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Contains fulltext : 167854.pdf (Publisher’s version ) (Open Access) AIMS: Phenotypic heterogeneity and incomplete penetrance are common in patients with hypertrophic cardiomyopathy (HCM). We aim to improve the understanding in genotype-phenotype correlations in HCM, particularly the contribution of an MYL2 founder mutation and risk factors to left ventricular hypertrophic remodelling. METHODS AND RESULTS: We analysed 14 HCM families of whom 38 family members share the MYL2 c.64G > A [p.(Glu22Lys)] mutation and a common founder haplotype. In this unique cohort, we investigated factors influencing phenotypic outcome in addition to the primary mutation. The mutation alone showed benign disease manifestation with low penetrance. The co-presence of additional risk factors for hypertrophy such as hypertension, obesity, or other sarcomeric gene mutation increased disease penetrance substantially and caused HCM in 89% of MYL2 mutation carriers (P = 0.0005). The most prominent risk factor was hypertension, observed in 71% of mutation carriers with HCM and an additional risk factor. CONCLUSION: The MYL2 mutation c.64G > A on its own is incapable of triggering clinical HCM in most carriers. However, the presence of an additional risk factor for hypertrophy, particularly hypertension, adds to the development of HCM. Early diagnosis of risk factors is important for early treatment of MYL2 mutation carriers and close monitoring should be guaranteed in this case. Our findings also suggest that the presence of hypertension or another risk factor for hypertrophy should not be an exclusion criterion for genetic studies.

Background The multifactorial pathogenesis leading to dilated cardiomyopathy (DCM) makes stratification difficult. The recent MOGE(S) (morphofunctional, organ involvement, genetic or familial, etiology, stage) classification addresses this issue. Objectives The purpose of this study was to investigate the applicability and prognostic relevance of the MOGE(S) classification in patients with DCM. Methods This study used patients from the Maastricht Cardiomyopathy Registry in the Netherlands and excluded patients with ischemic, valvular, hypertensive, and congenital heart disease. All other patients underwent a complete diagnostic work-up, including genetic evaluation and endomyocardial biopsy. Results A total of 213 consecutive patients with DCM were included: organ involvement was demonstrated in 35 (16%) and genetic or familial DCM in 70 (33%) patients, including 16 (8%) patients with a pathogenic mutation. At least 1 cause was found in 155 (73%) patients, of whom 48 (23%) had more than 1 possible cause. Left ventricular reverse remodeling was more common in patients with nongenetic or nonfamilial DCM than in patients with genetic or familial DCM (40% vs. 25%; p = 0.04). After a median follow-up of 47 months, organ involvement and higher New York Heart Association functional class were associated with adverse outcome (p Conclusions The MOGE(S) classification in DCM is applicable, and each attribute or the gene-environment interaction is associated with outcome. Importantly, the presence of multiple attributes was a strong predictor of adverse outcome. Finally, adaptation of the MOGE(S) involving multiple possible etiologies is recommended.

Energy expenditure in infants with congenital heart disease, including a meta-analysis. van der Kuip M, Hoos MB, Forget PP, Westerterp KR, Gemke RJ, de Meer K. Department of Paediatrics, VU University Medical Centre, Amsterdam, The Netherlands. AIM: To assess energy requirements and body composition in preoperative children with congenital heart disease (CHD). METHODS: In 11 infants with CHD (2-8 mo), total daily energy expenditure (TDEE) and total body water (TBW) were measured with doubly labelled water and compared with historic data from healthy controls. Within the patient group, energy expenditure of infants with versus those without congestive heart failure was compared. Subsequently, the data were pooled with literature data in meta-analyses. RESULTS: CHD patients showed increased TBW (mean +/- SD 66 +/- 3 vs 58 +/- 5% of body weight, p < 0.05) and energy expenditure (381 +/- 42 vs 298 +/- 36 kJ kg(-1) d(-1), p < 0.001). Meta-analyses showed that CHD infants have 35% increased TDEE (376 vs 278 kJ kg(-1) d(-1) , p < 0.00001) and 7% higher TBW (p < 0.0001). Coexistent congestive heart failure (treated with diuretics) had no influence on TDEE (mean difference 14 kJ kg(-1) d(-1) , not significant). In patients with heart failure and growth retardation, an energy balance study showed an average 12% loss of initially ingested energy due to vomiting, increased TDEE and low faecal energy loss, resulting in low energy available for growth, compared with controls (42 +/- 30 vs 96 +/- 61 kJ kg(-1) d(-1) , p < 0.05). CONCLUSION: Many infants with CHD require substantially higher energy intake (at least 100 kJ kg(-1) d(-1) extra) owing to increased TDEE, which is not explained by a higher percentage of body water. Coexistent heart failure does not appear to have an additional influence on TDEE. In infants with CHD and growth failure factors other than elevated TDEE, including vomiting, may explain the disturbed energy balance

Physical activity levels in children and adolescents.Hoos MB, Gerver WJ, Kester AD, Westerterp KR.Department of Pediatrics, University of Maastricht, The Netherlands. Marije.Hoos@kg.unimaas.nlBACKGROUND: Reference data for physical activity level (PAL) and activity-related energy expenditure (AEE) are needed for a better understanding of the effect of activity on childhood health, growth and development OBJECTIVE: Data from 17 studies measuring TDEE (TDEE) with doubly labelled water DLW were combined to construct a reference line for PAL and AEE as a function of age. DESIGN: A total of 17 studies from the literature were analyzed; 17 on girls and 16 on boys. Children were aged 3-16 y and of Caucasian origin. Weighted least-squares regression was used to obtain reference lines for PAL and AEE as a function of age and gender. The relative numbers of children per study were used as a weighting factor. Basal metabolic rate (BMR) or nonfasted (NF) resting metabolic rate and sex were included in the analysis. RESULTS: Although there was no difference in PAL between boys and girls, a significant difference in AEE was found between the two sexes. PAL: 0.025 x age+1.40. AEE (MJ/day): boys 0.30 x age+0.025; girls 0.21 x age+0.33. If BMR is measured under NF conditions, the obtained value has to be reduced by 0.21 for PAL and 0.75 MJ/day for AEE. No relation was found between AEE/kg and age. CONCLUSIONS: PAL and AEE were found to increase with age, showing the importance of age-dependent recommendations. Recommendations for AEE need to be differentiated for sex. To compare PAL and AEE between studies, the measurement conditions of BMR have to be taken into account. The increase in PAL and AEE values can be attributed to an increase in weight, because there was no relation between AEE/kg and age.

BACKGROUND & AIMS: Most stable-isotope methods to evaluate whole body protein metabolism in patients are invasive and difficult to use in children. In this study protein metabolism was evaluated with the non-invasive [15N]glycine single oral dose method in critically ill children and the value of the method is discussed. METHODS: [15N]glycine (100mg) was given orally to children (mean age 5.5 years; range 0.6-15.5 years) with meningococcal septic shock (MSS, n = 8), pneumonia (n = 5), and to healthy, fed and post-absorptive children (n = 10). Urine was collected during 9h, total amount of NH(3), labelled NH(3) and nitrogen were measured, and protein turnover, synthesis and breakdown were calculated using urinary NH(3) as end-product. RESULTS: Mean protein turnover in children with MSS, pneumonia and fed and post-absorptive healthy children was 0.63+/-0.13, 0.38+/-0.10, 0.28+/-0.03 and 0.28+/-0.02g N/kg/9h, respectively. Mean protein synthesis was 0.55+/-0.12, 0.29+/-0.09, 0.18+/-0.02, 0.20+/-0.02g N/kg/9h, respectively. Mean protein breakdown was 0.56+/-0.14, 0.28+/-0.12, 0.08+/-0.03, 0.28+/-0.02g N/kg/9h, respectively. Protein turnover, synthesis and breakdown were significantly increased in MSS patients compared to fed healthy children (P

AIM: Parents of children treated with growth hormone (GH) frequently report to the paediatrician that their children have become more physically active. In the present study, activity patterns of GH-treated children were measured and compared to those of healthy controls. METHODS: Subjects were 25 children at the start of GH treatment (age 8.4 +/- 2.6 y) and 19 age- and gender-matched controls (age 8.8 +/- 3.2 y). Physical activity was assessed with a tri-axial accelerometer for movement registration over two separate 2-wk intervals, one before the start of GH treatment and one 2 wk after the start of treatment. GH-treated subjects were categorized as poor responders (change in height over 1 y 0.7 SDS, n = 10). RESULTS: Before therapy, good responders showed a significantly lower physical activity compared to healthy controls, spending significantly less time on high-intensity activities. This difference disappeared 2 wk after the start of therapy. Physical activity in poor responders was not significantly different from controls before and after 2 wk of GH therapy. CONCLUSION: Children who respond well to GH therapy (change in height >0.7 SDS) showed a reduced amount of physical activity before therapy, which was normalized after 2 wk of GH therapy.