyopathy

OBJECTIVE To evaluate the prognostic value of metaiodobenzylguanidine (MIBG) imaging in childhood cardiomyopathy. DESIGN Prospective cohort study. SETTING Tertiary referral centre. PATIENTS 40 children (21 boys, 19 girls; mean (SD) age, 7.0 (5.6) years) with heart failure resulting from idiopathic dilated cardiomyopathy (n = 23) or various other disorders (n = 17). METHODS At the initial examination, cardiac 123I-MIBG uptake and release, circulating noradrenaline (norepinephrine) concentration,x ray cardiothoracic ratio, and echocardiographic variables were recorded. Cardiac MIBG uptake was obtained by measuring the heart to mediastinum activity ratio on the planar image obtained four hours after MIBG injection. MIBG washout rate was evaluated using relative decrease in cardiac activity measured at 20 minutes and four hours. Patients were treated with angiotensin converting enzyme inhibitors, diuretics, and digitalis, and were followed up for 12 (10) months. Fifteen patients did not respond to medical treatment (12 heart transplants; three deaths), and 25 did respond (improved or stable). RESULTS Cardiac MIBG uptake was positively correlated with x ray cardiothoracic index (r = 0.55, p = 0.0008) and echocardiographic left ventricular fractional shortening (r = 0.68, p < 0.0001). Among all the clinical and laboratory variables tested, multivariate discriminant analysis showed that the only independent predictor of an unfavourable outcome was a low MIBG uptake (p < 0.001). Survival curves had a mean threshold value of 1.54 for MIBG uptake. CONCLUSIONS Impaired cardiac adrenergic innervation is strongly related to adverse outcome in children with dilated cardiomyopathy, independently of the aetiology. MIBG imaging may help to stratify risk in such patients.