Altered Serum Proteins Suggest Inflammation, Fibrogenesis and Angiogenesis in Adult Patients with a Fontan Circulation.

Previous omics research in patients with complex congenital heart disease and single-ventricle circulation (irrespective of the stage of palliative repair) revealed alterations in cardiac and systemic metabolism, inter alia abnormalities in energy metabolism, and inflammation, oxidative stress or endothelial dysfunction. We employed an affinity-proteomics approach focused on cell surface markers, cytokines, and chemokines in the serum of 20 adult Fontan patients with a good functioning systemic left ventricle, and we 20 matched controls to reveal any specific processes on a cellular level. Analysis of 349 proteins revealed 4 altered protein levels related to chronic inflammation, with elevated levels of syndecan-1 and glycophorin-A, as well as decreased levels of leukemia inhibitory factor and nerve growth factor-ß in Fontan patients compared to controls. All in all, this means that Fontan circulation carries specific physiological and metabolic instabilities, including chronic inflammation, oxidative stress imbalance, and consequently, possible damage to cell structure and alterations in translational pathways. A combination of proteomics-based biomarkers and the traditional biomarkers (uric acid, γGT, and cholesterol) performed best in classification (patient vs. control). A metabolism- and signaling-based approach may be helpful for a better understanding of Fontan (patho-)physiology. Syndecan-1, glycophorin-A, leukemia inhibitory factor, and nerve growth factor-ß, especially in combination with uric acid, γGT, and cholesterol, might be interesting candidate parameters to complement traditional diagnostic imaging tools and the determination of traditional biomarkers, yielding a better understanding of the development of comorbidities in Fontan patients, and they may play a future role in the identification of targets to mitigate inflammation and comorbidities in Fontan patients.

Cardiomyopathy-associated mutations in the RS domain affect nuclear localization of RBM20.

Mutations in RBM20 encoding the RNA-binding motif protein 20 (RBM20) are associated with an early onset and clinically severe forms of cardiomyopathies. Transcriptome analyses revealed RBM20 as an important regulator of cardiac alternative splicing. RBM20 mutations are especially localized in exons 9 and 11 including the highly conserved arginine and serine-rich domain (RS domain). Here, we investigated in several cardiomyopathy patients, the previously described RBM20-mutation p.Pro638Leu localized within the RS domain. In addition, we identified in a patient the novel mutation p.Val914Ala localized in the (glutamate-rich) Glu-rich domain of RBM20 encoded by exon 11. Its impact on the disease was investigated with a novel TTN- and RYR2-splicing assay based on the patients' cardiac messenger RNA. Furthermore, we showed in cell culture and in human cardiac tissue that mutant RBM20-p.Pro638Leu is not localized in the nuclei but causes an abnormal cytoplasmic localization of the protein. In contrast the splicing deficient RBM20-p.Val914Ala has no influence on the intracellular localization. These results indicate that disease-associated variants in RBM20 lead to aberrant splicing through different pathomechanisms dependent on the localization of the mutation. This might have an impact on the future development of therapeutic strategies for the treatment of RBM20-induced cardiomyopathies.

Method comparison of HPLC-ninhydrin-photometry and UHPLC-PITC-tandem mass spectrometry for serum amino acid analyses in patients with complex congenital heart disease and controls.

INTRODUCTION: Metabolomics studies are not routine when quantifying amino acids (AA) in congenital heart disease (CHD). OBJECTIVES: Comparative analysis of 24 AA in serum by traditional high-performance liquid chromatography (HPLC) based on ion exchange and ninhydrin derivatisation followed by photometry (PM) with ultra-high-performance liquid chromatography and phenylisothiocyanate derivatisation followed by tandem mass spectrometry (TMS); interpretation of findings in CHD patients and controls. METHODS: PM: Sample analysis as above (total run time, ~ 119 min). TMS: Sample analysis by AbsoluteIDQ® p180 kit assay (BIOCRATES Life Sciences AG, Innsbruck, Austria), which employs PITC derivatisation; separation of analytes on a Waters Acquity UHPLC BEH18 C18 reversed-phase column, using water and acetonitrile with 0.1% formic acid as the mobile phases; and quantification on a Triple-Stage Quadrupole tandem mass spectrometer (Thermo Fisher Scientific, Waltham, MA) with electrospray ionisation in the presence of internal standards (total run time, ~ 8 min). Calculation of coefficients of variation (CV) (for precision), intra- and interday accuracies, limits of detection (LOD), limits of quantification (LOQ), and mean concentrations. RESULTS: Both methods yielded acceptable results with regard to precision (CV < 10% PM, < 20% TMS), accuracies (< 10% PM, < 34% TMS), LOD, and LOQ. For both Fontan patients and controls AA concentrations differed significantly between methods, but patterns yielded overall were parallel. CONCLUSION: Serum AA concentrations differ with analytical methods but both methods are suitable for AA pattern recognition. TMS is a time-saving alternative to traditional PM under physiological conditions as well as in patients with CHD. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier NCT03886935, date of registration March 27th, 2019 (retrospectively registered).

Health-related quality of life compared with cardiopulmonary exercise testing at the midterm follow-up visit after tetralogy of Fallot repair: a study of the German competence network for congenital heart defects.

This nationwide study aimed to evaluate health-related quality of life (QoL) experienced by children after tetralogy of Fallot repair and to compare self-reported physical ability with objective exercise performance. This prospective nonrandomized, government-funded multicenter study enrolled 168 patients (70 girls; ages 8-16 years) after tetralogy of Fallot repair at eight German heart centers. Health-related QoL was analyzed by the self-reported KINDL-R quality-of-life questionnaire. The patients' actual exercise capacity was evaluated by a cardiopulmonary exercise test. Health-related QoL and cardiopulmonary exercise capacity were compared with those of an age-matched German standard population. Correlation of health-related QoL with self-estimated physical rating and cardiopulmonary exercise capacity were analyzed. Health-related QoL in children and adolescents after tetralogy of Fallot repair is without limitation. Compared with the standard population, all the items evaluated by the KINDL-R questionnaire showed better or similar values, whereas objective exercise capacity compared with that of the standard population was impaired. Peak oxygen uptake correlated significantly with the physical well-being (p = 0.002) and the total score (p = 0.01) of the KINDL-R questionnaire. Health-related QoL experienced by children and adolescents after tetralogy of Fallot repair is comparable with that of the healthy standard population. However, closer inspection shows that self-estimated physical functioning is significantly overestimated compared with actual exercise capacity. Quality-of-life instruments and exercise tests, therefore, should be used in a complementary manner with children to avoid eventually fatal misinterpretation of patient-estimated physical ability.

Metabolomics and random forests in patients with complex congenital heart disease.

Introduction: It is increasingly common to simultaneously determine a large number of metabolites in order to assess the metabolic state of, or clarify biochemical pathways in, an organism ("metabolomics"). This approach is increasingly used in the investigation of the development of heart failure. Recently, the first reports with respect to a metabolomic approach for the assessment of patients with complex congenital heart disease have been published. Classical statistical analysis of such data is challenging. Objective: This study aims to present an alternative to classical statistics with respect to identifying relevant metabolites in a classification task and numerically estimating their relative impact. Methods: Data from two metabolomic studies on 20 patients with complex congenital heart disease and Fontan circulation and 20 controls were reanalysed using random forest (RF) methodology. Results were compared to those of classical statistics. Results: RF analysis required no elaborate data pre-processing. The ranking of the variables with respect to classification impact (subject diseased, or not) was remarkably similar irrespective of the evaluation method used, leading to identical clinical interpretation. Conclusion: In metabolomic classification in adult patients with complex congenital heart disease, RF analysis as a one-step method delivers the most adequate results with minimum effort. RF may serve as an adjunct to traditional statistics also in this small but crucial-to-monitor patient group.

Targeted metabolomic analysis of serum amino acids in the adult Fontan patient with a dominant left ventricle.

Growing interest lies in the assessment of the metabolic status of patients with a univentricular circulation after Fontan operation, especially in changes of amino acid metabolism. Using targeted metabolomic examinations, we investigated amino acid metabolism in a homogeneous adult Fontan-patient group with a dominant left ventricle, seeking biomarker patterns that might permit better understanding of Fontan pathophysiology and early detection of subtle ventricular or circulatory dysfunction. We compared serum amino acid levels (42 analytes; AbsoluteIDQ p180 kit, Biocrates Life Sciences, Innsbruck, Austria) in 20 adult Fontan patients with a dominant left ventricle and those in age- and sex-matched biventricular controls. Serum concentrations of asymmetric dimethylarginine, methionine sulfoxide, glutamic acid, and trans-4-hydroxyproline and the methionine sulfoxide/methionine ratio (Met-SO/Met) were significantly higher and serum concentrations of asparagine, histidine, taurine, and threonine were significantly lower in patients than in controls. Met-SO/Met values exhibited a significant negative correlation with oxygen uptake during exercise. The alterations in amino acid metabolome that we found in Fontan patients suggest links between Fontan pathophysiology, altered cell energy metabolism, oxidative stress, and endothelial dysfunction like those found in biventricular patients with congestive heart failure. Studies of extended amino acid metabolism may allow better understanding of Fontan pathophysiology that will permit early detection of subtle ventricular or circulatory dysfunction in Fontan patients.

Targeted metabolomic analysis of serum phospholipid and acylcarnitine in the adult Fontan patient with a dominant left ventricle.

BACKGROUND: Patients with a Fontan circulation have altered cholesterol and lipoprotein values. We analysed small organic molecules in extended phopsholipid and acylcarnitine metabolic pathways ('metabolomes') in adult Fontan patients with a dominant left ventricle, seeking differences between profiles in baseline and Fontan circulations. METHODS: In an observational matched cross-sectional study, we compared phosphatidylcholine (PC), sphingomyelin (SM), and acylcarnitine metabolomes (105 analytes; AbsoluteIDQ® p180 kit (Biocrates Life Sciences AG, Innsbruck, Austria) in 20 adult Fontan patients having a dominant left ventricle with those in 20 age- and sex-matched healthy controls. RESULTS: Serum levels of total PC (q-value 0.01), total SM (q-value 0.0002) were significantly lower, and total acylcarnitines (q-value 0.02) were significantly higher in patients than in controls. After normalisation of data, serum levels of 12 PC and 1 SM Fontan patients were significantly lower (q-values <0.05), and concentrations of 3 acylcarnitines were significantly higher than those in controls (q-values <0.05). CONCLUSION: Metabolomic profiling can use small specimens to identify biomarker patterns that track derangement in multiple metabolic pathways. The striking alterations in the phospholipid and acylcarnitine metabolome that we found in Fontan patients may reflect altered cell signalling and metabolism as found in heart failure in biventricular patients, chronic low-level inflammation, and alteration of functional or structural properties of lymphatic or blood vessels. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier NCT03886935.

A practical and transferable new protocol for treadmill testing of children and adults.

BACKGROUND: It is just as vital to have an exact overview of the physical fitness of young and growing people as it is for adults. The currently used exercise protocols have limitations in healthy small children, and in senior citizens. In particular with chronically ill patients, regardless of their age, there is a need for an exercise protocol that permits observations over the long term. With this need in mind, we have designed a new transferable standardised exercise protocol, constructing reference values based on improved assessments on a treadmill that permitted stepwise increases of speed and gradient every 90 seconds - the so called treadmill protocol from the German Society of Paediatric Cardiology. OBJECTIVES: We investigated the exercise performance in a healthy Caucasian population ranging in age from 4 to 75 years. METHODS: We measured, using a prospective study design, the distance run, the endurance, and the consumption of oxygen in 548 females and 647 males undergoing an enhanced spiroergometric treadmill protocol in two centres. RESULTS AND CONCLUSIONS: Until puberty, boys and girls have the same indicators of exercise performance. Subsequent to puberty, uptake of oxygen and distance run differ, with males showing higher uptake of oxygen. There is still an age-dependent dynamic of peak uptake of oxygen related to body surface area. Using these new reference values, covering the whole range of age, it proves possible to compare performance during growth and aging of the individual. In this fashion, we have calculated centiles for all recorded variables. External calibration, validation and quality control ensures transferability of our data to other spiroergometry units.

Diagnostics, monitoring and outpatient care in children with suspected pulmonary hypertension/paediatric pulmonary hypertensive vascular disease. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.

Pulmonary hypertension (PH) is a condition of multiple aetiologies with underestimated prevalence and incidence. Indeed, despite access to modern therapies, pulmonary hypertensive vascular disease (PHVD) remains a progressive, usually life-limiting condition, severely impacting on the patients' well-being. We herein provide practical, expert consensus recommendations on the initial diagnostic work-up, clinical management and follow-up of children and adolescents with PH/PHVD, including a diagnostic algorithm. The major topics and methods that need to be tailored and put into context of the individual patient include PH classification, clinical signs and symptoms, basic diagnostic and advanced imaging measures (ECG, chest X-ray, transthoracic echocardiography, cardiac magnetic resonance, chest CT angiography, cardiac catheterisation, ventilation-perfusion lung scan, abdominal ultrasound), lung function tests, 6 min walk and cardiopulmonary exercise testing, sleep study (polysomnography), laboratory/immunological tests, considerations for elective surgery/ general anaesthesia, physical education and exercise, flying on commercial airplanes, vaccinations, care of central intravenous lines and palliative care. Due to the complexity of PH/PHVD, the clinical care has to be multidisciplinary and coordinated by a dedicated specialist paediatric PH centre, not only to decrease mortality but to allow children with PH/PHVD to reach a reasonable quality of life.

Myocardial deformation parameters predict outcome in patients with repaired tetralogy of Fallot.

BACKGROUND: Parameters of myocardial deformation have been suggested to be superior to conventional measures of ventricular function and to predict outcome in repaired tetralogy of Fallot (ToF). We aimed to test the hypothesis that parameters of myocardial deformation on cardiac MRI (CMR) relate to symptoms and provide prognostic information in patients with repaired ToF. METHODS AND RESULTS: We included 372 patients with ToF (median age 16 years; 55% male), recruited within a nationwide, prospective study. Longitudinal (LS), circumferential (CS) and radial global strain (RS) were analysed by CMR-based feature tracking (FT). A combined endpoint of death, successful resuscitation or documented ventricular tachycardia was employed. Parameters of global strain were associated with New York Heart Association (NYHA) class and symptomatic deterioration. During a median follow-up of 7.4 years, 20 events occurred. Left ventricular (LV) CS and right ventricular (RV) LS emerged as predictors of outcome, independent of QRS duration, LV/RV ejection fraction and volumes, NYHA class and peak oxygen uptake. In combination, these parameters also identified a subgroup of patients at significantly increased risk of adverse of outcomes (HR 3.3, p=0.002). Furthermore, LV LS, RS, CS and RV LS were related to the risk of death and nearly missed death (p<0.05 for all). CONCLUSIONS: FT-CMR provides myocardial deformation parameters, easily derived from standard CMR studies. They relate to symptoms and clinical deterioration in patients with ToF. More importantly, they predict adverse outcome independent of established risk markers, and should be considered as a useful adjunct to established outcome predictors, especially in younger patients with ToF. CLINICAL TRIAL REGISTRATION NUMBER: http://www.clinicaltrials.gov: NCT00266188; Results.

Executive summary. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.

UNLABELLED: : The European Paediatric Pulmonary Vascular Disease (PVD) Network is a registered, non-profit organisation that strives to define and develop effective, innovative diagnostic methods and treatment options in all forms of paediatric pulmonary hypertensive vascular disease, including specific forms such as pulmonary arterial hypertension (PAH)-congenital heart disease, pulmonary hypertension (PH) associated with bronchopulmonary dysplasia, persistent PH of the newborn, and related cardiac dysfunction. METHODS: The writing group members conducted searches of the PubMed/MEDLINE bibliographic database (1990-2015) and held five face-to-face meetings with votings. Clinical trials, guidelines, and reviews limited to paediatric data were searched using the terms 'pulmonary hypertension' and 5-10 other keywords, as outlined in the other nine articles of this special issue. Class of recommendation (COR) and level of evidence (LOE) were assigned based on European Society of Cardiology/American Heart Association definitions and on paediatric data only, or on adult studies that included >10% children. RESULTS: A total of 9 original consensus articles with graded recommendations (COR/LOE) were developed, and are summarised here. The topics included diagnosis/monitoring, genetics/biomarker, cardiac catheterisation, echocardiography, cardiac magnetic resonance/chest CT, associated forms of PH, intensive care unit/ventricular assist device/lung transplantation, and treatment of paediatric PAH. CONCLUSIONS: The multipaper expert consensus statement of the European Paediatric PVD Network provides a specific, comprehensive, detailed but practical framework for the optimal clinical care of children with PH.

Peak oxygen uptake, ventilatory efficiency and QRS-duration predict event free survival in patients late after surgical repair of tetralogy of Fallot.

OBJECTIVE: Patients with repaired tetralogy of Fallot (ToF) have an increased long-term risk of cardiovascular morbidity and mortality. Risk stratification in this population is difficult. Initial evidence suggests that cardiopulmonary exercise testing (CPET) may be helpful to risk-stratify patients with repaired ToF. METHODS AND RESULTS: We studied 875 patients after surgical repair for ToF (358 females, age 25.5 ± 11.7 year, range 7-75 years) who underwent CPET between 1999 and 2009. During a mean follow-up of 4.1 ± 2.6 years after CPET, 30 patients (3.4%) died or had sustained ventricular tachycardia (VT). 225 patients (25.7%) had other cardiac related events (emergency admission, surgery, or catheter interventions). On multivariable Cox regression-analysis, %predicted peak oxygen uptake (V˙O2 %) (p=0.001), resting QRS duration (p=0.030) and age (p<0.001) emerged as independent predictors of mortality or sustained VT. Patients with a peak V˙O2 ≤ 65% of predicted and a resting QRS duration ≥ 170 ms had a 11.4-fold risk of death or sustained VT. Ventilatory efficiency expressed as V˙E/V˙CO2 slope (p<0.001), peak V˙O2 % (p=.001), QRS duration (p=.001) and age (p=0.046) independently predicted event free survival. V˙E/V˙CO2 slope ≥ 31.0, peak V˙O2 % ≤ 65% and QRS duration ≥ 170 ms were the cut-off points with best sensitivity and specificity to detect an unfavorable outcome. CONCLUSIONS: CPET is an important predictive tool that may assist in the risk stratification of patients with ToF. Subjects with a poor exercise capacity in addition to a prolonged QRS duration have a substantially increased risk for death or sustained ventricular tachycardia, as well as for cardiac-related hospitalizations.

Effect of bosentan therapy on ventricular and atrial function in adults with Eisenmenger syndrome. A prospective, multicenter study using conventional and Speckle tracking echocardiography.

BACKGROUND: The effect of bosentan on the ventricular and atrial performance in patients with Eisenmenger syndrome is unclear. In adult patients with Eisenmenger syndrome, we aimed to evaluate the midterm effect of bosentan on physical exercise, ventricular and atrial function, and pulmonary hemodynamics. METHODS: Forty adult patients before and after 24 weeks bosentan therapy underwent 6 min walk test, two-dimensional speckle tracking echocardiography, plasma NT-proBNP measurement and cardiac catheterization. RESULTS: After 24 weeks, bosentan therapy an improvement was observed regarding the 6 min walk distance from a median (quartile 1-quartile 3) of 382.5 (312-430) to 450 (390-510) m (p = 0.0001), NT-proBNP from 527.5 (201-1,691.25) to 369 (179-1,246) pg/ml (p = 0.021), right ventricular mean longitudinal systolic strain from 18 (13-22) to 19 (14.5-25) % (p = 0.004), left ventricular mean longitudinal systolic strain from 16 (12-21) to 17 (16-22) % (p = 0.001), right atrial mean peak longitudinal strain from 26 (18-34) to 28 (22-34) % (p = 0.01) and right atrial mean peak contraction strain from 11 (8-16) to 13 (11-16) % (p = 0.005). The invasively obtained Qp:Qs and Rp:Rs did not significantly change under bosentan therapy. CONCLUSIONS: In adult patients with Eisenmenger syndrome, bosentan therapy improves ventricular and atrial functions resulting in enhancement of physical exercise and reduction in the NT-proBNP level, while the pulmonary vascular resistance does not change substantially.

Poorer right ventricular systolic function and exercise capacity in women after repair of tetralogy of fallot: a sex comparison of standard deviation scores based on sex-specific reference values in healthy control subjects.

BACKGROUND: In repaired congenital heart disease, there is increasing evidence of sex differences in cardiac remodeling, but there is a lack of comparable data for specific congenital heart defects such as in repaired tetralogy of Fallot. METHODS AND RESULTS: In a prospective multicenter study, a cohort of 272 contemporary patients (158 men; mean age, 14.3±3.3 years [range, 8-20 years]) with repaired tetralogy of Fallot underwent cardiac magnetic resonance for ventricular function and metabolic exercise testing. All data were transformed to standard deviation scores according to the Lambda-Mu-Sigma method by relating individual values to their respective 50th percentile (standard deviation score, 0) in sex-specific healthy control subjects. No sex differences were observed in age at repair, type of repair conducted, or overall hemodynamic results. Relative to sex-specific controls, repaired tetralogy of Fallot in women had larger right ventricular end-systolic volumes (standard deviation scores: women, 4.35; men, 3.25; P=0.001), lower right ventricular ejection fraction (women, -2.83; men, -2.12; P=0.011), lower right ventricular muscle mass (women, 1.58; men 2.45; P=0.001), poorer peak oxygen uptake (women, -1.65; men, -1.14; P<0.001), higher VE/VCO2 (ventilation per unit of carbon dioxide production) slopes (women, 0.88; men 0.58; P=0.012), and reduced peak heart rate (women, -2.16; men -1.74; P=0.017). Left ventricular parameters did not differ between sexes. CONCLUSIONS: Relative to their respective sex-specific healthy control subjects, derived standard deviation scores in repaired tetralogy of Fallot suggest that women perform poorer than men in terms of right ventricular systolic function as tested by cardiac magnetic resonance and exercise capacity. This effect cannot be explained by selection bias. Further outcome data are required from longitudinal cohort studies.

Right ventricular function in grown-up patients after correction of congenital right heart disease.

AIMS: We investigated whether a correlation exists between biomarkers of the neurohumoral system and clinical markers in grown-up patients with congenital heart disease (GUCH) and right ventricular function. METHODS AND RESULTS: Prospective, cross-sectional, multicenter study of 104 GUCH patients (median) 16 years (range 6-43 years) after corrective surgery with RV pressure and/or volume overload and 54 healthy controls. Clinical, functional, and laboratory parameters were assessed. Natriuretic peptide levels were significantly increased in GUCH patients (NTproBNP 101 vs. 25 pg/ml, p < 0.001), but we observed no differences in norepinephrine, aldosterone, angiotensin II and Endothelin-1 levels. NTproBNP correlated significantly with clinical markers such as NYHA classification, prolonged QRS duration and reduced exercise capacity (VO(2) peak) (all p < 0.001), as well as self-reported quality of life (p < 0.001). MRI and echocardiography derived RV volumes were elevated and ejection fraction reduced in the patients (both p < 0.001). Tissue Doppler parameter showed significantly restricted ventricular longitudinal systolic function (longitudinal tricuspid valve movement, 1.7 vs. 2.3 cm, p < 0.001), suggesting stiffness and reduced RV compliance. CONCLUSION: In conclusion, grown-up patients with congenital right heart disease NTproBNP correlates well with various clinical markers of RV failure, such as prolongation of QRS duration, exercise capacity, echocardiography and MRI parameters, and quality of life.

Impact of gender and age on cardiovascular function late after repair of tetralogy of Fallot: percentiles based on cardiac magnetic resonance.

BACKGROUND: The impact of gender and age on cardiac function by cardiac magnetic resonance (CMR) in repaired tetralogy of Fallot (TOF) is unknown, which limits the value of currently discussed volumetric thresholds and the accuracy of individual follow-up. METHODS AND RESULTS: In a nationwide, prospective, 14-center study, 407 consecutive patients with repaired TOF (age, 17.9±8.3 years; range, 8-59 years; 226 male patients) underwent standardized CMR ventricular volumetry and flow quantification (pulmonary artery/ascending aorta). There were no sex differences for age at TOF repair, type of repair, number of prior repair palliations or reinterventions after repair, pulmonary regurgitation fraction, and maximal gradient across the right ventricular outflow tract. Biventricular volumes and mass (indexed to body surface area), available in 380 of 407 patients, respectively, were higher in male patients (P<0.003), but biventricular ejection fraction was higher in female patients (P<0.012). As opposed to reported data of healthy populations, sex-specific reference percentiles computed for an age range of 8 to 40 years (lambda-mu-sigma method) demonstrated (1) an increase of end-diastolic and end-systolic left ventricular volumes, particularly in female patients; (2) an increase of end-systolic right ventricular volumes in both sexes; and (3) a decrease of biventricular ejection fraction in male patients, whereas in female patients, only right ventricular ejection fraction decreased. CONCLUSIONS: Significant gender differences of biventricular volumes, function, and mass by CMR exist late after repair of TOF, suggesting that age and gender cannot be ignored when discussing thresholds. Gender-specific percentiles may present a more relevant framework of reference for an individual patient at a given age and suggest a gradual decline of biventricular systolic function over time.

Exercise capacity of a contemporary cohort of children with hypoplastic left heart syndrome after staged palliation.

OBJECTIVE: Outcome of staged palliation for hypoplastic left heart syndrome has improved over the past decades. However, only little is known about the exercise capacity of children with palliated hypoplastic left heart syndrome where a systemic right ventricle supports the systemic circulation. The aim of the study was to assess exercise capacity in a contemporary cohort of children with hypoplastic left heart syndrome palliated in a single centre according to a uniform surgical strategy. METHODS: Standardised cardiopulmonary exercise testing on a treadmill was performed in 46 consecutive hypoplastic left heart patients (median age: 6.0 (4.1-11.4) years). All but one patient reached the anaerobic threshold. Exercise data were compared to normal values obtained with a similar exercise protocol in a large cohort of paediatric volunteers. RESULTS: Oxygen uptake at anaerobic threshold (26.9+/-6.0 ml kg(-1)min(-1); 74.5+/-18.2% of predicted) and maximal oxygen uptake (31.0+/-6.8 ml kg(-1)min(-1); 60.8+/-15.0% of predicted) were significantly reduced compared with controls (P<0.0001 for both). The limitation in exercise capacity was due to an impaired rise in heart rate (158+/-23 bpm; 79.7+/-11.5% of predicted; P<0.0001) and oxygen pulse (4.5+/-1.6 ml per beat; 85.5+/-22.0% of predicted; P<0.0001). Furthermore, respiration during exercise was inefficient with an elevated respiratory rate and reduced maximal tidal volume and minute ventilation at maximal exercise. CONCLUSIONS: The exercise capacity of children with hypoplastic left heart syndrome is markedly reduced. Limitations in heart rate increase and stroke volume augmentation are the major contributors to this. An abnormal ventilatory response to exercise also adds to their limitation in exercise tolerance. However, the degree of physical disability does not justify discouraging these patients from school and leisure sports.