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In patients with congenital heart disease (CHD), reduced exercise capacity can be a predictor for late complications and may be used to guide interventions. Yet, the interpretation of exercise capacity is challenged by changes in body composition during growth. Our aim was to create an overview of disease-specific exercise capacity in children with CHD. We performed a multicentre retrospective study of exercise capacity of CHD patients, aged 6–18 years, tested between January 2001 and October 2018. Sex-specific distribution graphs were made using the LMS method and height to relate to body size. We included all CHD with N > 50, including severe defects (e.g., univentricular heart, tetralogy of Fallot) and "simple" lesions as ventricular septum defect and atrial septum defect. We included 1383 tests of 1208 individual patients for analysis. The peak oxygen uptake (VO2peak, 37.3 ml/min/kg (25th–75th percentile 31.3–43.8)) varied between specific defects; patients with univentricular hearts had lower VO2peak compared with other CHD. All groups had lower VO2peak compared to healthy Dutch children. Males had higher VO2peak, Wpeak and O2pulsepeak than females. Sex- and disease-specific distribution graphs for VO2peak, Wpeak and O2pulsepeak showed increase in variation with increase in height. Conclusion: Disease-specific distribution graphs for exercise capacity in children with CHD from a large multicentre cohort demonstrated varying degrees of reduced VO2peak and Wpeak. The distribution graphs can be used in the structured follow-up of patients with CHD to predict outcome and identify patients at risk. What is Known: • Children with congenital heart disease (COnHD) are at risk to develop heart failure, arrhytmia's and other complications. Exercise capacity may be an important predictor for outcome in children with ConHD. In children, the interpretation of exercise capacity poses an additional challenge related to physical changes during growth. What is New: • In this report of a multi-center cohort >1300 childrewn with ConHD, we related the changes in exercise capacity to length. We demonstrated that exercise capacity was reduced as compared with healthy children and we observed variation between disease groups. Patients with a univentricular circulation (Fontan) had worse exercise capacity. We constructed disease specific charts of development of exercise capacity throughout childhood, accessible via a web-site. These graphs may help practitioner to guide children with ConHD. [ABSTRACT FROM AUTHOR]

MRI is an important additional tool in the diagnostic work-up of children with congenital heart disease. This review aims to summarise the role MRI has in this patient population. Echocardiography remains the main diagnostic tool in congenital heart disease. In specific situations, MRI is used for anatomical imaging of congenital heart disease. This includes detailed assessment of intracardiac anatomy with 2-D and 3-D sequences. MRI is particularly useful for assessment of retrosternal structures in the heart and for imaging large vessel anatomy. Functional assessment includes assessment of ventricular function using 2-D cine techniques. Of particular interest in congenital heart disease is assessment of right and single ventricular function. Two-dimensional and newer 3-D techniques to quantify flow in these patients are or will soon become an integral part of quantification of shunt size, valve function and complex flow patterns in large vessels. More advanced uses of MRI include imaging of cardiovascular function during stress and tissue characterisation of the myocardium. Techniques used for this purpose need further validation before they can become part of the daily routine of MRI assessment of congenital heart disease. [ABSTRACT FROM AUTHOR]

Objective: To study the changes over time in biventricular size and function, and clinical parameters in patients after repair of tetralogy of Fallot (TOF) without subsequent pulmonary valve replacement (PVR). Methods: We prospectively included 78 non-PVR patients (age 20(6–60)years at baseline), who were studied twice with a 5-year interval. Patients underwent magnetic resonance imaging for assessment of biventricular size and function. Exercise testing and electrocardiography were performed to determine peak oxygen uptake (peak VO2) and QRS duration. N-terminal prohormone brain natriuretic peptide (NT-proBNP) was assessed additionally. Results: Pulmonary regurgitation (PR), right ventricular (RV) volumes and QRS duration increased during 5-year follow-up (RV end-diastolic volume (EDV) 130±30ml/m2 to 138±34ml/m2; QRS 132±27msec to 139±27msec); peak VO2 decreased (96±19% to 91±17%). RV ejection fraction, RV effective stroke volume (eff.SV), and NT-proBNP levels remained unchanged. The slope of RVEDV increase was 1.6±3.0ml/m2/year, and depended on RVeff.SV, not on RVEDV, at baseline. Increase in RVEDV correlated with increase in QRS duration over time (r =0.28, p =0.016), and with decrease in RV mass/EDV ratio over time (r =−0.42, p <0.001), not with decrease in peak VO2. In subgroup analysis, patients with larger RVs at baseline showed larger increase in PR during follow-up and larger decrease in NYHA class over time. Conclusions: In TOF patients with moderate RV dilatation, RVEDV increased by 1.6±3.0ml/m2/year, irrespective of RV size at baseline, but depended on RVeff.SV at baseline. Despite limited progression in RV size, unfavourable changes occurred during 5years follow-up, which suggests there is a need for close follow-up. [ABSTRACT FROM AUTHOR]

Because right ventricular (RV) dysfunction predicts a poor outcome in patients with congenital heart disease (CHD), regular monitoring of RV function is indicated. To date, cardiac magnetic resonance (CMR) imaging has been the reference method. A more practical, more accessible, and accurate tool would be preferred. We defined normality regarding RV systolic function using healthy controls and tested the ability of real-time 3-dimensional echocardiographic (RT3DE) findings to identify patients with CHD with RV dysfunction. The cutoff values for the RV volumes and ejection fraction (EF) were derived from the CMR imaging findings from 41 healthy controls (mean age 27 ± 8 years, 56% men). In 100 patients with varying CHDs (mean age 27 ± 11 years, 65% men), both RT3DE data sets (iE33) and short-axis CMR imaging (1.5 T) were obtained within 2 hours. The RT3DE and CMR RV volumes and EF were calculated using commercially available software. Receiver operating characteristic curves were created to obtain the sensitivity and specificity of the RT3DE data to identify RV dysfunction. Applying the cutoff values derived from the healthy controls using the CMR data of patients with CHD, we identified 23 patients with an enlarged indexed end-diastolic volume, 29 patients with an enlarged indexed end-systolic volume, and 21 patients with an impaired RVEF. The best cutoff values predicting RV dysfunction using the RT3DE findings were identified (indexed end-diastolic volume >105 ml/m2, indexed end-systolic volume >54 ml/m2, and EF <43%). The RT3DE findings revealed 23 patients with impaired RVEF, with 95% sensitivity, 89% specificity, and a negative predictive value of 99%. In conclusion, real-time 3-dimensional echocardiography is a very sensitive tool to identify RV dysfunction in patients with CHD and could be applied clinically to rule out RV dysfunction or to indicate additional quantitative analysis of RV function. [ABSTRACT FROM AUTHOR]

Myocardial hyperplasia is generally considered to occur only during fetal development. However, recent evidence suggests that this type of response may also be triggered by cardiac overload after birth. In congenital heart disease, loading conditions are frequently abnormal, thereby affecting ventricular function. We hypothesized that chronic right ventricular pressure overload imposed on neonatal hearts initiates a hyperplastic response in the right ventricular myocardium. To test this, young lambs (aged 2–3 weeks) underwent adjustable pulmonary artery banding to obtain peak right ventricular pressures equal to left ventricular pressures for 8 weeks. Transmural cardiac tissue samples from the right and left ventricles of five banded and five age-matched control animals were studied. We found that chronic right ventricular pressure overload resulted in a twofold increase in right-to-left ventricle wall thickness ratio. Morphometric right ventricular myocardial tissue analysis revealed no changes in tissue composition between the two groups; nor were right ventricular myocyte dimensions, relative number of binucleated myocytes, or myocardial DNA concentration significantly different from control values. In chronic pressure overloaded right ventricular myocardium, significantly ( P < 0.01) more myocyte nuclei were positive for the proliferation marker proliferating cellular nuclear antigen than in control right ventricular myocardium. Chronic right ventricular pressure overload applied in neonatal sheep hearts results in a significant increase in right ventricular free wall thickness which is primarily the result of a hyperplastic myocardial response. [ABSTRACT FROM AUTHOR]

Whilst stenosis of systemic and pulmonary arteries in Williams syndrome is frequently described, aneurysm formation is uncommon. We provide the first description of a Williams patient with development of an aneurysm of the arterial duct. This aneurysm developed concomitantly with supravalvar aortic, and peripheral pulmonary stenosis. The duct was closed interventionally to reduce the risk of rupture. [ABSTRACT FROM AUTHOR]

Examines the biventricular systolic function in lambs subject to chronic systemic right ventricular (RV) pressure overload. Use of indexes to determine the biventricular function; Increase of pulmonary artery banding; Outcome of the chronic RV pressure overload.

Focuses on a study which quantified the remodeling of right and left ventricles during a period of chronic right ventricle pressure overload at the level of systemic pressure. Methods; Results; Interpretation of findings.

Background: The CRUCIAL trial (NCT04217421) is investigating the effect of postnatal and perioperative administration of allopurinol on postoperative brain injury in neonates with critical congenital heart disease (CCHD) undergoing cardiac surgery with cardiopulmonary bypass (CPB) shortly after birth. Objective: This study aimed to characterize the pharmacokinetics (PK) of allopurinol and oxypurinol during the preoperative, intraoperative, and postoperative phases in this population, and to evaluate target attainment of the current dosing strategy. Methods: Nonlinear mixed-effects modeling was used to develop population PK models in 14 neonates from the CRUCIAL trial who received up to five intravenous allopurinol administrations throughout the postnatal and perioperative periods. Target attainment was defined as achieving an allopurinol concentration >2 mg/L in at least two-thirds of the patients during the first 24 h after birth and between the start and 36 h after cardiac surgery with CPB. Results: A two-compartment model for allopurinol was connected to a one-compartment model for oxypurinol with an auto-inhibition effect on the conversion, which best described the PK. In a typical neonate weighing 3.5 kg who underwent cardiac surgery at a postnatal age (PNA) of 5.6 days, the clearance (CL) of allopurinol and oxypurinol at birth was 0.95 L/h (95% confidence interval 0.75–1.2) and 0.21 L/h (0.17–0.27), respectively, which subsequently increased with PNA to 2.97 L/h and 0.41 L/h, respectively, before CPB. During CPB, allopurinol and oxypurinol CL decreased to 1.38 L/h (0.9–1.87) and 0.12 L/h (0.05–0.22), respectively. Post-CPB, allopurinol CL increased to 2.21 L/h (1.74–2.83), while oxypurinol CL dropped to 0.05 L/h (0.01–0.1). Target attainment was 100%, 53.8%, and 100% at 24 h postnatally, 24 h after the start of CPB, and 36 h after the end of cardiac surgery, respectively. The combined concentrations of allopurinol and oxypurinol maintained ≥ 90% inhibition of xanthine oxidase (IC90XO) throughout the postnatal and perioperative period. Conclusions: The minimal target concentration of allopurinol was not achieved at every predefined time interval in the CRUCIAL trial; however, the dosing strategy used was deemed adequate, since it yielded concentrations well exceeding the IC90XO. The decreased CL of both compounds during CPB suggests influence of the hypothermia, hemofiltration, and the potential sequestration of allopurinol in the circuit. The reduced CL of oxypurinol after CPB is likely attributable to impaired kidney function. [ABSTRACT FROM AUTHOR]

A response from the author of the article "Long-term outcomes of transatrial-transpulmonary repair of tetralogy of Fallot" in the 2015 issue is presented.

Open in new tab Download slide OBJECTIVES Congenital supravalvular aortic stenosis (SVAS) is a rare form of congenital outflow tract obstruction and long-term outcomes are scarcely reported. This study aims to provide an overview of outcomes after surgical repair for congenital SVAS. METHODS A systematic review of published literature was conducted, including observational studies reporting long-term clinical outcome (>2 years) after SVAS repair in children or adults considering >20 patients. Early risks, late event rates and time-to-event data were pooled and entered into a microsimulation model to estimate 30-year outcomes. Life expectancy was compared to the age-, sex- and origin-matched general population. RESULTS Twenty-three publications were included, encompassing a total of 1472 patients (13 125 patient-years; pooled mean follow-up: 9.0 (6.2) years; median follow-up: 6.3 years). Pooled mean age at surgical repair was 4.7 (5.8) years and the most commonly used surgical technique was the single-patch repair (43.6%). Pooled early mortality was 4.2% (95% confidence interval: 3.2–5.5%) and late mortality was 0.61% (95% CI: 0.45–0.83) per patient-year. Based on microsimulation, over a 30-year time horizon, it was estimated that an average patient with SVAS repair (mean age: 4.7 years) had an observed life expectancy that was 90.7% (95% credible interval: 90.0–91.6%) of expected life expectancy in the matched general population. The microsimulation-based 30-year risk of myocardial infarction was 8.1% (95% credible interval: 7.3–9.9%) and reintervention 31.3% (95% credible interval: 29.6–33.4%), of which 27.2% (95% credible interval: 25.8–29.1) due to repair dysfunction. CONCLUSIONS After surgical repair for SVAS, 30-year survival is lower than the matched-general-population survival and the lifetime risk of reintervention is considerable. Therefore, lifelong monitoring of the cardiovascular system and in particular residual stenosis and coronary obstruction is recommended. [ABSTRACT FROM AUTHOR]

Fontan circulation is a highly abnormal circulatory state that may affect various organ systems. The effect on body composition is an important factor to assess the condition of the patient. This systematic review assesses body composition and possibly related adverse outcomes in patients with a Fontan circulation, to provide an overview of current insights. Studies evaluating body composition by compartment (either fat mass or lean/muscle mass) in Fontan patients published up to April 2023 were included in this systematic review. Of 1392 potential studies, 18 studies met the inclusion criteria. In total, body composition measurements of 774 Fontan patients were included. Body composition was measured using dual-energy X-ray absorptiometry (DXA) (n = 12), bioelectrical impedance analysis (BIA) (n = 5), computer tomography (CT) (n = 1), or magnetic resonance imaging (MRI) (n = 1). All studies reported a normal body mass index (BMI) in Fontan patients, compared to controls. Five out of nine studies reported significantly higher body fat values, and twelve out of fifteen studies reported significantly lower muscle or lean mass values in the Fontan population compared to the healthy population. Unfavorable body composition in Fontan patients was associated with decreased exercise capacity, worse cardiac function, and adverse outcomes including hospital admissions and death. Conclusions: Despite having a normal BMI, Fontan patients have an increased fat mass and decreased muscle mass or lean mass compared to the healthy population. This unfavorable body composition was associated with various adverse outcomes, including a decreased exercise capacity and worse cardiac function. What is Known: • Patients with a Fontan circulation have a decreased exercise capacity compared to healthy peers, an unfavorable body composition might be a contributor to their impaired exercise capacity. What is New: • Fontan patients are predisposed to an unfavorable body composition, characterized by increased fat mass and decreased muscle mass accompanied by a normal BMI compared to the healthy population. • Among others, unfavorable body composition was associated with decreased exercise capacity, cardiac function, and increased morbidity in patients with a Fontan circulation. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES To support clinical decision-making in children with aortic valve disease, by compiling the available evidence on outcome after paediatric aortic valve repair (AVr). METHODS A systematic review of literature reporting clinical outcome after paediatric AVr (mean age at surgery <18 years) published between 1 January 1990 and 23 December 2021 was conducted. Early event risks, late event rates and time-to-event data were pooled. A microsimulation model was employed to simulate the lives of individual children, infants and neonates following AVr. RESULTS Forty-one publications were included, encompassing 2 623 patients with 17 217 patient-years of follow-up (median follow-up: 7.3 years; range: 1.0–14.4 years). Pooled mean age during repair for aortic stenosis in children (<18 years), infants (<1 year) or neonates (<30 days) was 5.2 ± 3.9 years, 35 ± 137 days and 11 ± 6 days, respectively. Pooled early mortality after stenosis repair in children, infants and neonates, respectively, was 3.5% (95% confidence interval: 1.9–6.5%), 7.4% (4.2–13.0%) and 10.7% (6.8–16.9%). Pooled late reintervention rate after stenosis repair in children, infants and neonates, respectively, was 3.31%/year (1.66–6.63%/year), 6.84%/year (3.95–11.83%/year) and 6.32%/year (3.04–13.15%/year); endocarditis 0.07%/year (0.03–0.21%/year), 0.23%/year (0.07–0.71%/year) and 0.49%/year (0.18–1.29%/year); and valve thrombosis 0.05%/year (0.01–0.26%/year), 0.15%/year (0.04–0.53%/year) and 0.19%/year (0.05–0.77%/year). Microsimulation-based mean life expectancy in the first 20 years for children, infants and neonates with aortic stenosis, respectively, was 18.4 years (95% credible interval: 18.1–18.7 years; relative survival compared to the matched general population: 92.2%), 16.8 years (16.5–17.0 years; relative survival: 84.2%) and 15.9 years (14.8–17.0 years; relative survival: 80.1%). Microsimulation-based 20-year risk of reintervention in children, infants and neonates, respectively, was 75.2% (72.9–77.2%), 53.8% (51.9–55.7%) and 50.8% (47.0–57.6%). CONCLUSIONS Long-term outcomes after paediatric AVr for stenosis are satisfactory and dependent on age at surgery. Despite a high hazard of reintervention for valve dysfunction and slightly impaired survival relative to the general population, AVr is associated with low valve-related event occurrences and should be considered in children with aortic valve disease. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular magnetic resonance (CMR) imaging during supine exercise at (sub)maximal oxygen consumption (VO2) offers unique diagnostic insights. However, maximal VO2 is not achievable in the supine position and standardizing submaximal exercise intensities remains challenging. Using heart rate or workload could be a viable option to translate VO2‐based submaximal exercise intensities. Aim: To translate submaximal exercise intensities upright cycling exercise (UCE) to supine push–pull exercise (SPPE), by comparing heart rate or workload determined during UCE, with heart rate and workload during SPPE at similar exercise intensities. Methods and Results: Sixteen healthy young adults (20.4 ± 2.2 years; 8 female) underwent cardiopulmonary UCE and SPPE testing [mean ± standard deviation maximal VO2: 3.2 ± 0.6 vs. 5 ± 0.3 L min−1, p < 0.001 and median (interquartile range) of the maximum workload: 310 (244, 361) vs. 98 (98, 100), p < 0.001, respectively]. Heart rate at 40% and 60% of maximal VO2, as determined by UCE, showed low bias (−3 and 0 bpm, respectively) and wide limits of agreement (±26 and ±28 bpm, respectively), in Bland–Altman analysis. VO2/Workload relation was exponential and less efficient during SPPE compared to UCE. Generalized estimated equation analysis predicted model‐based mean workload during SPPE, with acceptable 95% confidence interval. Conclusion: Heart rate during UCE at submaximal exercise intensities can reasonably well be used to for SPPE in healthy subjects. Using workload, an ergometer specific, model‐based mean can be used to determine exercise intensities during SPPE. Individual variations in response to posture and movement change are high. During clinical interpretation of exercise CMR, individual exercise intensity has to be considered. [ABSTRACT FROM AUTHOR]

With the trend towards childhood surgery in patients with Ebstein anomaly (EA), thorough imaging is crucial for patient selection. This study aimed to assess biventricular function by echocardiography and cardiac magnetic resonance (CMR) and compare EA severity classifications. Twenty-three patients (8–17 years) underwent echocardiography and CMR. Echocardiographic parameters included tricuspid annular plane systolic excursions (TAPSE), fractional area change of the functional right ventricle (fRV-FAC), fRV free wall peak systolic myocardial velocity (fRVs'), and tricuspid regurgitation (TR). End-diastolic and end-systolic volume (EDV resp. ESV), fRV- and LV ejection fraction (EF) and TR were obtained by CMR. EA severity classifications included displacement index, Celermajer index and the total-right/left-volume index. Median fRV-FAC was 38% (IQR 33–42). TAPSE and fRVs' were reduced in 39% and 75% of the patients, respectively. Echocardiographic TR was visually graded as mild, moderate, or severe in nine, six and eight patients, respectively. By CMR, median fRVEF was 49% (IQR 36–58) and TR was graded as mild, moderate, or severe in nine, twelve and two patients, respectively. In 70% of cases, fRV-EDV was higher than LV-EDV. LVEF was decreased in 17 cases (74%). There was excellent correlation between echocardiography-derived fRV-FAC and CMR-derived fRVEF (rho = 0.812, p < 0.001). While echocardiography is a versatile tool in the complex geometry of the Ebstein heart, it has limitations. CMR offers a total overview and has the advantage of reliable volume assessment of both ventricles. Comprehensive evaluation of pediatric patients with EA may therefore require a synergistic implementation of echocardiography and CMR. [ABSTRACT FROM AUTHOR]

To determine the potential prognostic value and clinical correlations of blood biomarkers in a cohort of patients with Tetralogy of Fallot (TOF). In the setting of multicenter prospective research studies TOF patients underwent blood sampling, cardiopulmonary exercise testing and low-dose dobutamine stress cardiac magnetic resonance (CMR) imaging. In the blood sample NT-proBNP, GDF-15, Galectin-3, ST-2, DLK-1, FABP4, IGFBP-1, IGFBP-7, MMP-2, and vWF were assessed. During subsequent follow-up, patients were evaluated for reaching the study endpoint (cardiac death, arrhythmia-related hospitalization or cardioversion/ablation, VO 2 max ≤65% of predicted). Regression analysis was used to explore the correlation between blood biomarkers (corrected for age and gender) and other clinical parameters. The potential predictive value of blood biomarkers and events were assessed with Kaplan-Meier analysis and Cox proportional hazard analysis. We included 137 Fallot patients, median age 19.2 (interquartile range: 14.6–25.7) years, median age at TOF-repair 0.9 (0.5–1.9) years. After a median follow-up of 8.7 (6.3–10.7) years, 20 (14.6%) patients reached the composite endpoint. In a multivariable cox-regression analysis corrected for age at study baseline, elevated IGFBP-7 and MMP-2 levels were associated with the composite endpoint. We also noted a correlation between DLK-1 and relative change in right ventricular end systolic volume during dobutamine stress CMR (β = −0.27, p = 0.010), a correlation between FABP4 and Max VO 2 (β = −0.41, p ≤0.001 and between MMP-2 and tricuspid valve E/A ratio (β = −0.15, p = 0.037). IGFBP-7, MMP-2 and DLK-1 levels are related to cardiac function and long-term outcome in TOF patients. • Survival of patients with tetralogy of Fallot has improved spectacular over the following decades. • However long term complications remain for which there is a lack of adequate prognostic predictors. • We researched a large panel of biomarkers in a cohort of 137 young patients with tetralogy of Fallot. • IGFBP-7, MMP-2 and DLK-1 levels are related to cardiac function and long-term outcome in TOF patients. [ABSTRACT FROM AUTHOR]

Background: Derangements in the maternal methylation pathway, expressed by global hypomethylation and hyperhomocysteinemia, are associated with the risk of having a child with a congenital heart defect (CHD). It is not known whether periconception exposure to these metabolic derangements contributes to chromosome segregation and metabolic programming of this pathway in the foetus. Design: In a Dutch population-based case–control study of 143 children with CHD and 186 healthy children, we investigated S- adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), total homocysteine (tHcy), the vitamins folate and B12 and the functional single nucleotide polymorphisms in the folate gene MTHFR 677C>T and 1298A>C. Comparisons were made between cases and controls adjusting for age, medication, vitamin use and CHD family history. Results: In the overall CHD group, the median concentrations of SAM (P = 0Æ011), folate in serum (P = 0Æ021) and RBC (P = 0Æ030) were significantly higher than in the controls. Subgroup analysis showed that this was mainly attributable to complex CHD with higher SAM (P < 0Æ001), SAH (P = 0 Æ012) and serum folate (P = 0Æ010) independent of carriership of MTHFR polymorphisms. Highest concentrations of SAM, SAH and folate RBC were observed in complex syndromic CHD. The subgroup of children with Down syndrome, however, showed significantly higher SAH (P = 0Æ037) and significantly lower SAM:SAH ratio (P = 0Æ034) compared with other complex CHD, suggesting a state of global hypomethylation. Conclusion:High concentrations of methylation biomarkers in very young children are associated with complex CHD. Down syndrome and CHD may be associated with a global hypomethylation status, which has to be confirmed in tissues and global DNA methylation in future studies. [ABSTRACT FROM AUTHOR]

The article presents a study investigating the association between the maternal methylation status to the risk of congenital heart diseases (CHD) in the west part of Netherlands. In accordance to the study, it is noted that plasma total homocysteine is significantly dissimilar between the total case group and the nonisolated cases as compared with controls. Based on the data, it is analyzed that the maternal hyperhomocysteinemia is a risk factor for bearing a child with CHD.

Background: Neonates with critical congenital heart disease (CCHD) undergoing cardiac surgery with cardiopulmonary bypass (CPB) are at risk of brain injury that may result in adverse neurodevelopment. To date, no therapy is available to improve long-term neurodevelopmental outcomes of CCHD neonates. Allopurinol, a xanthine oxidase inhibitor, prevents the formation of reactive oxygen and nitrogen species, thereby limiting cell damage during reperfusion and reoxygenation to the brain and heart. Animal and neonatal studies suggest that allopurinol reduces hypoxic-ischemic brain injury and is cardioprotective and safe. This trial aims to test the hypothesis that allopurinol administration in CCHD neonates will result in a 20% reduction in moderate to severe ischemic and hemorrhagic brain injury.Methods: This is a phase III, randomized, quadruple-blinded, placebo-controlled, multicenter trial. Neonates with a prenatal or postnatal CCHD diagnosis requiring cardiac surgery with CPB in the first 4 weeks after birth are eligible to participate. Allopurinol or mannitol-placebo will be administered intravenously in 2 doses early postnatally in neonates diagnosed antenatally and 3 doses perioperatively of 20 mg/kg each in all neonates. The primary outcome is a composite endpoint of moderate/severe ischemic or hemorrhagic brain injury on early postoperative MRI, being too unstable for postoperative MRI, or mortality within 1 month following CPB. A total of 236 patients (n = 188 with prenatal diagnosis) is required to demonstrate a reduction of the primary outcome incidence by 20% in the prenatal group and by 9% in the postnatal group (power 80%; overall type 1 error controlled at 5%, two-sided), including 1 interim analysis at n = 118 (n = 94 with prenatal diagnosis) with the option to stop early for efficacy. Secondary outcomes include preoperative and postoperative brain injury severity, white matter injury volume (MRI), and cardiac function (echocardiography); postnatal and postoperative seizure activity (aEEG) and regional cerebral oxygen saturation (NIRS); neurodevelopment at 3 months (general movements); motor, cognitive, and language development and quality of life at 24 months; and safety and cost-effectiveness of allopurinol.Discussion: This trial will investigate whether allopurinol administered directly after birth and around cardiac surgery reduces moderate/severe ischemic and hemorrhagic brain injury and improves cardiac function and neurodevelopmental outcome in CCHD neonates.Trial Registration: EudraCT 2017-004596-31. Registered on November 14, 2017. ClinicalTrials.gov NCT04217421. Registered on January 3, 2020. [ABSTRACT FROM AUTHOR]

Presents information on a study which evaluated biventricular diastolic function in lambs. Methodology; Results and discussion.

After atrial correction of transposition of the great arteries (TGA), dysfunction of the systemic right ventricle at rest and during exercise has been reported. Information on changes in systemic right ventricular function during recovery from exercise is lacking. This study evaluates cardiac recovery from supine exercise using magnetic resonance (MR) imaging in patients with asymptomatic TGA after atrial correction. Flow in the ascending aorta, representing stroke volume of the systemic ventricle, was assessed with MR flow mapping in 10 asymptomatic patients with atrially corrected TGA and in 12 controls at rest during exercise and an 8-minute recovery period. In response to exercise, the patients had a smaller increase in heart rate, stroke volume, and cardiac output than did controls. After exercise, no significant difference in halftime of heart rate recovery was observed (patients, 48 +/- 7 seconds; controls, 39 +/- 4 seconds [p >0.05]). In the patients, the time course of stroke volume recovery was significantly different (p <0.001). Stroke volume in the patients, as a percent difference from rest, remained significantly elevated, from 2.5 minutes (+16 +/- 5% vs +7 +/- 6%; p <0.05) to 8 minutes (+4 +/- 7% vs -3 +/- 5%; p <0.05) after exercise. Subsequently, cardiac output remained significantly elevated, from 4.5 minutes (+27 +/- 13% vs +15 +/- 11%; p <0.05) to 7 minutes (+22 +/- 11% vs +12 +/- 12%; p <0.05) after exercise. We conclude that heart rate recovery is within normal limits in patients with atrially corrected TGA. Furthermore, cardiac recovery from exercise, assessed with MR flow mapping, is prolonged in patients with asymptomatic TGA after atrial correction. Abnormal recovery may reflect dysfunction of the systemic right ventricle and an altered metabolic response to exercise. [ABSTRACT FROM AUTHOR]

Physical injury and illness are common potentially traumatic events during childhood and adolescence. Many children experience psychosocial difficulties after medical events. The sample consisted of 399 children aged 4 to 15 who had been hospitalized for physical illness or injury. Elevated psychological symptomatology (PTSS, depression, anxiety) was more frequent after multiple (type II) compared to single (type I) medical events, but only a few differences were statistically significant. The strongest risk factor of child PTSS was parental stress. Type II trauma and low parental education were significant risk factors only for parent report of child PTSS (not for child report). The analyzed risk factors did not differ for type I versus II trauma. We recommend standardized screening and monitoring for mental health in the standard pediatric health care. Furthermore, pediatricians should be trained in signaling stress signs of parents. [ABSTRACT FROM AUTHOR]

Cardiovascular magnetic resonance (CMR) has become the reference standard for quantitative and qualitative assessment of ventricular function, blood flow, and myocardial tissue characterization. There is a preponderance of large CMR studies and registries in adults; However, similarly powered studies are lacking for the pediatric and congenital heart disease (PCHD) population. To date, most CMR studies in children are limited to small single or multicenter studies, thereby limiting the conclusions that can be drawn. Within the PCHD CMR community, a collaborative effort has been successfully employed to recognize knowledge gaps with the aim to embolden the development and initiation of high-quality, large-scale multicenter research. In this publication, we highlight the underlying challenges and provide a practical guide toward the development of larger, multicenter initiatives focusing on PCHD populations, which can serve as a model for future multicenter efforts. [Display omitted] [ABSTRACT FROM AUTHOR]

Ethnic differences in cardiovascular risk factors and disease are well-known and may originate in early-life. We examined the ethnic differences in cardiac structure and function in children using cardiac magnetic resonance imaging in a European migrant population, and whether any difference was explained by early life factors. We used a prospective population-based cohort study among 2317 children in Rotterdam, the Netherlands. We compared children from Dutch (73%), Cape Verdean (3.5%), Dutch Antillean (3.3%), Moroccan (6.1%), Surinamese-Creoles (3.9%), Surinamese-Hindustani (3.4%), and Turkish (6.4%) background. Main outcomes were cMRI-measured cardiac structures and function. Cardiac outcomes were standardized on body surface area. Cape Verdean, Surinamese-Hindustani, and Turkish children had smaller right ventricular end-diastolic volume and left ventricular end-diastolic volume relative to their body size than Dutch children (p < 0.05). These results were not fully explained by fetal and childhood factors. Right ventricular ejection fraction and left ventricular ejection fraction did not differ between ethnicities after adjustment for fetal and childhood factors. Conclusion: Right ventricular end-diastolic volume and left ventricular end-diastolic volume differ between ethnic subgroups in childhood, without affecting ejection fraction. Follow-up studies are needed to investigate whether these differences lead to ethnic differences in cardiac disease in adulthood. What is Known: • Ethnic differences in cardiovascular risk factors and disease are well-known and may originate in early-life. • The prevalence of cardiovascular disease differs between ethnic groups. What is New: • We examined ethnic differences in left and right cardiac structure and function in children using cMRI. • Right and left cardiac dimensions differ between ethnic groups in childhood and are only partly explained by fetal and childhood factors. [ABSTRACT FROM AUTHOR]

Aims: Medical procedures and hospitalizations can be experienced as traumatic and can lead to post-traumatic stress reactions. Eye movement desensitization and reprocessing (EMDR) shows promising results but very few long-term studies have been published. Therefore, our aim was to test the long-term (8 months post-treatment) effectiveness of EMDR in children and adolescents with medically related subthreshold post-traumatic stress disorder (PTSD). Methods and results: Seventy-four children (including 39 with congenital or acquired heart disease) aged 4–15 (M = 9.6 years) with subthreshold PTSD after previous hospitalization were included into a parallel group randomized controlled trial. Participants were randomized to EMDR (n = 37) or care-as-usual (CAU) (n = 37; medical care only). The primary outcome was PTSD symptoms of the child. Secondary outcomes were symptoms of depression and blood–injection–injury (BII) phobia, sleep problems, and health-related quality of life (HrQoL) of the child. Assessments of all outcomes were planned at baseline and 8 weeks and 8 months after the start of EMDR/CAU. We hypothesized that the EMDR group would show significantly more improvements on all outcomes over time. Both groups showed improvements over time on child's symptoms of PTSD (only parent report), depression, BII phobia, sleep problems, and most HrQoL subscales. GEE analyses showed no significant differences between the EMDR group (nT2 = 33, nT3 = 30) and the CAU group (nT2 = 35, nT3 = 32) on the primary outcome. One superior effect of EMDR over time was found for reducing parent-reported BII phobia of the child. Conclusion: EMDR did not perform better than CAU in reducing subthreshold PTSD up to 8 months post-treatment in previously hospitalized children. Possible explanations and clinical implications are discussed. [ABSTRACT FROM AUTHOR]

The purpose of this study was to directly assess (patho)physiology of intraventricular hemodynamic interplay between fourdimensional flow cardiovascular magnetic resonance imaging (4D Flow MRI)-derived vorticity with kinetic energy (KE) and viscous energy loss (EL) over the cardiac cycle and their association to ejection fraction (EF) and stroke volume (SV). Fifteen healthy subjects and thirty Fontan patients underwent whole heart 4D Flow MRI. Ventricular vorticity, KE, and EL were computed over systole (vorticity_volavg systole, KEavg systole, and ELavg systole) and diastole (vorticity_volavg diastole, KEavg diastole, and ELavg diastole). The association between _vorticity_vol and KE and EL was tested by Spearman correlation. Fontan patients were grouped to normal and impaired EF groups. A significant correlation was found between SV and vorticity in healthy subjects (systolic: r = 0.84, P 0.001; diastolic: r = 0.81, P < 0.001) and in Fontan patients (systolic: r = 0.61, P < 0.001; diastolic: r = 0.54, P = 0.002). Healthy subjects showed positive correlation between vorticity _vol versus KE (systole: r = 0.96, P < 0.001; diastole: r = 0.90, P < 0.001) and EL (systole: r = 0.85, P < 0.001; diastole: r = 0.84, P < 0.001). Fontan patients showed significantly elevated vorticity vol compared with healthy subjects (vorticity_volavg systole: 3.1 [2.3–3.9] vs. 1.7 [1.3–2.4] L/s, P < 0.001; vorticity_volavg diastole: 3.1 [2.0– 3.7] vs. 2.1 [1.6–2.8] L/s, P = 0.002). This elevated vorticity in Fontan patients showed strong association with KE (systole: r = 0.91, P < 0.001; diastole: r = 0.85, P < 0.001) and EL (systole: r = 0.82, P < 0.001; diastole: r = 0.89, P < 0.001). Fontan patients with normal EF showed significantly higher vorticity_volavg systole and ELavg systole, but significantly decreased KE avg diastole, in the presence of normal SV, compared with healthy subjects. Healthy subjects show strong physiological hemodynamic interplay between vorticity with KE and EL. Fontan patients demonstrate a pathophysiological hemodynamic interplay characterized by correlation of elevated vorticity with KE and EL in the presence of maintained normal stroke volume. Altered vorticity and energetic hemodynamics are found in the presence of normal EF in Fontan patients. NEW & NOTEWORTHY Physiologic intraventricular hemodynamic interplay/coupling is present in the healthy left ventricle between vorticity versus viscous energy loss and kinetic energy from four-dimensional flow cardiovascular magnetic resonance imaging (4D Flow MRI). Conversely, Fontan patients present compensatory pathophysiologic hemodynamic coupling by an increase in intraventricular vorticity that positively correlates to viscous energy loss and kinetic energy levels in the presence of maintained normal stroke volume. Altered vorticity and energetics are found in the presence of normal ejection fraction in Fontan patients. [ABSTRACT FROM AUTHOR]

To assess the role of atrial function on exercise capacity and clinical events in Fontan patients. We included 96 Fontan patients from 6 tertiary centers, aged 12.8 (IQR 10.1–15.6) years, who underwent cardiac magnetic resonance imaging and cardiopulmonary exercise testing within 12 months of each other from 2004 to 2017. Intra-atrial lateral tunnel (ILT) and extracardiac conduit (ECC) patients were matched 1:1 with regard to age, gender and dominant ventricle. The pulmonary venous atrium was manually segmented in all phases and slices. Atrial function was assessed by volume-time curves. Furthermore, atrial longitudinal and circumferential feature tracking strain was assessed. We determined the relation between atrial function and exercise capacity, assessed by peak oxygen uptake and VE/VCO 2 slope, and events (mortality, listing for transplant, re-intervention, arrhythmia) during follow-up. Atrial maximal and minimal volumes did not differ between ILT and ECC patients. ECC patients had higher reservoir function (21.1 [16.4–28.0]% vs 18.2 [10.9–22.2]%, p =.03), lower conduit function and lower total circumferential strain (13.8 ± 5.1% vs 18.0 ± 8.7%, p =.01), compared to ILT patients. Only for ECC patients, a better late peak circumferential strain rate predicted better VE/VCO 2 slope. No other parameter of atrial function predicted peak oxygen uptake or VE/VCO 2 slope. During a median follow-up of 6.2 years, 42 patients reached the composite end-point. No atrial function parameters predicted events during follow-up. ECC patients have higher atrial reservoir function and lower conduit function. Atrial function did not predict exercise capacity or events during follow-up. • Atrial function in Fontan patients differs depending on Fontan modification. • Patients with an ILT have lower atrial reservoir and higher conduit function. • Atrial function does not predict exercise capacity or events during follow-up. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide Open in new tab Download slide OBJECTIVES Our goal was to report the long-term serial follow-up after transatrial–transpulmonary repair of tetralogy of Fallot (TOF) and to describe the influence of the timing of the repair on outcome. METHODS We included all patients with TOF who had undergone transatrial–transpulmonary repair between 1970 and 2012. Records were reviewed for patient demographics, operative details and events during the follow-up period (death, pulmonary valve replacement, cardiac reinterventions and hospitalization/intervention for arrhythmias). In patients with elective early primary repair of TOF after 1990, a subanalysis of the optimal timing of TOF repair was performed. RESULTS A total of 453 patients were included (63% male patients; 65% had transannular patch); 261 patients underwent primary elective repair after 1990. The median age at TOF repair was 0.7 years (25th–75th percentile 0.3–1.3) and decreased from 1.7 to 0.4 years from before 1990 to after 2000, respectively (P  < 0.001). The median follow-up duration after TOF repair was 16.8 years (9.6–24.7). Events developed in 182 (40%) patients. In multivariable analysis, early repair of TOF (<6 months) [hazard ratio (HR) 3.06; P  < 0.001] and complications after TOF repair (HR 2.18; P  = 0.006) were found to be predictive for an event. In a subanalysis of the primary repair of TOF after 1990, the patients (n  = 125) with elective early repair (<6 months) experienced significantly worse event-free survival compared to patients who had elective repair later (n  = 136). In multivariable analysis, early repair (HR 3.00; P  = 0.001) and postoperative complications (HR 2.12; P  = 0.010) were associated with events in electively repaired patients with TOF. CONCLUSIONS Transatrial–transpulmonary repair of TOF before the age of 6 months may be associated with more events during the long-term follow-up period. [ABSTRACT FROM AUTHOR]

A single 6-min walk test (6MWT) can be used to identify children with dilated cardiomyopathy (DCM) with a high risk of death or heart transplantation. To determine if repeated 6MWT has added value in addition to a single 6MWT in predicting death or heart transplantation in children with DCM. Prospective multicenter cohort study including ambulatory DCM patients ≥ 6 years. A 6MWT was performed 1 to 4 times per year. The distance walked was expressed as percentage of predicted (6MWD%). We compared the temporal evolution of 6MWD% in patients with and without the study endpoint (SE: all-cause death or heart transplantation), using a linear mixed effects model. In 57 patients, we obtained a median of 4 (IQR 2–6) 6MWTs per patient during a median of 3.0 years of observation (IQR 1.5–5.1). Fourteen patients reached a SE (3 deaths, 11 heart transplantations). At any time during follow-up, the average estimate of 6MWD% was significantly lower in patients with a SE compared to patients without a SE. In both patients groups, 6MWD% remained constant over time. An absolute 1% lower 6MWD% was associated with an 11% higher risk (hazard) of the SE (HR 0.90, 95% CI 0.86–0.95 p < 0.001). Children with DCM who died or underwent heart transplantation had systematically reduced 6MWD%. The performance of all patients was stable over time, so repeated measurement of 6MWT within this time frame had little added value over a single test. [ABSTRACT FROM AUTHOR]

View large Download slide View large Download slide OBJECTIVES In patients with the Fontan circulation, systemic venous return flows passively towards the lungs. Because of the absence of the subpulmonary ventricle, favourable blood flow patterns with minimal energy loss are clinically relevant. The region where the inferior vena cava, the hepatic veins and the extracardiac conduit join (IVC–conduit junction) is a potential source of increased energy loss. The aim of this study was to evaluate the relationship between geometry and blood flow patterns in the IVC–conduit junction with associated kinetic energy and energy loss using 4-dimensional flow magnetic resonance imaging (MRI). METHODS Fourteen extracardiac conduit-Fontan patients underwent 4-dimensional flow MRI. The IVC–conduit junctions were ranked into 3 groups for 3 categories: the geometry, the flow complexity and the conduit mean velocity. The relative increase in the mean velocity from the IVC to the conduit (representing IVC–conduit mismatch) was determined. The peak kinetic energy and mean kinetic energy and energy loss were determined and normalized for volume. RESULTS In 4 of 14 patients, adverse geometries led to helical flow patterns and/or acute changes in flow direction. For each category, the most adverse IVC–conduit junctions were associated with an approximate 2.3–3.2-fold and 2.0–2.9-fold increase in kinetic energy and energy loss, respectively. The IVC–conduit mismatch is strongly correlated with the mean kinetic energy and energy loss (r   = 0.80, P   =  0.001 and ρ  = 0.83, P  <  0.001, respectively) and with body surface area in patients with 16- mm conduits (r   =  0.88, P   =  0.010). CONCLUSIONS The IVC–conduit junction is a potential source of increased energy loss. Junctions with increased energy loss showed: (i) a distorted geometry leading to adverse blood flow patterns and/or (ii) the IVC–conduit mismatch. Sixteen-millimetre conduits appear to be inadequate for older patients. [ABSTRACT FROM AUTHOR]

The aims of this study were to provide an overview of the cardiac stress response in Fontan patients and of the use, safety and clinical value of stress imaging in Fontan patients. Studies evaluating cardiac function using stress imaging in Fontan patients published up until 12 December 2021 were included in this review. From 1603 potential studies, 32 studies met the inclusion criteria. In total, stress imaging tests of 728 Fontan patients were included. Cardiac function was most often measured using physical stress (61%), all other studies used dobutamine-induced stress. Stroke volume (SV) increased in most studies (71%), mean SV at rest ranged from 27 mL/m2 to 60 mL/m2 versus 27 mL/m2 to 101 mL/m2 during stress, and increased with an average of 4%. Ejection fraction increased in almost all studies, whereas both end-systolic volume and end-diastolic volume decreased during stress. Higher heart rates were obtained with physical stress (82–180) compared to dobutamine induced stress (73–128). Compared to controls, increases in heartrate and SV were lower and end-diastolic volume decreased abnormally in 75% of reporting studies. No major adverse events were reported. Poorer cardiac stress response was related to decreased exercise capacity and higher risk for long-term (adverse) outcomes in Fontan patients. Cardiac stress response in Fontan patients differs from healthy subjects, reflected by lower increases in heart rate, diminished preload and decreased cardiac output, especially during higher levels of exercise. Stress imaging is safe, however the added clinical value needs to be investigated in more detail. [Display omitted] [ABSTRACT FROM AUTHOR]

Left ventricular (LV) strain and rotation are emerging functional markers for early detection of LV dysfunction and have been associated with the burden of myocardial fibrosis in several disease states. This study examined the association between LV deformation (i.e., LV strain and rotation) and extent and location of LV myocardial fibrosis in pediatric patients with Duchenne muscular dystrophy (DMD). 34 pediatric patients with DMD underwent cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) to assess LV myocardial fibrosis. Offline CMR feature-tracking analysis was used to assess global and segmental longitudinal and circumferential LV strain, and LV rotation. Patients with fibrosis (n = 18, 52.9%) were older than those without fibrosis (14 ± 3 years (yrs) vs 11 ± 2 yrs., p = 0.01). There was no significant difference in LV ejection fraction (LVEF) between subjects with and without fibrosis (54 ± 6% vs 56 ± 4%, p = 0.18). However, lower endocardial global circumferential strain (GCS), but not LV rotation, was associated with presence of fibrosis (adjusted Odds Ratio 1.25 [95% CI 1.01–1.56], p = 0.04). Both GCS and global longitudinal strain correlated with the extent of fibrosis (r =.52, p = 0.03 and r =.75, p < 0.01, respectively). Importantly, segmental strain did not seem to correspond to location of fibrosis. A lower global, but not segmental, strain is associated with presence and extent of LV myocardial fibrosis in pediatric DMD patients. Therefore, strain parameters might detect structural myocardial alterations, however currently more research is needed to evaluate its value (e.g., prognostic) in clinical practice. [Display omitted] • Global circumferential strain, but not LV rotation, measured with CMR-FT is associated with the presence and extent of myocardial fibrosis in DMD. • Segmental strain differences did not correspond with the location of myocardial fibrosis. • LV ejection fraction correlates with the extent of myocardial fibrosis. [ABSTRACT FROM AUTHOR]

Objectives This study aimed to evaluate the predicting value of quantitative and qualitative dyssynchrony parameters as assessed by two-dimensional speckle tracking echocardiography ( STE) on outcome in children with dilated cardiomyopathy ( DCM). Furthermore, the reproducibility of these parameters was investigated. Background In previous studies in adults with heart failure, several dyssynchrony parameters have been shown to be a valuable predictor of clinical outcome. Methods This multicenter, prospective study included 75 children with DCM and 75 healthy age-matched controls. Using STE, quantitative (time to global peak strain and parameters describing intraventricular time differences) and qualitative dyssynchrony parameters (pattern analysis) of the apical four-chamber, three-chamber, two-chamber views, and the short axis of the left ventricle were assessed. Cox regression was used to identify risk factors for the primary endpoints of death or heart transplantation. Inter-observer and intra-observer variability were described. Results During a median of 21 months follow-up, 10 patients (13%) reached an endpoint. Although quantitative dyssynchrony measures were higher in patients as compared to controls, the inter-observer and intra-observer variability were high. Pattern analysis showed mainly reduced strain, instead of dyssynchronous patterns. Conclusions In this study, quantitative dyssynchrony parameters were not reproducible, precluding their use in children. Qualitative pattern analysis showed predominantly reduced strain, suggesting that in children with DCM dyssynchrony may be a minor problem. [ABSTRACT FROM AUTHOR]

Cardiopulmonary exercise testing is an important tool to predict prognosis in children and adults with heart failure. A much less sophisticated exercise test is the 6 min walk test, which has been shown an independent predictor for morbidity and mortality in adults with heart failure. Therefore, we hypothesized that the 6 min walk test could be predictive for outcome in children with dilated cardiomyopathy. We prospectively included 49 children with dilated cardiomyopathy ≥6 years who performed a 6 min walk test. Median age was 11.9 years (interquartile range [IQR] 7.4-15.1), median time after diagnosis was 3.6 years (IQR 0.6-7.4). The 6 min walk distance was transformed to a percentage of predicted, using age- and gender-specific norm values (6MWD%). For all patients, mean 6MWD% was 70 ± 21%. Median follow-up was 33 months (IQR 14-50). Ten patients reached the combined endpoint of death or heart transplantation. Using univariable Cox regression, a higher 6MWD% resulted in a lower risk of death or transplantation (hazard ratio 0.95 per percentage increase, p = 0.006). A receiver operating characteristic curve was generated to define the optimal threshold to identify patients at highest risk for an endpoint. Patients with a 6MWD% < 63% had a 2 year transplant-free survival of 73%, in contrast to a transplant-free survival of 92% in patients with a 6MWD% ≥ 63% ( p = 0.003). In children with dilated cardiomyopathy, the 6 min walk test is a simple and feasible tool to identify children with a higher risk of death or heart transplantation. [ABSTRACT FROM AUTHOR]

Background: The objective assessment of global and regional cardiac function in children has shown to be clinically relevant but is challenging to conduct. Cardiovascular magnetic resonance (CMR) has emerged as a valuable diagnostic modality especially in patients with cardiomyopathy or congenital heart disease. However, data on the normal cardiac deformation in children assessed by CMR is lacking at present. Thus, the aim of this study was to provide reference values for cardiac strain and strain rate in children and adolescents derived from CMR feature tracking (FT) measurements. Methods: In this binational study, eighty children and adolescents (age 0.4-18.0 years, 41 male, 39 female) free from cardiac diseases from two centers underwent CMR in 1.5 T whole-body scanners in supine position. Global peak radial, circumferential and longitudinal systolic strains as well as the corresponding early peak diastolic strain rates were assessed applying FT on short axis as well as 3- and 4-chamber views of standard cine steady-state free precession images. Results: The difference between genders yielded no significance for all assessed strains. Yet, all strains showed a significant parabolic relation to age and an even stronger one to body surface area (BSA). Therefore, BSA-specific reference values were determined using a polynomial regression model. The apical cardiac segments featured significant higher peak circumferential but lower peak radial systolic strains than the midventricular and basal segments (all p < 0.001). Conclusions: The assessment of cardiac deformation by CMR-FT is feasible in children. This is the first CMR study providing specific reference values for FT-derived strain and strain rate in the pediatric age range. [ABSTRACT FROM AUTHOR]

Aims Evaluation of left ventricular ( LV) myocardial deformation by speckle tracking echocardiography ( STE) is useful for clinical and research purposes. However, strain measurements depend on the used software. Normative data for QLAB 10 (Philips) are scarce. Additionally, little is known about the influence of anthropometric factors. We aimed to establish normal adult STE-derived strain and strain rate values and to evaluate associations with anthropometrics. Methods One hundred fifty-five healthy subjects aged 20 to 72 years (≥28 subjects per decile) were prospectively gathered and examined with electrocardiography and two-dimensional echocardiography. With STE, we assessed peak systolic LV global longitudinal strain ( GLS), segmental longitudinal strain, and strain rate from the three standard apical views. Results We included 147 healthy subjects (age 44.6±13.7 years, 50% female, GLS −20.8±2.0%). Men had significantly lower GLS than women (−20.1±1.8% vs −21.5±2.0%, P<.001). GLS was significantly lower in subjects with age above 55 years ( P=.029), higher blood pressure ( P<.001), higher body surface area ( BSA, P<.001), larger LV end-systolic and end-diastolic volumes (both P<.001), lower LV ejection fraction ( P<.001), and some indices of diastolic function. After multivariable regression analysis, the correlation with systolic blood pressure, E-wave, and LV end-systolic volume remained significant. The systolic strain rates of most segments correlated with BSA. Conclusions Our study resulted in normative LV GLS values assessed with QLAB 10. Male sex, higher BSA, and higher blood pressure negatively influence GLS. Therefore, these factors should be taken into account for strain interpretation in clinical practice. [ABSTRACT FROM AUTHOR]

Background: There are sex differences in the risk of development of cardiovascular disease (CVD). According to the developmental origins of health and disease paradigm (DOHaD), CVD originates in fetal life. This study examines fetal sex differences in cardiovascular development in utero. Methods: In 1028 pregnant women, we assessed fetal circulation using pulsed wave Doppler examinations between 28 and 34 weeks gestation. To test associations between fetal sex and fetal circulation measurements, linear regression models were used adjusting for fetal size, gestational age, and fetal heart rate. Results: A higher pulsatility index in the ductus venosus was observed in male fetuses compared to female fetuses (difference 0.02, 95% CI 0.01; 0.05) with a lower E/A ratio of the tricuspid (difference -0.01, 95% CI -0.03; -0.00) and mitral (difference -0.02, 95% CI -0.03; -0.01) valves. This was mainly determined by differences in the E wave of the tricuspid and mitral valves (differences -1.02, 95% CI -1.81; -0.24 and -1.28, 95% CI -2.11; -0.46, respectively). Also in males, a lower peak systolic velocity was seen in the pulmonary artery (difference -1.33, 95% CI -2.63; -0.03) with a similar lower trend regarding peak systolic velocity in the ascending aorta. Conclusions: Male fetuses exhibit an increased preload and reduced afterload conditions compared to females. While it is difficult to relate these measurements to exact cardiac function, our findings strongly suggest that the known differences in cardiovascular performance between the sexes already start in utero. [ABSTRACT FROM AUTHOR]

Pulmonary arterial (PA) flow is abnormal after the Fontan operation and is marked by a lack of pulsatility. We assessed the effects of this abnormal flow on the size and function of the PA's in Fontan patients in long-term serial follow-up. Twenty-three Fontan patients with serial follow-up were included. Median age was 11.1 (9.5-16.0) years at baseline and 15.5 (12.5-22.7) years at follow-up. Median follow-up duration was 4.4 (4.0-5.8) years. Flow and size of the left pulmonary artery were determined using phase-contrast MRI. From this wall shear stress (WSS), distensibility and pulsatility were determined. A group of healthy peers was included for reference. Flow and pulsatility were significantly lower in patients than in controls ( p < 0.001). Mean area was comparable in patients and controls, but distensibility was significantly higher in controls ( p < 0.001). Mean and peak WSS were significantly lower in Fontan patients ( p < 0.001). Between baseline and follow-up, there was a significant increase in normalized flow (15.1 (14.3-19.1) to 18.7 (14.0-22.6) ml/s/m, p = 0.023). Area, pulsatility, distensibility and WSS did not change, but there was a trend toward a lower mean WSS ( p = 0.068). Multivariable regression analysis showed that flow, area and age were important predictors for WSS. WSS in Fontan patients is decreased compared to healthy controls and tends to decrease further with age. Pulsatility and distensibility are significantly lower compared to healthy controls. Pulmonary artery size, however, is not significantly different from healthy controls and long-term growth after Fontan operation is proportionate to body size. [ABSTRACT FROM AUTHOR]

In adults with heart failure, central sleep apnea (CSA), often manifested as Cheyne-Stokes respiration, is common, and has been associated with adverse outcome. Heart failure in children is commonly caused by dilated cardiomyopathy (DCM). It is unknown whether children with heart failure secondary to DCM have CSA, and whether CSA is related to the severity of heart failure. In this prospective observational study, 37 patients (<18 year) with heart failure secondary to DCM were included. They underwent polysomnography, clinical and laboratory evaluation and echocardiographic assessment. After a median follow-up time of 2 years, eight patients underwent heart transplantation. CSA (apnea-hypopnea index [AHI] ≥1) was found in 19 % of the patients. AHI ranged from 1.2 to 4.5/h. The occurrence of CSA was not related to the severity of heart failure. Three older patients showed a breathing pattern mimicking Cheyne-Stokes respiration, two of whom required heart transplantation. CSA was found in 19 % of the children with heart failure secondary to DCM. No relation was found with the severity of heart failure. In a small subset of children with severe DCM, a pattern mimicking Cheyne-Stokes respiration was registered. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Rhythm disturbances are an important cause of morbidity in Fontan patients. Currently, the total cavopulmonary connection is performed by using the intra-atrial lateral tunnel (ILT) ('baffle ILT' or 'prosthetic ILT'), or the extracardiac conduit (ECC). The aim of the study was to evaluate rhythm abnormalities and compare the surgical techniques in a contemporary cohort. METHODS: In a cross-sectional multicentre study, 115 patients (age 12.5 ± 3.1 years) underwent rhythm evaluation using ECG, exercise testing and Holter, including heart rate variability. Medical history was reviewed for episodes of arrhythmia. RESULTS: Sinus node dysfunction (SND) was found in 29%, 3 of whom required pacemaker therapy. No difference was found in the incidence of SND between ILT and ECC patients. Sinus pauses occurred only in the ILT group. Exercise testing showed no difference in peak heart rate between the groups. Heart rate reserve (P = 0.023) and heart rate recovery (HRrecovery) (P < 0.001) were lower in ILT patients. Atrial arrhythmias were more common in ILT patients (15 vs 1%, P = 0.004), but only in those with a baffle ILT. One patient had symptomatic ventricular tachycardia (VT). Holter recordings showed sub-clinical VT in 6% of patients, which was associated with larger end-diastolic (P = 0.035) and end-systolic volumes (P = 0.029). CONCLUSIONS: The overall incidence of arrhythmia was low, although SND was frequently present in both Fontan groups. ILT patients had slower HRrecovery, and ILT patients with the more extensive baffle technique had more atrial arrhythmias and more sinus pauses. The significance of asymptomatic ventricular arrhythmias in this young population remains to be determined. [ABSTRACT FROM AUTHOR]

Sub-valvular aortic stenosis (SAS) is a common form of left ventricular outflow tract (LVOT) obstruction, which can lead to aortic valve damage. Although surgery for SAS is an accepted treatment, the timing of surgical intervention of SAS remains controversial. This review aims to establish an overview of the natural history and outcome after surgery and factors associated with prognosis in paediatric SAS patients. We searched PubMed and EMBASE for studies that reported factors that negatively affected the prognosis of patients with SAS. Studies were included if they were written in English, published between 1 January 1997 and 31 December 2012 and the mean patient age was <18 years at the time of study entry. Studies were excluded if the study size was <20 patients. A distinction was made between natural history and surgical cohorts. Twenty-four studies were included in this review, encompassing a total of 809 natural history and 1476 surgical patients. Fifty-one percent of natural history patients required surgery. After surgery, there was a substantial reoperation rate. Higher LVOT gradient and the presence of aortic regurgitation (AR) were identified as the foremost independent predictors of a worse outcome. Valve-to-membrane distance was also found to be associated with prognosis, although the results were contradictory. This systematic review underlines the importance of LVOT gradient, aortic valve-to-membrane distance and AR in surgical decision-making in paediatric SAS patients. There is need for collaborative effort to further study the optimal timing of surgery based on LVOT gradient, valve-to-membrane distance and the presence of AR. [ABSTRACT FROM AUTHOR]

Background The policy for listing and transplant for children with dilated cardiomyopathy (DCM) in The Netherlands has been conservative because of low donor availability. The effects of this policy on outcome are reported. Methods This was a multicenter, nationwide study performed in 148 children with DCM. The primary outcome was death or heart transplant. Results Overall, 43 patients (29%) died or were transplanted. Within 1 year of diagnosis, 21 patients died, and only 4 underwent transplantation (3 on mechanical circulatory support). The 1-year survival was 85% (95% confidence interval [CI] = 79–91), and 5-year survival was 84% (95% CI = 78–90). Transplantation-free survival at 1 year was 82% (95% CI = 75–88) and at 5 years was 72% (95% CI = 64–80). Within 1 year of diagnosis, with death as the main end-point (21 of 25, 84%), intensive care unit admission (hazard ratio = 2.6, p = 0.05) and mechanical circulatory support (hazard ratio = 3.2, p = 0.03) were risk factors (multivariable Cox analysis); inotropic support was longer in patients reaching an end-point. At >1 year after diagnosis, with transplantation as the main end-point (15 of 18, 83%), age >6 years (hazard ratio = 6.1, p = 0.02) was a risk factor. There were 56 (38%) children who recovered, 50% within 1 year of diagnosis. Recovery was associated with younger age; was similar in patients with myocarditis (43%) and idiopathic disease (41%); and was similar in patients initially admitted to the intensive care unit, admitted to the ward, or treated as outpatients. Conclusions The transplantation rate in our cohort in the first year was low, with 1-year and 5-year survival rates similar to other cohorts. Our results suggest that a conservative approach to list children for transplantation early after presentation may be justifiable except for patients with prolonged intensive care unit or mechanical circulatory support. [ABSTRACT FROM AUTHOR]

OBJECTIVES The surgical approach to repair of tetralogy of Fallot (ToF) has shifted over the years. We aimed to report the long-term follow-up after ToF repair with the transatrial–transpulmonary approach and to determine predictors of long-term outcomes. METHODS Retrospective analysis of patients operated on in two tertiary referral centres. Primary outcome measures were: death, pulmonary valve replacement (PVR), reintervention for other reasons, internal cardiodefibrillator and/or pacemaker placement. Kaplan–Meier assessment of overall and event-free survival as well as uni- and multivariate analyses of risk factors for outcomes were performed. RESULTS Four hundred and fifty-three patients were included. Median age at operation was: 0.6 years (range 0–19.6) and median age at the last follow-up was 14.3 years (range 0.1–42.1). Median age at repair decreased from 1.2 years (range 0.6–5.8) (1970–80) to 0.3 years (range 0–4.7) (2000–12). A transannular patch (TP) was used in 65% of all patients. The use of a TP showed a decline from 89% in the initial years of the cohort to 64% in 2000–12. Early mortality was 1.1% (5 patients) for the entire cohort and late mortality 2.4% (11 patients). Overall survival for the entire cohort was 97.3% (95% CI 95.7–98.8) and 91.8% (95% CI 85.9–97.7) at 10 and 25 years, respectively. For patients with a TP (n = 294) vs non-TP (n = 159), this was 97.2% (95% CI 95.2–99.2) vs 97.5% (95% CI 95.1–99.9) at 10-year and 91.0% (95% CI 83.9–98.1) vs 96.3% (95% CI 93.0–99.6) at 25-year follow-up (P = 0.958). Fifty-two patients underwent PVR, and in 5 a pacemaker was inserted. Event-free survival for TP versus non-TP patients was 80.2% (95 CI% 75.5–84.9) vs 81.7% (95% CI 75.2–88.2) at 10-year and 27.9% (95% CI 17.7–38.1) vs 78.5% (95% CI 71.4–85.6) at 25-year follow-up (P = 0.016). In multivariate analysis, both the use of a TP (HR 1.705, 95% CI 1.023–2.842) and the year of surgical repair of tetralogy of Fallot (HR 1.039, 95% CI 1.006–1.073) were associated with a higher probability of an event. CONCLUSIONS ToF patients corrected with the transatrial–transpulmonary approach have good long-term survival. PVR is a frequent event at longer follow-up, and other events are limited. The use of a TP is a predictor for poorer event-free outcomes, increasing the risk of the composite endpoint 1.7 times. [ABSTRACT FROM PUBLISHER]

To evaluate the moderating influence of parental variables on changes in health-related quality of life (HRQoL) in adolescents with Tetralogy of Fallot (ToF) or a Fontan circulation after participation in standardized exercise training. A multicenter randomized controlled trail in which 56 patients, aged 10-15, were randomly allocated (stratified by age, gender, and congenital heart disease) to a 12-week period with either: (a) 3 times per week standardized exercise training or (b) care-as-usual (randomization ratio 2:1). Adolescents and their parents filled in online questionnaires at baseline and at 12-week follow-up. In this randomized controlled trail, primary analyses involved influence of parental mental health and parental social support for exercise on changes in the TNO/AZL Child Quality of Life Questionnaire Child Form at follow-up. Secondary analyses concerned comparing levels of parental characteristics with normative data. Compared with controls, adolescents in the exercise group reported a decrease in social functioning when their parents had more anxiety/insomnia or severe depression themselves. Adolescents also reported a decrease in social functioning when their parents showed poorer overall mental health themselves. Parents reported comparable or even better mental health compared with normative data. The effect of a standardized exercise program on HRQoL changes in adolescents with ToF or a Fontan circulation is moderated by parental mental health, more specifically by parental anxiety/insomnia and severe depression. The trial registration number of this article is NTR2731 (). [ABSTRACT FROM AUTHOR]

BACKGROUND: Prospective data on long-term survival and clinical outcome beyond 30 years after surgical correction of tetralogy of Fallot are nonexistent. METHODS AND RESULTS: This longitudinal cohort study consists of the 144 patients with tetralogy of Fallot who underwent surgical repair at <15 years of age between 1968 and 1980 in our center. They are investigated every 10 years. Cumulative survival (data available for 136 patients) was 72% after 40 years. Late mortality was due to heart failure and ventricular fibrillation. Seventy-two of 80 eligible survivors (90%) participated in the third in-hospital investigation, consisting of ECG, Holter, echocardiography, cardiopulmonary exercise testing, N-terminal pro-brain natriuretic peptide measurement, cardiac magnetic resonance (including dobutamine stress testing), and the Short Form-36 questionnaire. Median follow-up was 36 years (range, 31-43 years). Cumulative event-free survival was 25% after 40 years. Subjective health status was comparable to that in the normal Dutch population. Although systolic right and left ventricular function declined, peak exercise capacity remained stable. There was no progression of aortic root dilation. A previous shunt operation, low temperature during surgery, and early postoperative arrhythmias were found to predict late mortality (hazard ratio, 2.9, 1.1, and 2.5, respectively). An increase in QRS duration and a deterioration of exercise tolerance and ventricular dysfunction did not predict mortality. Insertion of a transannular patch was a predictor for late arrhythmias (hazard ratio, 4.0; 95% confidence interval, 1.2-13.4). CONCLUSIONS: Although many patients needed a reoperation or developed arrhythmias, late mortality was low, and the clinical condition and subjective health status of most patients remained good. Previous shunt, low temperature during surgery, and early postoperative arrhythmias were found to predict late mortality. [ABSTRACT FROM AUTHOR]

Background--Prospective data on long-term survival and clinical outcome beyond 30 years after surgical correction of tetralogy of Fallot are nonexistent. Methods and Results--This longitudinal cohort study consists of the 144 patients with tetralogy of Fallot who underwent surgical repair at <15 years of age between 1968 and 1980 in our center. They are investigated every 10 years. Cumulative survival (data available for 136 patients) was 72% after 40 years. Late mortality was due to heart failure and ventricular fibrillation. Seventy-two of 80 eligible survivors (90%) participated in the third in-hospital investigation, consisting of ECG, Holter, echocardiography, cardiopulmonary exercise testing, N-terminal pro-brain natriuretic peptide measurement, cardiac magnetic resonance (including dobutamine stress testing), and the Short Form-36 questionnaire. Median follow-up was 36 years (range, 31-3 years). Cumulative event-free survival was 25% after 40 years. Subjective health status was comparable to that in the normal Dutch population. Although systolic right and left ventricular function declined, peak exercise capacity remained stable. There was no progression of aortic root dilation. A previous shunt operation, low temperature during surgery, and early postoperative arrhythmias were found to predict late mortality (hazard ratio, 2.9, 1.1, and 2.5, respectively). An increase in QRS duration and a deterioration of exercise tolerance and ventricular dysfunction did not predict mortality. Insertion of a transannular patch was a predictor for late arrhythmias (hazard ratio, 4.0; 95% confidence interval, 1.2-13.4). Conclusions--Although many patients needed a reoperation or developed arrhythmias, late mortality was low, and the clinical condition and subjective health status of most patients remained good. Previous shunt, low temperature during surgery, and early postoperative arrhythmias were found to predict late mortality. [ABSTRACT FROM AUTHOR]

Objective Exercise intolerance is common in total cavopulmonary connection (TCPC) patients. It has been suggested that power loss (Ploss) inside the TCPC plays a role in reduced exercise performance. Our objective is to establish the role of Ploss inside the TCPC during increased flow, simulating exercise in a patient-specific way. Methods Cardiac MRI (CMR) was used to obtain flow rates from the caval veins during rest and increased flow, simulating exercise with dobutamine. A 3D reconstruction of the TCPC was created using CMR data. Computational fluid dynamics (CFD) simulations were performed to calculate Ploss inside the TCPC structure for rest and stress conditions. To reflect the flow distribution during exercise, a condition where inferior caval vein (IVC) flow was increased twofold compared with rest was added. 29 TCPC patients (15 intra-atrial lateral tunnel (ILT) and 14 extracardiac conduit (ECC)) were included. Results Mean Ploss at rest was 1.36±0.94 (ILT) and 3.20±1.26 (ECC) mW/m2 ( p<0.001), 2.84±1.95 (ILT) and 8.41±3.77 (ECC) mW/m2 (p<0.001) during dobutamine and 5.21±3.50 (ILT) and 15.28±8.30 (ECC) mW/m2 (p=0.001) with twofold IVC flow. The correlation between cardiac index and Ploss was exponential (ILT: R2=0.811, p<0.001; ECC: R2=0.690, p<0.001). Conclusions Ploss inside the TCPC structure is limited but increases with simulated exercise. This relates to the anatomy of TCPC and the surgical technique used. In all flow conditions, ILT patients have lower Ploss than ECC patients. We did not find a relationship between Ploss and exercise capacity. [ABSTRACT FROM AUTHOR]

Background Foetal smoke exposure might lead to foetal developmental adaptations that permanently affect the cardiovascular system. We assessed the associations of both maternal and paternal smoking during pregnancy with childhood cardiovascular structures and function.Method In a prospective cohort study among 5565 children, we examined whether maternal and paternal smoking during pregnancy are associated with blood pressure, carotid-femoral pulse wave velocity and left cardiac structures and function in 6-year-old children.Results As compared with children from non-smoking mothers, children from mothers who smoked more than 10 cigarettes per day had a higher diastolic blood pressure [difference 1.43 mmHg (95% confidence interval: 0.22, 2.63)]. Maternal smoking during pregnancy was not associated with systolic blood pressure, childhood carotid-femoral pulse wave velocity or left cardiac structures. Maternal smoking of 10 or more cigarettes per day was associated with a higher fractional shortening in childhood [difference 1.01% (95% confidence interval: 0.18, 1.84)]. Among mothers who did not smoke during pregnancy, paternal smoking was associated with aortic root diameter but not with other cardiovascular outcomes.Conclusions Maternal smoking during pregnancy is associated with higher diastolic blood pressure and fractional shortening, although the effect estimates are small. The stronger effect estimates for maternal smoking compared with paternal smoking might suggest that direct intrauterine adaptive responses are involved as underlying mechanisms. [ABSTRACT FROM AUTHOR]

Background: Atrial enlargement may reflect ventricular diastolic dysfunction. Although patients with tetralogy of Fallot (TOF) have been studied extensively, little is known about atrial size and function. We assessed bi-atrial size and function in patients after TOF repair, and related them to biventricular systolic and diastolic function, and clinical parameters. Methods: 51 Patients (21±8years) and 30 healthy controls (31±7years) were included and underwent magnetic resonance imaging to assess bi-atrial and biventricular size, systolic and diastolic function. Patients also underwent exercise testing, and N-terminal prohormone brain natriuretic peptide (NT-proBNP) assessment. Results: In patients, right atrial (RA) minimal volume (34±8ml/m2 vs. 28±8ml/m2, p =0.001) and late emptying fraction were increased; RA early emptying fraction was decreased. Patients had longer right ventricular (RV) deceleration time (0.24±0.10 vs. 0.13±0.04, p <0.001), reflecting impaired RV relaxation, and larger RV volumes. Patients with end-diastolic forward flow (EDFF) had larger RA and RV size, abnormal RA emptying, higher NT-proBNP levels, higher VE/VCO2 slope (ventilatory response to carbon dioxide production), and the most abnormal LV diastolic function (impaired compliance). Patients with abnormal RA emptying (reservoir function <30% and pump function >24%) had higher NT-proBNP levels and worse exercise capacity. RA minimal volume was associated with RV end-diastolic volume (r =0.35, p =0.013). Conclusions: In TOF patients with moderate RV dilatation, abnormal bi-atrial function and biventricular diastolic dysfunction are common. Abnormal RA emptying was associated with signs of impaired clinical condition, as was the presence of EDFF. These parameters, together with RA enlargement, could serve as useful markers for clinically relevant RV diastolic dysfunction. [ABSTRACT FROM AUTHOR]

Abstract: Background: Maternal psychological distress during pregnancy might lead to higher fetal cortisol exposure, which subsequently leads to fetal cardiovascular developmental adaptations and cardiovascular dysfunction in later life. Aims: We examined whether maternal and paternal psychological distress was associated with the cardiovascular outcome measurements in school age children. Study design and subjects: In a population-based prospective cohort study among 4831 children, we assessed maternal and paternal psychological distress during pregnancy by questionnaire, using the Brief Symptom Inventory (see Fig. 1). Outcome measures: At the child age of six years, we performed blood pressure and carotid–femoral pulse wave velocity measurements, and M-mode measurements of left cardiac structures and fractional shortening. Results: We did not observe associations of high maternal and paternal psychological symptom scores with childhood blood pressure and carotid–femoral pulse wave velocity after adjustment for potential confounders. Maternal overall psychological symptoms were associated with a lower childhood left ventricular mass (difference −1.10g (95% confidence interval −2.13 to −0.07) between mothers with high scores and normal scores), but not with other cardiac structures and fractional shortening. Paternal overall psychological symptoms showed a similar association with childhood left ventricular mass (difference −1.34 grams (95% confidence interval −3.69 to 1.02) between fathers with high scores and normal scores). Conclusions: Our results do not support the hypothesis that maternal psychological distress affects cardiovascular development in early life. Similar associations of maternal and paternal psychological distress with left ventricular mass suggest that these associations could be due to unmeasured social and environmental factors, rather than direct intra-uterine effects. [Copyright &y& Elsevier]