INTRODUCTION:Reduced exercise performance is common in patients with repaired tetralogy of Fallot (rToF) and relates to adverse outcomes. The effects of high-intensity interval training (HIIT) in rToF are unknown. Furthermore, it is unknown if home-based, online-monitored exercise training is effective in rToF. We aimed to examine the feasibility, safety and effects of home-based HIIT in patients with rToF. METHODS:Patients aged 12-30 years (n=34, median age 16 (IQR 14-23)) with rToF were randomised to a 12-week home-based HIIT programme or standard of care (SOC). HIIT was prescribed in three 30 min sessions/week, with heart rate telemonitoring. SOC included exercise as usual. Co-primary end points were mean differences in peak oxygen consumption (VO2) and maximal workload, analysed using linear mixed-effects (LME) models. Secondary end points were: echocardiography, ECG and MRI-derived measures of cardiac structure and function. RESULTS:No serious adverse events occurred. After HIIT, peak VO2 increased from 38.3 (34.0-42.5) mL/kg/min to 40.9 (36.6-45.2) mL/kg/min (∆ 4.0 mL/kg/min, compared with control period (95% CI 1.52 to 6.53)), workload increased from 204 (174-234) W to 218 (188-248) W (∆ 17 W, compared with control period (95% CI 5 to 30)). No changes in cardiac volumes and ejection fraction were observed after HIIT. VO2 improved after HIIT independent of baseline fitness, body mass index and biventricular size. Notably, lower right ventricular ejection fraction (RV EF) was associated with greater improvement. CONCLUSION:HIIT significantly enhances exercise capacity in adolescents and young adults with rToF without adverse effects on cardiac structure or function, although the sample size limits the detection of subtle changes and can be successfully performed at home with online monitoring. This intervention offers a feasible alternative to traditional, on-site supervised exercise programmes, for patients with rToF, including those with lower RV EF. TRIAL REGISTRATION NUMBER:NTR2731.

AIMS:Implantable cardioverter defibrillator (ICD) therapy is effective in preventing sudden cardiac death in children. Unnecessary shocks should be avoided. ICD programming strategies and remote monitoring have been proven to be effective in preventing ICD shock therapy in adults; the present study evaluates the effectiveness in children. METHODS AND RESULTS:Retrospective multi-centre study, including children with transvenous or epicardial ICD implantation. During follow-up data on ICD shocks, programming variables and remote monitoring were collected. One hundred sixteen children were included, median age 13.4 years (min-max 0.3-18) and median follow-up 5.2 years (IQR 3.7-6.6), 53 with an ICD implanted before 2010 and 63 after 2010. The total appropriate and inappropriate annual shock rate decreased from 10.5 to 8% [difference in mean cumulative function (MCF) P = 0.008], 7.8 to 5.8% (MCF P = 0.036), and 4.3 to 2.6% (MCF P = 0.28), respectively, without increase in cardiac-related death. Remote monitoring was associated with a decrease of total shocks (MCF P = 0.013) and appropriate shocks (MCF P = 0.052). The ventricular fibrillation (VF) zone was programmed higher (≥210 bpm) at the time of appropriate vs. inappropriate shocks (86 vs. 79%; P = 0.0016), with no significant change in VF zone programming after 2010 compared to before 2010 (90 vs. 76%; P = 0.142) and in patients with vs. without shocks (79 vs. 89%; P = 0.243). CONCLUSION:The incidence of ICD shocks has significantly decreased in children with implantation after 2010, which appears to be multifactorial. A changed programming behaviour and remote monitoring are associated with this decrease and support its use in strategies to prevent unnecessary shocks in children.

Pulmonary regurgitation is a common consequence following the repair of tetralogy of Fallot and can lead to heart failure. Early detection of right ventricular dysfunction remains challenging, and current clinical markers have limited predictive value to identify which patients are at risk for heart failure and require interventions. This study aimed to investigate the potential of ventriculo-arterial coupling as a marker of early right ventricular dysfunction in a porcine model of chronic pulmonary regurgitation following transannular patch repair of neonatal pulmonary stenosis. Neonatal swine were subjected to pulmonary artery banding for 1 mo to induce right ventricular (RV) pressure overload, followed by transannular patch repair (rTAP, n = 10) to create chronic pulmonary regurgitation, and were compared with Sham animals (n = 6). Longitudinal hemodynamic assessments, including pressure-volume analysis and cardiac magnetic resonance imaging, were performed. Ventriculo-arterial coupling (VAC) was defined as the ratio of end-systolic elastance to effective arterial elastance. Over the follow-up period of 4 mo, VAC was preserved in the rTAP group. Effective arterial elastance was significantly lower in rTAP animals (P = 0.001), whereas end-systolic elastance remained unchanged. Lower end-diastolic pulmonary artery pressures and increased early systolic ejection were observed in rTAP, correlating with higher VAC. Ventriculo-arterial coupling remains preserved in chronic pulmonary regurgitation due to decreased afterload, making it unsuitable as an early marker for right ventricular dysfunction. Low afterload, a consequence of diastolic emptying of the pulmonary artery into the right ventricle, may pseudo-normalize systolic function. Alternative markers, for example, focusing on diastolic function and atrio-ventricular interactions should be investigated.NEW & NOTEWORTHY We used a porcine model of sequential loading with pulmonary artery banding and transannular patch mimicking tetralogy of Fallot to test ventriculo-arterial coupling as a marker of early right ventricular dysfunction. Ventriculo-arterial coupling is preserved despite right ventricular dysfunction and afterload is decreased. Pulmonary regurgitation results in low afterload following pulmonary artery pressure drop during diastole. Early systolic ejection is increased and correlates with ventriculo-arterial coupling.

Background: Wearables are increasingly used in pediatric cardiology for heart rate (HR) monitoring due to advantages over traditional HR monitoring, such as prolonged monitoring time, increased patient comfort, and ease of use. However, their validation in this population is limited. Objective: The objective of this paper was to assess HR accuracy and validity from 2 wearables, the Corsano CardioWatch bracelet and the Hexoskin smart shirt, in children attending the pediatric cardiology outpatient clinic, exploring factors that influence accuracy, the Hexoskin shirt's arrhythmia detection efficacy, and patient satisfaction. Methods: Children with an indication for 24-hour Holter monitoring were equipped with a 24-hour Holter electrocardiogram (ECG; gold standard), together with both wearables. HR accuracy was defined as the percentage of HRs within 10% of Holter values, and agreement was assessed using Bland-Altman analysis. Subgroup analyses were conducted based on BMI, age, and time of wearing, among other factors. The association between accelerometry (expressed in gravitational units, g) and HR accuracy was analyzed to assess the impact of bodily movement on measurement accuracy. A blinded pediatric cardiologist analyzed Hexoskin shirt data for rhythm classification. Patient satisfaction was measured using a 5-point Likert scale questionnaire. Results: A total of 31 participants (mean age 13.2, SD 3.6 y; n=14, 45% female) and 36 participants (mean age 13.3, SD 3.9 y) were included for the CardioWatch and Hexoskin measurements, respectively. Mean accuracy was 84.8% (SD 8.7%) for the CardioWatch and 87.4% (SD 11%) for the Hexoskin shirt. Hexoskin shirt accuracy was notably higher in the first 12 hours (94.9%, SD 7.4%) compared to the latter 12 (80%, SD 16.7%; P<.001). Higher accuracy was observed at lower HRs (low vs high HR: CardioWatch: 90.9%, SD 9.3% vs 79%, SD 10.6%; P<.001 and Hexoskin shirt: 90.6%, SD 14% vs 84.5, SD 11.8%; P<.001). Both wearables demonstrated good agreement in their HR measurement with Holter readings (CardioWatch bias: -1.4 beats per minute [BPM]; 95% limits of agreement [LoA] -18.8 to 16.0. Hexoskin shirt bias: -1.1 BPM; 95% LoA-19.5 to 17.4). HR measurement accuracy declined during more intense bodily movements. Correct classification of the Hexoskin's shirt rhythm recordings was achieved in 86% (31/36) of cases. Patient satisfaction scores were significantly higher for both the CardioWatch (median 3.8, range 3.5-4.3; P<.001) and Hexoskin shirt (median 3.7, range 3.0-4.0; P<.001) compared to the Holter (median 2.6, range 2.1-3.2). Conclusions: The Corsano CardioWatch and Hexoskin shirt demonstrate good accuracy in pediatric HR monitoring and provide higher patient comfort than conventional monitoring. Both wearables show good agreement in relation to the gold standard device. However, measurement accuracy declines with increasing bodily movement and higher heart rates. More research is needed to explore the underlying causes for these inaccuracies and how to counteract them. The Hexoskin shirt also shows potential in arrhythmia detection. While further development is warranted, these wearables show promise in enhancing diagnostics, therapeutic monitoring, and patient safety in pediatric cardiology.

Living myocardial slices (LMSs) have shown great promise in cardiac research, allowing multicellular and complex interplay analyses with disease and patient specificity, yet their wider clinical use is limited by the large tissue sizes usually required. We therefore produced mini-LMSs (<10 mm2) from routine human cardiac surgery specimens and compared them with medium (10-30 mm2) and large (>30 mm2) slices. Size effects on biomechanical properties were examined with mathematical modeling, and viability, contraction profiles, and histological integrity were followed for 14 days. In total, 34 mini-, 25 medium, and 30 large LMS were maintained viable, the smallest measuring only 2 mm2. Peak twitch force proved to be size-independent, whereas time-to-peak shortened as slice area decreased. Downsized LMSs displayed excellent contractile behavior for five to six days, after which a gradual functional decline and micro-architectural changes emerged. These findings confirm, for the first time, that mini-LMSs are feasible and viable, enabling short-term, patient-specific functional studies and pharmacological testing when tissue is scarce.

Introduction: Patients after surgical correction of Tetralogy of Fallot (ToF) often show adverse cardiac remodeling. To better understand the underlying biological processes, we studied the relation between changes in blood biomarkers and changes in biventricular size and function as assessed by cardiac magnetic resonance imaging (CMR). Methods: This study included 50 ToF patients, who underwent blood biomarker and CMR analysis at least twice between 2002 and 2018.34 (68 %) of these patients were male. Patients had an average age of 16.1 at first visit. Biomarkers were chosen based on earlier research by our group and included: NT-proBNP, ST2, GDF-15, DLK-1, IGFBP-1/7, and FABP-4. Pearson correlations coefficients (rpearson) were determined to quantify the relationship between changes in biomarkers and CMR measurements. Results: For changes in parameters of right ventricular (RV) size significant correlations were observed with changes in NT-proBNP, ST -2, GDF-15, IGFBP7 and FABP4 (rpearson between 0.28 and 0.51). Correlations with NT-proBNP were driven by changes in RV size induced by pulmonary valve replacement (n = 9). For LV serial size changes, significant correlations were noted with changes in NT-pro-BNP, ST -2, GDF-15 and FABP-4 (rpearson between 0.32 and 0.52). Conclusion: In clinically stable ToF patients changes in right and left ventricular size and function correlated with alterations in blood biomarkers of inflammation and immune response to stress.

Secondary tricuspid regurgitation (TR) has long been considered a benign and well-tolerated valvular lesion that resolves after treatment of the underlying disease. This view has been challenged by data indicating that long-standing TR can be a progressive disorder, contributing to right ventricular failure and end-organ damage, despite adequate treatment of the underlying disease. Surgical correction is curative, but infrequently performed and historically associated with poor outcomes. This may be due to delayed diagnosis, lack of well-defined surgical indications, and, consequently, late intervention in patients in poor clinical condition with failing right ventricles. Because of limited evidence about timing and corresponding outcome of tricuspid valve surgery, current guideline recommendations are rather conservative and show several inconsistencies. Nevertheless, there has been a trend toward a more aggressive approach in the surgical treatment of TR with improved outcomes. Moreover, emerging transcatheter options claim to provide a lower-risk alternative for selected patients. This may facilitate earlier treatment and improve the attitude toward an early treatment strategy of secondary TR, yet is not reflected in the guidelines. Future research is needed for risk stratification to determine inclusion criteria and optimal timing for intervention.

Introduction: Early identification of preterm born infants most at risk for respiratory problems is challenging due to a lack of valid and feasible lung function tests. We aim to assess the value of the hypoxic challenge test (HCT) as a test for lung and pulmonary vascular function in preterm born infants with and without bronchopulmonary dysplasia (BPD). Methods: Infants born <32 weeks of gestation were included. The HCT was performed at 6 months of age corrected for prematurity. A cut-off point of 85% oxygen saturation was used as test fail point. Echocardiographic parameters collected prior to and immediately after the HCT were used to evaluate pulmonary vascular reactivity: pulmonary artery acceleration time (PAAT)/right ventricle ejection time (RVET) ratio, eccentricity index, and systolic duration (SD) to diastolic duration (DD) time ratio. For each infant, the change in pulmonary vascular reactivity caused by the HCT was calculated. Outcomes on respiratory morbidity were collected until 12 months of age corrected for prematurity. Differences in outcomes were evaluated between infants that failed and passed the HCT. Results: We included 40 infants (21 severe BPD, 19 mild/no BPD). Eleven infants failed the HCT, of whom 8 with severe BPD (38.1%) and 3 with mild/no BPD (15.8%). No significant differences were seen in PAAT/RVET ratio (p=0.711), eccentricity index (p=0.954), and the SD/DD ratio (p=0.091), between passing or failing the HCT. The risk of re-hospitalization for respiratory infections in the first year was higher in infants failing the HCT (OR=6.86, 95% CI [1.03–45.6]). Conclusion: The HCT is a valuable lung function test in preterm infants, but does not pick up on changes in pulmonary vascular reactivity.

OBJECTIVES Studies concerning cardiopulmonary outcomes of adults born with congenital diaphragmatic hernia (CDH) are sparse. Moreover, they don't include participants who have been treated with extracorporeal membrane oxygenation (ECMO) during the neonatal period. This study evaluated the cardiopulmonary morbidities in young adults born with CDH.METHODS We assessed 68 participants between the ages of 18 and 30 years. The assessment included auxology assessment, lung function tests, pulmonary imaging, cardiopulmonary exercise testing, and echocardiography.RESULTS Lung function parameters in the overall group were significantly worse than normal values. Mean (SD) scores postbronchodilator forced expiratory volume in 1 second were -2.91 (1.38) in the ECMO-treated and -1.20 (1.53) in the non-ECMO-treated participants. Chest computed tomography scans showed mild to moderate abnormal lung structure in all ECMO-treated participants, and to a lesser extent in non-ECMO treated participants. A recurrent diaphragmatic defect was observed in 77% of the ECMO-treated group and in 43% of the non-ECMO-treated group. Except for 2 cases with acute symptoms, no clinical problems were noted in cases of recurrence. Cardiopulmonary exercise testing revealed mean (SD) percentage predicted peak oxygen consumption per kilogram of 73 (14)% and 88 (16)% in ECMO-treated and non-ECMO-treated participants, respectively. The mean (SD) workload was normal in the non-ECMO-treated group (111 [25]% predicted); in the ECMO-treated group, it was 89 (23)%. Cardiac evaluation at rest revealed no signs of pulmonary hypertension.CONCLUSIONS In young adults who survived treatment of CDH, significant pulmonary morbidity, reduced exercise capacity, and frequent hernia recurrence should be anticipated. Lifelong follow-up care, with the emphasis on prevention of further decline, is to be recommended.

Right ventricular dysfunction is a major determinant of outcome in patients with complex congenital heart disease, as in tetralogy of Fallot. In these patients, right ventricular dysfunction emerges after initial pressure overload and hypoxemia, which is followed by chronic volume overload due to pulmonary regurgitation after corrective surgery. Myocardial adaptation and the transition to right ventricular failure remain poorly understood. Combining insights from clinical and experimental physiology and myocardial (tissue) data has identified a disease phenotype with important distinctions from other types of heart failure. This phenotype of the right ventricle in tetralogy of Fallot can be described as a syndrome of dysfunctional characteristics affecting both contraction and filling. These characteristics are the end result of several adaptation pathways of the cardiomyocytes, myocardial vasculature and extracellular matrix. As long as the long-term outcome of surgical correction of tetralogy of Fallot remains suboptimal, other treatment strategies need to be explored. Novel insights in failure of adaptation and the role of cardiomyocyte proliferation might provide targets for treatment of the (dysfunctional) right ventricle under stress.

Low-level vagus nerve stimulation through the tragus (tLLVNS) is increasingly acknowledged as a therapeutic strategy to prevent and treat atrial fibrillation. However, a lack in understanding of the exact antiarrhythmic properties of tLLVNS has hampered clinical implementation.In this study, we aimed to study the effects of tLLVNS on atrial electrophysiology by performing intraoperative epicardial mapping during acute and chronic tLLVNS.Epicardial mapping of the superior right atrium was performed before and after arterial graft harvesting in patients undergoing coronary artery bypass grafting without a history of atrial fibrillation. The time needed for arterial graft harvesting was used to perform chronic tLLVNS. Electrophysiological properties were compared before and during chronic tLLVNS.A total of 10 patients (median age 74 years [IQR: 69-78 years]) underwent tLLVNS for a duration of 56 minutes (IQR: 43-73 minutes). During acute and chronic tLLVNS, a shift of the sinoatrial node exit site toward a more cranial direction was observed in 5 (50%) patients. Unipolar potential voltage increased significantly during acute and chronic tLLVNS (3.9 mV [IQR: 3.1-4.8 mV] vs 4.7 mV [IQR: 4.0-5.3 mV] vs 5.2 mV [IQR: 4.8-7.0 mV]; P = 0.027, P = 0.02, respectively). Total activation time, slope of unipolar potentials, amount of fractionation, low-voltage areas and conduction velocity did not differ significantly between baseline measurements and tLLVNS. Two patients showed consistent “improvement” of all electrophysiological properties during tLLVNS, while 1 patient appeared to have no beneficial effect.We demonstrated that tLLVNS resulted in a significant increase in unipolar potential voltage. In addition, we observed the following in selective patients: 1) reduction in total activation time; 2) steeper slope of unipolar potentials; 3) decrease in the amount of fractionation; and 4) change in sinoatrial node exit sites.

ObjectivesRight ventricular (RV) failure is a leading cause of death in patients with congenital heart disease. RV failure is kept at bay during childhood. Limited proliferation of cardiomyocytes is present in the postnatal heart. We propose that cardiomyocyte proliferation improves RV adaptation to pressure load (PL). We studied adaptation in response to increased RV PL and the role of increased cardiomyocyte cell cycle activity (CCA) in rat pups growing into adulthood.MethodsWe induced RV PL at day of weaning in rats (3 weeks; 30-40 g) by pulmonary artery banding and followed rats into adulthood (300 g). We performed histological analyses and RNA sequencing analysis. To study the effects of increased cardiomyocyte cell cycle activity, we administered neuregulin-1 (NRG1), a growth factor involved in cardiac development.ResultsPL induced an increase in CCA, with subsequent decline of CCA (sham/PL at 4 weeks: 0.14%/0.83%; P = .04 and 8 weeks: 0.00%/0.00%; P = .484) and cardiac function (cardiac index: control/PL 4 weeks: 4.41/3.29; P = .468 and 8 weeks: 3.57/1.44; P = .024). RNA sequencing analysis revealed delayed maturation and increased CCA pathways. NRG1 stimulated CCA (PL vehicle/NRG1 at 2 weeks: 0.62%/2.28%; P = .003), improved cardiac function (cardiac index control vs vehicle/NRG1 at 2 weeks: 4.21 vs 3.07/4.17; P = .009/.705) and postponed fibrosis (control vs vehicle/NRG1 at 4 weeks: 1.66 vs 4.82%/2.97%; P = .009/.078) in RV PL rats during childhood.ConclusionsRV PL during growth induces a transient CCA increase. Further CCA stimulation improves cardiac function and delays fibrosis. This proof-of-concept study shows that stimulation of CCA can improve RV adaptation to PL in the postnatal developing heart and might provide a new approach to preserve RV function in patients with congenital heart disease.

Cardiac hypertrophy is often a risk factor for heart failure, leading to high morbidity and mortality worldwide. Despite the urgency to prevent cardiac hypertrophy, effective therapies are still lacking. microRNAs are emerging as therapeutic targets, with oligonucleotide-based therapeutics showing promising results. We have previously found miR-199b to play a detrimental role in left ventricle (LV) pressure overload by amplifying the calcineurin/NFAT pathway. By repressing Dyrk1a, miR-199b prevents translocation of NFAT from the nucleus back into the cytoplasm, promoting the expression of pro-hypertrophic genes. Silencing of this microRNA with a specific antagomir abolished hypertrophy and improved cardiac function after induced LV pressure overload [1]. Here, we show that miR-199b not only plays a deleterious role in LV but also in right ventricle (RV) remodeling. Overexpression of this microRNA in transgenic mice subjected to pulmonary artery banding (PAB) resulted in aggravated RV hypertrophy and dysfunction, unveiling an inverse correlation between RV function and miR-199b expression. Molecular changes in the RV include significant upregulation of hypertrophic markers but no changes in Dyrk1a expression. Instead, there was decreased Vegfr2 expression and lower relative capillary density, suggesting capillary network remodeling. RV pressure overload also resulted in alterations in LV shape and remodeling, with extensive molecular differences, including downregulation of Dyrk1a, similarly to our previous observations. Our results suggest that molecular mechanisms governing miR-199b-induced hypertrophy are distinct for the two ventricles, but that modulation of this microRNA could have a therapeutic effect in both. Our current studies consist of optimizing therapeutic delivery of antagomir-199b to treat LV hypertrophy in pigs, as well as to ameliorate RV hypertrophy in mice subjected to PAB. Although the contribution of this microRNA to RV remodeling is still unknown, we believe that our findings emphasize miR-199b pleiotropy and highlight its therapeutic potential. Moreover, a better understanding of the differences between a stressed RV and LV can be a major asset to prevent heart failure. [1] Da Costa Martins PA, Salic K, Gladka MM, et al. MicroRNA-199b targets the nuclear kinase Dyrk1a in an auto-amplification loop promoting calcineurin/NFAT signalling. Nat Cell Biol. 2010;12(12):1220–1227. doi:https://doi.org/10.1038/ncb2126.

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.

Sex is increasingly emerging as determinant of right ventricular (RV) adaptation to abnormal loading conditions. It is unknown, however, whether sex-related differences already occur in childhood. Therefore, this study aimed to assess sex differences in a juvenile model of early RV pressure load by pulmonary artery banding (PAB) during transition from pre to postpuberty. Rat pups (n = 57, 3 wk old, 30-45 g) were subjected to PAB or sham surgery. Animals were euthanized either before or after puberty (4 and 8 wk postsurgery, respectively). Male PAB rats demonstrated failure to thrive already after 4 wk, whereas females did not. After 8 wk, female PAB rats showed less clinical symptoms of RV failure than male PAB rats. RV pressure-volume analysis demonstrated increased end-systolic elastance after 4 wk in females only, and a trend toward preserved end-diastolic elastance in female PAB rats compared with males (P = 0.055). Histology showed significantly less RV myocardial fibrosis in female compared with male PAB rats 8 wk after surgery. Myosin heavy chain 7-to-6 ratio switch and calcineurin signaling were less pronounced in female PAB rats compared with males. In this juvenile rat model of RV pressure load, female rats appeared to be less prone to clinical heart failure compared with males. This was driven by increased RV contractility before puberty, and better preservation of diastolic function with less RV myocardial fibrosis after puberty. These findings show that RV adaptation to increased loading differs between sexes already before the introduction of pubertal hormones. NEW & NOTEWORTHY In this study, we describe sex differences in our unique weanling rat model of increased RV pressure load by pulmonary artery banding. We are the first to assess temporal sex-related differences in RV adaptation during pubertal development. Female rats show superior RV function and less diastolic dysfunction and fibrosis compared with male rats. These differences are already present before puberty, indicating that the differences in RV adaptation are not only determined by sex hormones.

Right ventricular function is an important determinant of prognosis and outcome in congenital heart diseases. Right ventricular (RV) adaptation to congenital heart diseases (CHD) has many faces as there is a wide variety in defects involving the right ventricle as well as in treatment strategies. This variety induces differences in loading conditions and also changes over time as a result of surgical interventions. Also, treatment practice has evolved changing the nature and outcome of survivors of CHD. Lastly, several lesions also affect the left ventricle (LV) that may interact with RV function and thereby change the RV function.Although in practice sometimes artificially, for educational and conceptual purposes the effects on the RV can be divided into three types of abnormal loading conditions, i.e., increased preload (e.g., shunts or valvular insufficiency), increased afterload (e.g., stenosis or connection to systemic circulation), or a mixture of both. During the process of maturation and aging and as a result of interventions loading conditions can shift from increased afterload to increased preload. In this chapter we describe the different faces of the RV with a focus on the functional capacity. We differentiate between lesions affecting preload, afterload, and a mixture of those. Special attention is given to the RV in corrected tetralogy of Fallot and the systemic RV in congenitally corrected transposition of the great arteries, after the atrial switch procedure for transposition of the great arteries or in hypoplastic left-heart syndrome.

Background Patients who have undergone the Fontan procedure are at high risk of circulatory failure. In an exploratory analysis we aimed to determine the prognostic value of blood biomarkers in a young cohort who have undergone the Fontan procedure. Methods and Results In multicenter prospective studies patients who have undergone the Fontan procedure underwent blood sampling, cardiopulmonary exercise testing, and stress cardiac magnetic resonance imaging. Several biomarkers including NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), GDF‐15 (growth differentiation factor 15), Gal‐3 (galectin‐3), ST2 (suppression of tumorigenicity 2), DLK‐1 (protein delta homolog 1), FABP‐4 (fatty acid‐binding protein 4), IGFBP‐1 (insulin‐like growth factor‐binding protein 1), IGFBP‐7, MMP‐2 (matrix metalloproteinase 2), and vWF (von Willebrand factor) were assessed in blood at 9.6 (7.1–12.1) years after Fontan completion. After this baseline study measurement, follow‐up information was collected on the incidence of adverse cardiac events, including cardiac death, out of hospital cardiac arrest, heart transplantation (listing), cardiac reintervention (severe events), hospitalization, and cardioversion/ablation for arrhythmias was collected and the relation with blood biomarkers was assessed by Cox proportional hazard analyses. The correlation between biomarkers and other clinical parameters was evaluated. We included 133 patients who have undergone the Fontan procedure, median age 13.2 (25th, 75th percentile 10.4–15.9) years, median age at Fontan 3.2 (2.5–3.9) years. After a median follow‐up of 6.2 (4.9–6.9) years, 36 (27.1%) patients experienced an event of whom 13 (9.8%) had a severe event. NT‐proBNP was associated with (all) events during follow‐up and remained predictive after correction for age, sex, and dominant ventricle (hazard ratio, 1.89; CI, 1.32–2.68). The severe event‐free survival was better in patients with low levels of GDF‐15 ( P =0.005) and vWF ( P =0.008) and high levels of DLK‐1 ( P =0.041). There was a positive correlation (β=0.33, P =0.003) between DLK‐1 and stress cardiac magnetic resonance imaging functional reserve. Conclusions NT‐proBNP, GDF‐15, vWF, DLK‐1, ST‐2 FABP‐4, and IGFBP‐7 levels relate to long‐term outcome in young patients who have undergone the Fontan procedure.