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Muscle strength is decreased in adults with pulmonary arterial hypertension (PAH). We aim to investigate muscle strength in children with PAH in relation to a cohort of healthy children, and investigate correlations with disease severity markers. This prospective study included children with PAH aged 4-18 years, who visited the Dutch National Referral Center for Pulmonary Hypertension in Childhood between October 2015 and March 2016. Muscle strength was assessed using handgrip strength and maximum voluntary isometric contractility (MVIC) of four peripheral muscles. Dynamic muscle function was evaluated with the Bruininks-Oseretsky test of motor proficiency (BOT-2). These measurements were compared with those in two cohorts of healthy children and correlated with 6-minute walk distance (6MWD), World Health Organization functional class (WHO-FC), N-terminal pro-brain natriuretic peptide (NT-proBNP), and time since diagnosis. Eighteen children with PAH aged 14.0 [interquartile range: 9.9-16.0] years showed reduced muscle strength. Handgrip strength z-score -2.4 ± 1.2, p < 0.001, total MVIC z-score -2.9 ± 1.2, p < 0.001, and BOT-2 z-score -1.0 ± 0.9, p < 0.001. 6MWD (67 ± 11% predicted) correlated with most muscle measurements (r = 0.49-0.71, p = 0.001). Dynamic muscle function (BOT-2) differed between WHO-FC, whereas handgrip strength and MVIC did not. NT-proBNP and time since diagnosis did not show significant correlations with muscle strength measurements. Muscle strength was significantly reduced in children with PAH and correlated with 6MWD, but not with disease severity markers WHO-FC and NT-pro-BNP. The nature of this reduced muscle strength is yet unclear, but its occurrence in children with seemingly mild or well-controlled PAH supports the concept of PAH being a systemic syndrome involving peripheral skeletal muscles.

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Background The aim of this study is to describe muscle strength in pediatric patients with repaired tetralogy of Fallot compared with healthy peers and to analyze the correlation between muscle strength and peak oxygen uptake, exercise capacity (mL/min). Methods and Results A prospective, cross-sectional study was carried out in the University Medical Center Groningen between March 2016 and December 2019, which included 8 -to-19-year-old patients with repaired tetralogy of Fallot. Exclusion criteria comprised the following: Down syndrome, unstable pulmonary disease and severe scoliosis affecting pulmonary function, neuromuscular disease, and mental or physical limitations that prohibit the execution of the functional tests. Muscle strength was compared with 2 healthy pediatric cohorts from the Northern Netherlands. Handgrip strength, maximal voluntary isometric contraction, and dynamic muscle strength in correlation with peak oxygen uptake, exercise capacity (mL/min) were the main outcomes of the study. The 67 patients with repaired tetralogy of Fallot (42% female; aged 12.9 [interquartile range, 10.0-16.3] years old) were compared with healthy children. The patients showed reduced grip strength (z-score [mean±SD] -1.5±1.2, P<0.001), and total muscle strength (z-score -0.9±1.3, P<0.001). Dynamic strength (Bruininks-Oseretsky test) was significantly reduced (z-score -0.3±0.8, P=0.001), but running, speed, and agility were normal (z-score 0.1±0.7, P=0.4). Univariate correlation analyses showed strong correlations between absolute peak oxygen uptake, exercise capacity (mL/min), and muscle strength (grip strength r=0.83, total muscle strength r=0.88; P<0.001). In multivariate analyses, including correction for age and sex, total muscle strength (B 0.3; P=0.009), and forced vital capacity (B 0.5; P=0.02) correlated with peak oxygen uptake, exercise capacity (mL/min), independent of conventional cardiovascular parameters. Conclusions Children with repaired tetralogy of Fallot show reduced muscle strength, which strongly correlated with their exercise performance.

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OBJECTIVES: This study aimed to provide a perspective for the interpretation of exercise capacity (peakVO2) in patients with repaired Tetralogy of Fallot (patients with rTOF) by describing the course of peakVO2 from patients aged 6-63 years. METHODS: A retrospective study was performed between September 2001 and December 2016 in the German Heart Centre Munich, Germany, and in the University Medical Centre Groningen, the Netherlands. A total of 1175 cardiopulmonary exercise tests (CPETs) were collected from 586 patients with rTOF, 46% female. Maximal exertion was verified using a respiratory exchange ratio ≥1.00. PeakVO2 was modelled using time-dependent multilevel models for repeated measurements (n=889 in 300 patients), and compared with subject-specific reference values calculated by the models of Bongers et al and Mylius et al. RESULTS: The peakVO2 of patients with rTOF was reduced at all ages. At the age of 6, the peakVO2 was 614 mL/min (70% of predicted (95% CI 67 to 73)). The reduced increase in peakVO2 during adolescence resulted in a significant lower maximum peakVO2 of 1209 mL/min at 25 years (65% predicted, p<0.001). A linear decline after 25 years was observed in patients and references, although patients showed an accelerated decline, with a -0.24% point of predicted (95% CI 0.11 to 0.38) per year without differences between sexes (p=0.263). CONCLUSIONS: This study provides a context for peakVO2 across ages in patients with rTOF under contemporary treatment strategies. It showed that the reduction in peakVO2 originates from childhood and declines over time. Sex differences in patients with rTOF were similar to natural existing sex differences.

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Background We investigated serial serum levels of GDF-15 (growth differentiation factor 15) in Fontan patients and their relation to outcome. Methods and Results In this single-center prospective study of consecutive Fontan patients, serial serum GDF-15 measurement and clinical assessment was done at baseline (n=81) and after 2 years (n=51). The association between GDF-15 and the combined end point of all-cause mortality, heart transplant listing, and Fontan-related hospitalization was investigated. Median age at baseline was 21 years (interquartile range: 15-28 years). Median GDF-15 serum levels at baseline were 552 pg/mL (interquartile range: 453-729 pg/mL). GDF-15 serum levels correlated positively with age, age at Fontan initiation, New York Heart Association class, and serum levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide) and É£GT (γ-glutamyltransferase) and negatively with exercise capacity. During a median follow-up of 4.8 years (interquartile range: 3.3-5.5 years), the combined end point occurred in 30 patients (37%). Multivariate Cox regression showed that patients with the highest baseline GDF-15 (n=20, defined as the upper quartile) had a higher risk of hospitalization or death than the lowest 3 quartiles (hazard ratio [HR], 2.76; 95% CI, 1.27-6.00; P=0.011). After 2 years of follow-up, patients in whom serum level of GDF-15 increased to >70 pg/mL (n=13) had a higher risk of hospitalization or death than the lowest 3 quartiles (HR, 2.69; 95% CI, 1.03-6.99; P=0.043). Conclusions In Fontan patients, elevated serum levels of GDF-15 are associated with worse functional status and predict Fontan-related events. Furthermore, serial measurements showed that an increase in GDF-15 serum level was associated with increased risk for adverse outcome.

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Purpose Substantial differences between sexes exist with respect to cardiovascular diseases, including congenital heart disease. Nevertheless, clinical decisions in the long-term follow-up of patients with repaired tetralogy of Fallot (rTOF) are currently based on unisex thresholds for cardiac magnetic resonance (CMR) measurements. This study aimed to assess whether sex differences exist in cardiac adaptation to hemodynamic loading conditions in patients with rTOF. Methods and Results This cross-sectional, two-center, combined pediatric and adult cohort included 320 rTOF patients (163 males, 51%) who underwent routine CMR. Despite similar age (median and interquartile range [m + IQR] 23.4 [15.2-34.4] years), surgical history, and hemodynamic loading, males with rTOF demonstrated higher biventricular CMR-derived volumes and masses, indexed for body surface area, compared to females (e.g. m + IQR right ventricular (RV) end-diastolic volume: males 123 [100-151] mL/m2, females 114 [94-131] mL/m2, P = 0.007). Sex-specific Z-scores of biventricular volumes and masses were similar for males and females. RV volumes and masses correlated with hemodynamic loading, but these relations did not differ between sexes. Biventricular ejection fraction (EF) appeared to be lower in male patients, compared to female patients (e.g. m + IQR RVEF: males 48 [43-54]%, females 52 [46-57]%, P < 0.001). Conclusion Indexed ventricular volumes and masses are higher in males with rTOF, compared to females, similar to the healthy population. RV hypertrophy and dilatation correlated to loading conditions similarly for both sexes. However, under comparable loading conditions, males demonstrated more severe functional impairment. These results indicate that sex-differences should no longer be ignored in treatment strategies, including timing of pulmonary valve replacement.

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BACKGROUND: In Fontan patients, attrition of ventricular function is well recognized, but early detection of ventricular dysfunction is difficult. The aim of this study is to longitudinally assess ventricular strain in Fontan patients using a new method for cardiac magnetic resonance (CMR) feature tracking, and to investigate the relationship between ventricular strain and cardiac systolic function. METHODS AND RESULTS: In this prospective, standardized follow-up study in 51 Fontan patients, age ≥ 10 years, CMR and concomitant clinical assessment was done at the start of the study and after 2 years. CMR feature tracking was done combining the dominant and hypoplastic ventricles. Global longitudinal strain (GLS) (-17.3% versus -15.9%, P = 0.041) and global circumferential strain (GCS) (-17.7 versus -16.1, P = 0.047) decreased over 2 years' time. Ejection fraction (EF) (57%), cardiac index (CI) (2.7 l/min/m2) and NYHA functional class (97% in class I/II) were preserved. The strain values of the combined dominant and hypoplastic ventricles were significantly worse compared to those of the dominant ventricle only (GLS -16.8 (-19.5 to -14.0) versus -18.8 (-21.3 to -15.3) respectively, P = 0.001, GCS -18.3 (-22.1 to -14.8) versus -22.5 (-26.3 to -19.4) respectively, P < 0.001). CONCLUSIONS: This study showed a decrease in cardiac strain over 2 years in Fontan patients without clinical signs of Fontan failure, where EF, CI and clinical status were still preserved. Cardiac strain might be a sensitive early indicator of systolic ventricular decline. Furthermore, combined strain of the hypoplastic and dominant ventricles seems a more accurate representation of cardiac strain in functionally univentricular hearts.

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OBJECTIVE: In the Fontan circulation, non-pulsatile pulmonary blood flow is suggested to negatively affect pulmonary artery growth. The pulmonary vasculature is regarded a key determinant of outcome after Fontan completion. We hypothesised that in Fontan patients pulmonary artery size correlates with follow-up and functional clinical status. METHODS: This is a single-centre, cross-sectional cohort study. Thirty-nine paediatric and adult Fontan patients with a concomitant cardiac magnetic resonance (CMR) scan and a cardiopulmonary exercise test between 2012 and 2013 were included. CMR-derived left and right pulmonary artery cross-sectional areas were expressed as Nakata index. Functional status was defined as peak oxygen consumption (pVO2) indexed for weight, as percentage of predicted (pred) and as New York Heart Association Functional Class (NYHA-FC). RESULTS: Age at CMR was 18±7.2 years. Time since Fontan completion was 11.9±7.4 years. Nakata index was lower versus the reference values (238.6±78.5 vs 330±30 mm2/m2, p<0.001). Nakata index correlated negatively with age at CMR (r=-0.393, p=0.013) and time since Fontan completion (r=-0.341, p=0.034). pVO2 was 27.9±8.9 mL/min/kg and pVO2pred was 58.1%±14.1%. Nakata index correlated positively with pVO2 (r=0.468, p=0.003) and pVO2pred (r=0.353, p=0.028). Nakata index correlated negatively with NYHA-FC (r=-0.450, p=0.004). Nakata index was an independent predictor (ß=0.359, p=0.007) for pVO2 (adjusted R2=0.442, with maximum heart rate and oxygen pulse at peak exercise). CONCLUSIONS: Pulmonary artery size expressed as Nakata index is a novel independent predictor for functional clinical status. Nakata index negatively correlated with follow-up duration, suggesting that chronic abnormal non-pulsatile pulmonary blood flow plays a role in lagging pulmonary arterial growth in the Fontan circulation.

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The unique, unphysiological Fontan circulation is associated with an impaired functional status of the patients that is suggested to deteriorate over time. Unfortunately, previous studies did not integrate both pulmonary and cardiac determinants of functional status. In addition, a comparison with the natural decrease in exercise capacity in healthy subjects (in both children and adults) is lacking. This single-center study aims to investigate the functional status in a cohort of Fontan patients in relation to time since Fontan completion and to identify its determinants, including cardiac characteristics and pulmonary characteristics. Eighty-five consecutive Fontan patients ≥10 years who performed adequate cardiopulmonary exercise testing (respiratory exchange ratio >1.01) were included. Mean time since Fontan completion was 15 ± 9 years (range 2 to 37 years). New York Heart Association functional class was I in 36 patients (42%), II in 41 patients (48%), and III in 8 patients (9%). Peak oxygen uptake during exercise (VO2 index) was 25.7 ± 7.9 ml/min/m2 (58 ± 14% of predicted). New York Heart Association functional class and peak VO2 index both correlated with time since the Fontan operation; however, peak VO2 as percentage of predicted (VO2(pred)) did not. In multivariate analyses, peak VO2(pred) was independently associated with maximum heart rate, oxygen pulse at peak exercise, and forced expiratory volume in 1 second (R2 = 0.579) but not with cardiac output in rest. In conclusion, the present data suggest that functional status in Fontan patients is impaired already shortly after Fontan completion, whereas its subsequent deterioration seems to follow the natural decline of aging. Furthermore, functional status in Fontan patients correlates with pulmonary function and cardiac functional parameters during exercise but not with conventional cardiac measurements at rest.

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