Longitudinal Myocardial Deformation Does Not Predict Single Ventricle Ejection Fraction Assessed by Cardiac Magnetic Resonance Imaging in Children with a Total Cavopulmonary Connection.

Survival of children with single ventricle heart defects after the total cavopulmonary connection (TCPC) has improved, but impaired cardiac function remains a major cause of morbidity and mortality. Cardiac magnetic resonance imaging (cMRI) is the gold standard in assessing single ventricle volume and function, but high costs and limited availability hamper its routine use. A cheaper and more available alternative is echocardiography. Myocardial function can be studied in more detail using speckle tracking echocardiography (STE). The purpose of the study was to describe the association between myocardial deformation assessed by speckle tracking echocardiography (STE) and single ventricle function assessed by cMRI and to evaluate differences in myocardial deformation in children with single left and single right ventricular morphology. Cross-sectional, multicenter study in 77 children after TCPC was conducted. STE segmental and global longitudinal peak strain and systolic strain rate (SR) of the dominant ventricle were measured. Impaired SV function by cMRI was defined as ejection fraction (EF) < 45%. Mean age was 11.8 (range 9.7-14.3) years. Pearson R for cMRI EF versus global longitudinal strain and SR was - 0.25 (p = 0.06) and - 0.03 (p = 0.82), respectively. Global single ventricle longitudinal strain and SR was similar in patients after TCPC with single left and single right ventricular morphology (- 19.0 ± 3.1% vs 19.2 ± 3.2%, p = 0.94). STE myocardial deformation parameters do not correlate with single ventricle ejection fraction assessed by cMRI.

Is 2D speckle tracking echocardiography useful for detecting and monitoring myocardial dysfunction in adult m.3243A>G carriers? - a retrospective pilot study.

OBJECTIVES: Cardiomyopathy is a common complication of mitochondrial disorders, associated with increased mortality. Two dimensional speckle tracking echocardiography (2DSTE) can be used to quantify myocardial deformation. Here, we aimed to determine the usefulness of 2DSTE in detecting and monitoring subtle changes in myocardial dysfunction in carriers of the 3243A>G mutation in mitochondrial DNA. METHODS: In this retrospective pilot study, 30 symptomatic and asymptomatic carriers of the mitochondrial 3243A>G mutation of whom two subsequent echocardiograms were available were included. We measured longitudinal, circumferential and radial strain using 2DSTE. Results were compared to published reference values. RESULTS: Speckle tracking was feasible in 90 % of the patients for longitudinal strain. Circumferential and radial strain showed low face validity (low number of images with sufficient quality; suboptimal tracking) and were therefore rejected for further analysis. Global longitudinal strain showed good face validity, and was abnormal in 56-70 % (depending on reference values used) of the carriers (n = 27). Reproducibility was good (mean difference of 0.83 for inter- and 0.40 for intra-rater reproducibility; ICC 0.78 and 0.89, respectively). The difference between the first and the second measurement exceeded the measurement variance in 39 % of the cases (n = 23; feasibility of follow-up 77 %). DISCUSSION: Even in data collected as part of clinical care, two-dimensional strain echocardiography seems a feasible method to detect and monitor subtle changes in longitudinal myocardial deformation in adult carriers of the mitochondrial 3243A>G mutation. Based on our data and the reported accuracy of global longitudinal strain in other studies, we suggest the use of global longitudinal strain in a prospective follow-up or intervention study.

Ventricular function and cardiac reserve in contemporary Fontan patients.

BACKGROUND/OBJECTIVE: Total cavopulmonary connection (TCPC) has been the preferred treatment for patients with univentricular hearts. Current TCPC-techniques are the intra-atrial lateral tunnel (ILT) and the extracardiac conduit (ECC). We aimed to determine ventricular function during rest and stress, and to compare results for both techniques and for left (LV) versus right ventricular (RV) dominance. METHODS: 99 patients, aged 12.5 ± 4.0 years underwent echocardiography and magnetic resonance imaging (MRI), and 69 patients underwent stress MRI. RESULTS: Echocardiography showed impaired systolic and diastolic function. MRI parameters were comparable between ILT and ECC at rest. During dobutamine there was a decrease in end-diastolic volume (EDVi) (91 ± 21 vs. 80 ± 20 ml/m(2) p<0.001). Ejection fraction (EF) and cardiac index (CI) during dobutamine were lower for ILT patients (59 ± 11 (ILT) vs. 64 ± 7% (ECC), p=0.027 and 4.2 ± 1.0 (ILT) vs. 4.9 ± 1.0L/min/m(2) (ECC), p=0.006), whereas other parameters were comparable. TEI-index was higher in ILT-patients (0.72 ± 0.27 (ILT) vs. 0.56 ± 0.22 (ECC), p=0.002). Diastolic function was frequently impaired in patients with a dominant RV (67% (RV) vs. 39% (LV), p=0.011). Patients with dominant LV's had smaller end-systolic volume (ESVi) (40 ± 13 (LV) vs. 47 ± 16 (RV) ml/m(2), p=0.030) and higher EF (55 ± 8 (LV) vs. 49 ± 9 ml/m(2) (RV), p=0.001) and contractility (2.3 ± 0.8 (LV) vs. 1.9 ± 0.7 mmHg/ml/m(2) (RV), p=0.050) during rest and higher EF during dobutamine (63 ± 8 (LV) vs. 58 ± 10 ml/m(2) (RV), p=0.043). CONCLUSION: Ventricular function is relatively well preserved in modern-day Fontan patients. With dobutamine stress there is a decrease in EDVi. ECC patients have higher CI and EF during stress. Patients with a dominant RV have lower systolic, including impaired contractility, and diastolic function.

New biomarkers for early detection of cardiotoxicity after treatment with docetaxel, doxorubicin and cyclophosphamide.

OBJECTIVE: Assessing a diverse biomarker panel (NT-proBNP, TNF-α, galectin-3, IL-6, Troponin I, ST2 and sFlt-1) to detect subclinical cardiotoxicity after treatment with anthracyclines. METHODS: Of 55 breast cancer patients biomarkers were assessed and echocardiography was performed one year after treatment with anthracyclines. RESULTS: 29.1% of patients showed abnormal biomarker levels: NT-proBNP in 18.2%, TNF-α and Galectin-3 in 7.3%. IL-6, troponin I, ST2 and sFlt-1 were normal in all patients. A correlation between left ventricular ejection fraction (LVEF) and NT-proBNP was observed (r = -0.564, p ≤ 0.01). CONCLUSION: The evaluated biomarkers do not contribute to early detection. Future research should focus on NT-proBNP.

The effect of exercise training on cardiac remodelling in children and young adults with corrected tetralogy of Fallot or Fontan circulation: a randomized controlled trial.

BACKGROUND: Exercise can improve physical fitness in children and adults with congenital heart disease. We hypothesized that exercise training would not lead to adverse cardiac remodelling in this population. METHODS AND RESULTS: This multi-centre randomized controlled trial included children and young adults (10 to 25 years) with either corrected tetralogy of Fallot or Fontan circulation. The exercise-group was enrolled in a 12 week standardized aerobic dynamic exercise training program. The control-group continued their life-style and received care as usual. Both groups underwent cardiopulmonary exercise testing, cardiac magnetic resonance imaging (MRI), echocardiography and neurohormonal assessment, within 2 weeks before and 2 weeks after the intervention period. Fifty-six patients were randomized to the exercise-group and 37 to the control-group. We assessed changes between the pre- and the post-intervention period for the exercise group compared to the changes in the control-group. Peak load increased significantly in the exercise-group compared to the control-group (exercise-group 6.9 ± 11.8 W; control-group 0.8 ± 13.9 W; p=0.047). There were no adverse events linked to the study. Ventricular systolic parameters, cardiac dimensions and neurohormonal markers during follow-up did not change in patients allocated to the exercise-group and control-group. Although there were some isolated minor changes in inflow parameters, there was no consistent pattern of changes, indicating a lack of true change in the diastolic function. CONCLUSION: We demonstrated that no clinically relevant adverse cardiac remodelling occurred after 12 weeks of exercise training in patients with either corrected tetralogy of Fallot or Fontan circulation. CLINICAL TRIAL REGISTRATION: www.trialregister.nl, identification NTR2731.

High prevalence of late adverse events in malignant bone tumour survivors diagnosed at adult age.

BACKGROUND: Late treatment-related adverse events are particularly prevalent in survivors of childhood bone cancer because of the combination of cytotoxic drugs, major surgery and radiotherapy. Existing studies for late toxicity in survivors of Ewing's sarcoma (ES) and osteosarcoma (OS) diagnosed at adult age have focused on specific sequelae. We investigated a broad spectrum of potential late effects in these patients. METHODS: Relapse-free OS and ES patients aged ≥ 16 at diagnosis and treated at the Radboud University Medical Centre (1982-2007) were invited for systematic late toxicity screening. This included history taking, physical examination, echocardiogram, bone densitometry, audiogram, and serum and urine screening for renal toxicity and infertility. Adverse events were graded according to the Common Terminology Criteria for Adverse Events version 3.0. RESULTS: In 24 survivors (63% male, mean age at screening 45.7 years, mean follow-up 10.9 years, 70% OS) we found a median of eight adverse events. Frequent findings included abnormal gait, osteoporosis, pain, left ventricular systolic dysfunction, obesity and nephropathy. The maximum grade of any adverse event was mild in four (17%), moderate in 11 (46%), severe in six (25%), and disabling in three cases (13%). There was a trend towards more events in patients diagnosed at an older age. CONCLUSION: The incidence of late adverse events in this study of survivors of bone tumours diagnosed at adult age is higher than in any previously published childhood cancer survivorship study. Older patients seem to be particularly at risk. Our findings underscore the need for systematic screening of late effects in bone cancer survivors of adult age at diagnosis.

Catecholamines influence myocardial 123I MIBG uptake in neuroblastoma patients.

AIM: Cardiac 123I metaiodobenzylguanidine (MIBG) imaging can be influenced by several factors. We evaluated the relationship between catecholamine measurements and cardiac 123I MIBG uptake in neuroblastoma patients. PATIENTS, METHODS: 30 neuroblastoma patients were retrospectively assessed on cardiac 123I MIBG uptake and urinary catecholamine dopamine and metabolites, homovanillic acid (HVA) and vanillylmandelic acid (VMA). Cardiac 123I MIBG uptake was quantified by heart-to-mediastinum (H/M) ratios, which were calculated into standard deviation scores (SDS) using age-specific reference values. RESULTS: In 17 (57%) and 12 patients (40%) H/M ratio measurements were below -1.0 and -2.0 SDS at diagnosis. A significant inverse correlation between the average of urine metabolites HVA and VMA, and H/M ratio SDS was observed (r -.39, p = 0.04). Furthermore, there was a significant correlation between the urinary catecholamine metabolite HVA and H/M ratio SDS (r -.40, p=0.04). CONCLUSION: Routine calculation of H/M ratios in 123I MIBG scintigrams of neuroblastoma patients is not helpful because it will not identify cardiac ventricular dysfunction in this patient category. A low H/M ratio on 123I MIBG scintigraphy is explained by increased cathecholamine levels secreted by neuroblastoma tumours.

Abnormal two-dimensional strain echocardiography findings in children with congenital valvar aortic stenosis.

PURPOSE: Congenital valvar aortic stenosis (VAS) causes a pressure overload to the left ventricle. In the clinical setting, the severity of stenosis is graded by the pressure drop over the stenotic valve (pressure gradient). This parameter is dependent on the hemodynamic status and does not provide information regarding myocardial performance. This study was undertaken to reveal the potential of two-dimensional strain echocardiography (2DSTE) for the detection of myocardial functional changes due to congenital VAS in children. MATERIALS AND METHODS: A total of 86 patients (aged from birth to 18 years) with various degrees of isolated congenital VAS were enrolled in this study. None of the patients had undergone any form of surgical or balloon intervention. 139 healthy children served as a control group. Two-dimensional cine-loop recordings of apical 4-chamber, mid-cavity short-axis and basal short-axis views were digitally stored for off-line analysis. Longitudinal, circumferential and radial peak systolic strain and strain rate values were determined as well as the time to peak systolic strain (T2P). Two-way analysis of variance was performed to assess the relationship between VAS severity and 2DSTE parameters. RESULTS: In all patients conventional echocardiographic findings did not indicate systolic left ventricular dysfunction. All strain parameters of the control group were significantly different from those of VAS patients. There was a statistically significant, inverse relationship between global peak systolic strain parameters in all three directions and the degree of VAS (p < 0.05). Local peak systolic strain (rate) in the interventricular septum was most affected. T 2P increased significantly with VAS severity (p < 0.05). The decline in LV longitudinal systolic performance preceded that in other directions. CONCLUSION: 2DSTE detects alterations in myocardial function in children diagnosed with congenital VAS, whose conventional echocardiographic findings did not indicate ventricular systolic dysfunction.

Three-dimensional cardiac strain imaging in healthy children using RF-data.

In this study, a new radio-frequency (RF)-based, three-dimensional (3-D) strain imaging technique is introduced and applied to 3-D full volume ultrasound data of the heart of healthy children. Continuing advances in performance of transducers for 3-D ultrasound imaging have boosted research on 3-D strain imaging. In general, speckle tracking techniques are used for strain imaging. RF-based strain imaging has the potential to yield better performance than speckle- based methods because of the availability of phase information but such a system output is commercially not available. Furthermore, the relatively low frame rate of 3-D ultrasound data has limited broad application of RF-based cardiac strain imaging. In this study, the previously reported two-dimensional (2-D) strain methodology was extended to the third dimension. Three-dimensional RF-data were acquired in 13 healthy children, in the age range of 6-15 years, at a relatively low frame rate of 38-51 Hz. A 3-D, free-shape, coarse-to-fine displacement and strain estimation algorithm was applied to the RF-data. The heart was segmented using 3-D ellipsoid fitting. Strain was estimated in the radial (R), circumferential (C) and longitudinal directions (L). Our preliminary results reveal the applicability of the 3-D strain estimation technique on full volume 3-D RF-data. The technique enabled 3-D strain imaging of all three strain components. The average strains for all children were in the lateral wall R = 37 ± 10% (infero-lateral) and R = 32% ± 10% (antero-lateral), C = -9% ± 4% (antero-lateral) and C = -9% ± 4% (infero-lateral), L = -18% ± 6 % (antero-lateral) and L = -15% ± 4% (infero-lateral). In the septum, strains were found to be R = 24% ± 10% (antero-septal) and R = 13% ± 5% (infero-septal), C = -13% ± 5% (antero-septal) and -13% ± 5% (infero-septal) and L = -13% ± 3% (antero-septal) and L = -16% ± 5% (infero-septal). Strain in the anterior and inferior walls seemed underestimated, probably caused by the low (in-plane) resolution and poor image quality. The field-of-view as well as image quality were not always sufficient to image the entire left ventricle. It is concluded that 3-D strain imaging using RF-data is feasible, but validation with other modalities and with conventional 3-D speckle tracking techniques will be necessary.

Cardiac biplane strain imaging: initial in vivo experience.

In this study, first we propose a biplane strain imaging method using a commercial ultrasound system, yielding estimation of the strain in three orthogonal directions. Secondly, an animal model of a child's heart was introduced that is suitable to simulate congenital heart disease and was used to test the method in vivo. The proposed approach can serve as a framework to monitor the development of cardiac hypertrophy and fibrosis. A 2D strain estimation technique using radio frequency (RF) ultrasound data was applied. Biplane image acquisition was performed at a relatively low frame rate (<100 Hz) using a commercial platform with an RF interface. For testing the method in vivo, biplane image sequences of the heart were recorded during the cardiac cycle in four dogs with an aortic stenosis. Initial results reveal the feasibility of measuring large radial, circumferential and longitudinal cumulative strain (up to 70%) at a frame rate of 100 Hz. Mean radial strain curves of a manually segmented region-of-interest in the infero-lateral wall show excellent correlation between the measured strain curves acquired in two perpendicular planes. Furthermore, the results show the feasibility and reproducibility of assessing radial, circumferential and longitudinal strains simultaneously. In this preliminary study, three beagles developed an elevated pressure gradient over the aortic valve (Deltap: 100-200 mmHg) and myocardial hypertrophy. One dog did not develop any sign of hypertrophy (Deltap = 20 mmHg). Initial strain (rate) results showed that the maximum strain (rate) decreased with increasing valvular stenosis (-50%), which is in accordance with previous studies. Histological findings corroborated these results and showed an increase in fibrotic tissue for the hearts with larger pressure gradients (100, 200 mmHg), as well as lower strain and strain rate values.

In vivo validation of cardiac output assessment in non-standard 3D echocardiographic images.

Automatic segmentation of the endocardial surface in three-dimensional (3D) echocardiographic images is an important tool to assess left ventricular (LV) geometry and cardiac output (CO). The presence of speckle noise as well as the nonisotropic characteristics of the myocardium impose strong demands on the segmentation algorithm. In the analysis of normal heart geometries of standardized (apical) views, it is advantageous to incorporate a priori knowledge about the shape and appearance of the heart. In contrast, when analyzing abnormal heart geometries, for example in children with congenital malformations, this a priori knowledge about the shape and anatomy of the LV might induce erroneous segmentation results. This study describes a fully automated segmentation method for the analysis of non-standard echocardiographic images, without making strong assumptions on the shape and appearance of the heart. The method was validated in vivo in a piglet model. Real-time 3D echocardiographic image sequences of five piglets were acquired in radiofrequency (rf) format. These ECG-gated full volume images were acquired intra-operatively in a non-standard view. Cardiac blood flow was measured simultaneously by an ultrasound transit time flow probe positioned around the common pulmonary artery. Three-dimensional adaptive filtering using the characteristics of speckle was performed on the demodulated rf data to reduce the influence of speckle noise and to optimize the distinction between blood and myocardium. A gradient-based 3D deformable simplex mesh was then used to segment the endocardial surface. A gradient and a speed force were included as external forces of the model. To balance data fitting and mesh regularity, one fixed set of weighting parameters of internal, gradient and speed forces was used for all data sets. End-diastolic and end-systolic volumes were computed from the segmented endocardial surface. The cardiac output derived from this automatic segmentation was validated quantitatively by comparing it with the CO values measured from the volume flow in the pulmonary artery. Relative bias varied between 0 and -17%, where the nominal accuracy of the flow meter is in the order of 10%. Assuming the CO measurements from the flow probe as a gold standard, excellent correlation (r = 0.99) was observed with the CO estimates obtained from image segmentation.

Preduodenal portal vein and malrotation: what causes the obstruction?

AIM AND METHOD: Preduodenal portal vein is a rare congenital abnormality, and occurs either as a single malformation, in association with other malformations or as part of "polysplenia" syndrome. Preduodenal portal vein has seldom been reported as a cause of intestinal obstruction, however corrective surgery is nearly always performed. We conducted a 25-year retrospective study in a single centre to investigate the cause of obstruction in patients with preduodenal portal vein. Furthermore, we reviewed the literature on preduodenal portal vein. RESULTS: Over a period of 25 years, preduodenal portal vein was diagnosed in five patients. The diagnosis was made during surgery performed because of symptoms of high intestinal obstruction. All five patients had intestinal malrotation as well and, in all patients, another cause for high intestinal obstruction than preduodenal portal vein was found. CONCLUSION: Preduodenal portal vein is mainly asymptomatic. It is often associated with other intestinal congenital abnormalities more likely to cause high intestinal obstruction. Therefore, the (paediatric) surgeon should always be alert for another associated cause of intestinal obstruction. Because of the potential for technical problems from preduodenal portal vein during surgery, it nevertheless should be on the surgeon's mind during surgery when the patient has high intestinal obstruction.

Congenital cardiovascular defects in children with intestinal malrotation.

Intestinal malrotation (IM) and cardiovascular defects (CCVD) are both common congenital defects. We investigated the prevalence and types of CCVD in a 25-year IM population, and its association with post-IM-operative morbidity and mortality. Data on the type of CCVD, other congenital defects, syndromes, associations, post-IM-operative morbidity and mortality were retrospectively reviewed from the records of IM patients born between 1980 and 2005. Data were analyzed on (significant) differences between CCVD subgroups, and risk factors for both morbidity and mortality were calculated. Seventy-seven of 284 IM patients (27.1%) were diagnosed with a major or minor CCVD (37 and 40 patients, respectively). Syndromes and associations were more frequently diagnosed in patients with major than with a minor CCVD (67.6 vs. 40%, respectively). Post-IM-operative complications, although frequently observed (61%), did not differ between patients with major and minor CCVD. Physical CCVD signs before IM surgery increased post-IM-operative morbidity significantly (OR 4.0, 95% CI 1.4-11.0). Fifteen patients died (19.5%), seven due to cardiovascular cause. Mortality risk was increased by intestinal ischemia and post-IM-operative complications and by major CCVD after correction for age at weight at the time of IM operation. Congenital cardiovascular defects in children with intestinal malrotation are common, with high morbidity and mortality rates after IM operation. Elective IM surgery in young patients with CCVD should be performed in a centre with adequate paediatric cardiac care. Benefits of laparoscopic intervention need further study.

A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy.

PURPOSE: To identify the biochemical and molecular genetic defect in a 16-year-old patient presenting with apical hypertrophic cardiomyopathy and neuropathy suspected for a mitochondrial disorder. METHODS: Measurement of the mitochondrial energy-generating system (MEGS) capacity in muscle and enzyme analysis in muscle and fibroblasts were performed. Relevant parts of the mitochondrial DNA were analysed by sequencing. Transmitochondrial cybrids were obtained by fusion of 143B206 TK(-) rho zero cells with patient-derived enucleated fibroblasts. Immunoblotting techniques were applied to study the complex V assembly. RESULTS: A homoplasmic nonsense mutation m.8529G-->A (p.Trp55X) was found in the mitochondrial ATP8 gene in the patient's fibroblasts and muscle tissue. Reduced complex V activity was measured in the patient's fibroblasts and muscle tissue, and was confirmed in cybrid clones containing patient-derived mitochondrial DNA. Immunoblotting after blue native polyacrylamide gel electrophoresis showed a lack of holocomplex V and increased amounts of mitochondrial ATP synthase subcomplexes. An in-gel activity assay of ATP hydrolysis showed activity of free F(1)-ATPase in the patient's muscle tissue and in the cybrid clones. CONCLUSION: We describe the first pathogenic mutation in the mitochondrial ATP8 gene, resulting in an improper assembly and reduced activity of the complex V holoenzyme.

The MTHFR 677C->T polymorphism and the risk of congenital heart defects: a literature review and meta-analysis.

BACKGROUND: Periconceptional folic acid supplementation may protect against congenital heart defects (CHDs). Identification of candidate genes in folate metabolism has suggested that the 677C-->T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene may be particularly associated with the risk of CHDs. AIM: To assess the relationship between MTHFR 677C-->T and CHDs by literature review and meta-analysis. METHODS: Studies were identified by searches of electronic literature for papers focussing on MTHFR 677C-->T and the risk of any type of CHD. Both case-control comparisons and transmission-disequilibrium tests (TDTs) in family-based designs were included. RESULTS: We found 13 eligible studies. Of 10 case-control studies, four focused on the fetal polymorphism, two studied the maternal polymorphism, and a further four investigated both. Three further publications used a family-based association study to assess the effect of the T allele on cardiac development. Overall analysis yielded odds ratios of 1.3 (95%CI 0.97-1.73) and 1.2 (95%CI 0.83-1.74) for fetal and maternal MTHFR TT genotypes, respectively. TDTs revealed no association between fetal 677T allele and CHDs. DISCUSSION: This relatively small meta-analysis found no substantial evidence of increased CHD risk in individuals with MTHFR 677CT and TT genotypes. Heterogeneity regarding population background, study design and type of heart defects complicates the pooling and comparison of the studies. The effect of modification by periconceptional folic acid intake should be taken into account. Further larger studies and well-defined phenotypic subcategory analyses are needed to decide whether the MTHFR 677C-->T polymorphism of the affected child and/or their mother is truly a risk factor for the development of CHDs.

Potential additional indicators for pacemaker requirement in isolated congenital atrioventricular block.

Low heart rate is the predominantly used indication for pacemaker intervention in patients with isolated congenital atrioventricular block (CAVB). The aim of this study was to compare the difference in heart rates recorded with ECG and Holter monitoring between paced (PM) and nonpaced (NPM) patients with isolated CAVB before pacemaker implantation to identify additional predictors for future PM need. Retrospective evaluation of atrial and ventricular rates (electrocardiography) and minimal and maximal (Holter) heart rates in 129 CAVB patients prior to PM implantation (n = 93) was performed, and results are expressed in V adjusted for age and sex. The average V score for the atrial rate was 0.51 (n = 50) in the PM group and 0.60 (n = 22) in the NPM group (not-significant). The average z score for the ventricular (average) rate was -0.91 (n = 83) in the PM group and -0.93 (n = 33) in the NPM group (not-significant). Minimal heart rate was -0.94 (n = 61) in the PM group and -0.86 (n = 25) in the NPM group (not significant). Maximal heart rate was -0.96 (n = 61) in the PM group and -0.95 (n = 26) in the NPM group (not significant). Initial recordings of the average heart rate and the minimal and maximal heart rate recorded during Holter monitoring do not seem to predict future pacemaker need in patients with CAVB. Studies with exercise stress tests are needed to confirm these findings.

New reference values for echocardiographic dimensions of healthy Dutch children.

AIM: To renew the echocardiographic reference values of heart dimensions in healthy children. METHODS AND RESULTS: Group 1 consisted of 587 children, of which 361 boys and 226 girls, age from birth to 18 years, body weight over 2500 g, who visited the Pediatric Cardiology outclinic during the period January 2000 till March 2004. All included children were diagnosed as normal, or as having innocent heart murmur. The second group was taken from an earlier study and comprised 160 children (77 boys and 83 girls). The echocardiographic measures were taken from conventional M-mode recording of the left ventricle (LV) parasternal long axis view. End diastolic septal (IVS) and LV posterior wall thickness (LVPW) and end diastolic as well as end systolic LV intracavity dimensions were retrospectively analyzed. The regression lines from all measured sizes are significantly different from those collected in the early eighties. Especially the thickness of the IVS is smaller. The regression lines are independent of gender. CONCLUSIONS: New reference values have been found which should replace the presently used ones. There is no difference between boys and girls. Why the muscular wall thicknesses are thinner than found 20 years ago needs to be further explored.

CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene.

BACKGROUND: CHARGE syndrome is a non-random clustering of congenital anomalies including coloboma, heart defects, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies, and deafness. A consistent feature in CHARGE syndrome is semicircular canal hypoplasia resulting in vestibular areflexia. Other commonly associated congenital anomalies are facial nerve palsy, cleft lip/palate, and tracheo-oesophageal fistula. Specific behavioural problems, including autistic-like behaviour, have been described. The CHD7 gene on chromosome 8q12.1 was recently discovered as a major gene involved in the aetiology of this syndrome. METHODS: The coding regions of CHD7 were screened for mutations in 107 index patients with clinical features suggestive of CHARGE syndrome. Clinical data of the mutation positive patients were sampled to study the phenotypic spectrum of mutations in the CHD7 gene. RESULTS: Mutations were identified in 69 patients. Here we describe the clinical features of 47 of these patients, including two sib pairs. Most mutations were unique and were scattered throughout the gene. All patients but one fulfilled the current diagnostic criteria for CHARGE syndrome. No genotype-phenotype correlations were apparent in this cohort, which is best demonstrated by the differences in clinical presentation in sib pairs with identical mutations. Somatic mosaicism was detected in the unaffected mother of a sib pair, supporting the existence of germline mosaicism. CONCLUSIONS: CHD7 mutations account for the majority of the cases with CHARGE syndrome, with a broad clinical variability and without an obvious genotype-phenotype correlation. In one case evidence for germline mosaicism was provided.

Cyclin E expression in breast cancer: predicting germline BRCA1 mutations, prognosis and response to treatment.

BACKGROUND: Elevated levels of the cell cycle protein cyclin E, and low levels of its inhibitor, p27(Kip1), have been associated with a poor prognosis following breast cancer. Some studies have found that germline mutations in the breast cancer susceptibility gene, BRCA1, are also associated with an inferior survival rate. The relationship between cyclin E/p27(Kip1) levels, BRCA1 status and outcome has not been studied in detail. PATIENTS AND METHODS: We analyzed a historical cohort of 288 Ashkenazi Jewish women who were diagnosed with breast cancer between 1980 and 1995 and were previously tested for BRCA1/2 mutations. Protein levels of cyclin E and p27(Kip1) were assessed by immunohistochemistry. Breast cancer-specific survival (BCSS) was the main outcome measured. RESULTS: The median follow-up was 8 years. Thirty tumors carried germline BRCA1 mutations. These tumors were more likely to have high cyclin E protein levels [odds ratio (OR) 9.5; P <0.001] and low p27(Kip1) protein levels (OR 2.8; P=0.03) than tumors from patients without BRCA1/2 mutations. High cyclin E expression level was the strongest predictor of BRCA1 germline mutations (multivariate OR 4.7; P=0.004). On univariate analysis, high cyclin E protein levels [relative risk (RR) 2.6; P <0.001] and low p27(Kip1) protein levels (RR 2.3; P=0.006) were significant prognostic factors for a poorer BCSS. In Cox multivariate models, high cyclin E levels remained an independent indicator of poor outcome only in the subgroup of patients who did not receive chemotherapy (P=0.002). CONCLUSIONS: In this ethnically restricted cohort, a high level of cyclin E is a characteristic of BRCA1-related breast cancer, and is a marker of poor prognosis following breast cancer, particularly in the absence of adjuvant chemotherapy.