Ventricular function and biomarkers in relation to repair and pulmonary valve replacement for tetralogy of Fallot.

OBJECTIVE: Cardiac surgery may cause temporarily impaired ventricular performance and myocardial injury. We aim to characterise the response to perioperative injury for patients undergoing repair or pulmonary valve replacement (PVR) for tetralogy of Fallot (ToF). METHODS: We enrolled children undergoing ToF repair or PVR from four tertiary centres in a prospective observational study. Assessment-including blood sampling and speckle tracking echocardiography-occurred before surgery (T1), at the first follow-up (T2) and 1 year after the procedures (T3). Ninety-two serum biomarkers were expressed as principal components to reduce multiple statistical testing. RNA Sequencing was performed on right ventricular (RV) outflow tract samples. RESULTS: We included 45 patients with ToF repair aged 4.3 (3.4 - 6.5) months and 16 patients with PVR aged 10.4 (7.8 - 12.7) years. Ventricular function following ToF repair showed a fall-and-rise pattern for left ventricular global longitudinal strain (GLS) (-18±4 to -13±4 to -20±2, p < 0.001 for each comparison) and RV GLS (-19±5 to -14±4 to 20±4, p < 0.002 for each comparison). This pattern was not seen for patients undergoing PVR. Serum biomarkers were expressed as three principal components. These phenotypes are related to: (1) surgery type, (2) uncorrected ToF and (3) early postoperative status. Principal component 3 scores were increased at T2. This increase was higher for ToF repair than PVR. The transcriptomes of RV outflow tract tissue are related to patients' sex, rather than ToF-related phenotypes in a subset of the study population. CONCLUSIONS: The response to perioperative injury following ToF repair and PVR is characterised by specific functional and immunological responses. However, we did not identify factors relating to (dis)advantageous recovery from perioperative injury. TRIAL REGISTRATION NUMBER: Netherlands Trial Register: NL5129.

Functional Echocardiographic and Serum Biomarker Changes Following Surgical and Percutaneous Atrial Septal Defect Closure in Children.

Background Ventricular performance is temporarily reduced following surgical atrial septal defect closure. Cardiopulmonary bypass and changes in loading conditions are considered important factors, but this phenomenon is incompletely understood. We aim to characterize biventricular performance following surgical and percutaneous atrial septal defect closure and to relate biomarkers to ventricular performance following intervention. Methods and Results In this multicenter prospective study, children scheduled for surgical or percutaneous atrial septal defect closure were included. Subjects were assessed preoperatively, in the second week postintervention (at 2-weeks follow-up), and 1-year postintervention (1-year follow-up). At each time point, an echocardiographic study and a panel of biomarkers were obtained. Sixty-three patients (median age, 4.1 [interquartile range, 3.1-6.1] years) were included. Forty-three patients underwent surgery. At 2-weeks follow-up, right ventricular global longitudinal strain was decreased for the surgical, but not the percutaneous, group (-17.6±4.1 versus -27.1±3.4; P<0.001). A smaller decrease was noted for left ventricular global longitudinal strain at 2-weeks follow-up for the surgical group (surgical versus percutaneous, -18.6±3.2 versus -20.2±2.4; P=0.040). At 1-year follow-up, left ventricular performance returned to baseline, whereas right ventricular performance improved, but did not reach preintervention levels. Eight biomarkers relating to cardiovascular and immunological processes differed across study time points. Of these biomarkers, only NT-proBNP (N-terminal pro-B-type natriuretic peptide) correlated with less favorable left ventricular global longitudinal strain at 2-weeks follow-up. Conclusions Right, and to a lesser degree left, ventricular performance was reduced early after surgical atrial septal defect closure. Right ventricular performance at 1-year follow-up remained below baseline levels. Several biomarkers showed a pattern over time similar to ventricular performance. These biomarkers may provide insight into the processes that affect ventricular function. Registration URL: https://www.trialregister.nl/; Unique identifier: NL5129.

Associations between blood biomarkers, cardiac function and adverse outcome in a young tetralogy of Fallot cohort.

BACKGROUND: To determine the potential prognostic value and clinical correlations of blood biomarkers in a cohort of patients with Tetralogy of Fallot (TOF). METHODS: 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, VO2 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. RESULTS: 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 (ß = -0.27, p = 0.010), a correlation between FABP4 and Max VO2 (ß = -0.41, p ≤0.001 and between MMP-2 and tricuspid valve E/A ratio (ß = -0.15, p = 0.037). CONCLUSIONS: IGFBP-7, MMP-2 and DLK-1 levels are related to cardiac function and long-term outcome in TOF patients.

Dobutamine stress testing for the evaluation of atrial and diastolic ventricular function in Fontan patients.

OBJECTIVE: To assess the atrial and ventricular diastolic function response to dobutamine stress in Fontan patients, and to relate these measurements to exercise capacity and events during the follow-up. METHODS: We performed a secondary analysis of a cross-sectional multicentre study of Fontan patients with intra-atrial lateral tunnel (ILT) or extracardiac conduit (ECC) modification. Subjects underwent cardiac MRI during rest and low-dose dobutamine stress, and cardiopulmonary exercise testing. Atrial and diastolic ventricular function parameters were derived from volume-time curves.Medical records were abstracted for a composite end-point of death, listing for transplant, arrhythmia and reintervention. Spearman's r correlation tests and Cox proportional hazards models were used to assess the relation between the dobutamine response for atrial and diastolic ventricular function and outcomes, including exercise capacity. RESULTS: We included 57 patients (26 ECC; 31 ILT) aged 12.8 (IQR (10.3-15.5)) years. During dobutamine stress atrial cyclic volume change increased (3.0 (0.4-5.9) mL/m2, p<0.001), as did early (1.9 (-1.6 to 3.6) mL/m2, p=0.001) and late emptying volume (2.2 (0.2-4.4) mL/m2, p<0.001).Ventricular early filling decreased (-1.6 (-5.7 to 0.7) mL/m2,p=0.046) and ventricular late filling increased (1.0 (-0.4 to 3.4) mL/m2,p<0.001) while stroke volume remained similar.Only for patients with the ECC modification, atrial early emptying volume increase correlated with peak oxygen uptake (ρ=0.66,p=0.002). No other parameter related to exercise capacity.During a median 7.1-year follow-up, 22 patients reached the composite endpoint. No parameter predicted events during the follow-up. CONCLUSIONS: Dobutamine stress augmented atrial reservoir and pump function for Fontan patients. Atrial early emptying reserve related to exercise capacity in ECC patients. No other atrial or diastolic ventricular function parameter related to outcomes.

Associations Between Blood Biomarkers, Cardiac Function, and Adverse Outcome in a Young Fontan Cohort.

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 (ß=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.

Atrial function in Fontan patients assessed by CMR: Relation with exercise capacity and long-term outcomes.

OBJECTIVE: To assess the role of atrial function on exercise capacity and clinical events in Fontan patients. DESIGN: 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/VCO2 slope, and events (mortality, listing for transplant, re-intervention, arrhythmia) during follow-up. RESULTS: 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/VCO2 slope. No other parameter of atrial function predicted peak oxygen uptake or VE/VCO2 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. CONCLUSIONS: ECC patients have higher atrial reservoir function and lower conduit function. Atrial function did not predict exercise capacity or events during follow-up.

Long-term follow-up after transatrial-transpulmonary repair of tetralogy of Fallot: influence of timing on outcome.

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.

Ventricular response to dobutamine stress cardiac magnetic resonance imaging is associated with adverse outcome during 8-year follow-up in patients with repaired Tetralogy of Fallot.

AIMS: The aim of this study was to evaluate the possible value of dobutamine stress cardiac magnetic resonance imaging (CMR) to predict adverse outcome in Tetralogy of Fallot (TOF) patients. METHODS AND RESULTS: In previous prospective multicentre studies, TOF patients underwent low-dose dobutamine stress CMR (7.5 µg/kg/min). Subsequently, during regular-care patient follow-up, patients were assessed for reaching the composite endpoint (cardiac death, arrhythmia-related hospitalization, or cardioversion/ablation, VO2 max ≤65% of predicted). A normal stress response was defined as a decrease in end-systolic volume (ESV) and increase in ejection fraction. The relative parameter change during stress was calculated as relative parameter change = [(parameterstress - parameterrest)/parameterrest] * 100. The predictive value of dobutamine stress CMR for the composite endpoint was determined using time-to-event analyses (Kaplan-Meier) and Cox proportional hazard analysis. We studied 100 patients [67 (67%) male, median age at baseline CMR 17.8 years (interquartile range 13.5-34.0), age at TOF repair 0.9 years (0.6-2.1)]. After a median follow-up of 8.6 years (6.7-14.1), 10 patients reached the composite endpoint. An abnormal stress response (30% vs. 4.4%, P = 0.021) was more frequently observed in composite endpoint patients. Also in endpoint patients, the relative decrease in right ventricular ESV decreased less during stress compared with the patients without an endpoint (-17 ± 15 vs. -26 ± 13 %, P = 0.045). Multivariable analyses identified an abnormal stress response (hazard ratio 10.4; 95% confidence interval 2.5-43.7; P = 0.001) as predictor for the composite endpoint. CONCLUSION: An abnormal ventricular response to dobutamine stress is associated with adverse outcome in patients with repaired TOF.

Current outcomes and treatment of tetralogy of Fallot.

Tetralogy of Fallot (ToF) is the most common type of cyanotic congenital heart disease. Since the first surgical repair in 1954, treatment has continuously improved. The treatment strategies currently used in the treatment of ToF result in excellent long-term survival (30 year survival ranges from 68.5% to 90.5%). However, residual problems such as right ventricular outflow tract obstruction, pulmonary regurgitation, and (ventricular) arrhythmia are common and often require re-interventions. Right ventricular dysfunction can be seen following longstanding pulmonary regurgitation and/or stenosis. Performing pulmonary valve replacement or relief of pulmonary stenosis before irreversible right ventricular dysfunction occurs is important, but determining the optimal timing of pulmonary valve replacement is challenging for several reasons. The biological mechanisms underlying dysfunction of the right ventricle as seen in longstanding pulmonary regurgitation are poorly understood. Different methods of assessing the right ventricle are used to predict impending dysfunction. The atrioventricular, ventriculo-arterial and interventricular interactions of the right ventricle play an important role in right ventricle performance, but are not fully elucidated. In this review we present a brief overview of the history of ToF, describe the treatment strategies currently used, and outline the long-term survival, residual lesions, and re-interventions following repair. We discuss important remaining challenges and present the current state of the art regarding these challenges.

Staged total cavopulmonary connection: serial comparison of intra-atrial lateral tunnel and extracardiac conduit taking account of current surgical adaptations.

OBJECTIVES: Our goals were to compare the outcome of the intra-atrial lateral tunnel (ILT) and the extracardiac conduit (ECC) techniques for staged total cavopulmonary connection (TCPC) and to compare the current modifications of the TCPC technique, i.e. the prosthetic ILT technique with the current ECC technique with a ≥18-mm conduit. METHODS: We included patients who had undergone a staged TCPC between 1988 and 2008. Records were reviewed for patient demographics, operative details and events during follow-up (death, surgical and catheter-based reinterventions and arrhythmias). RESULTS: Of the 208 patients included, 103 had the ILT (51 baffle, 52 prosthetic) technique and 105 had the ECC technique. Median follow-up duration was 13.2 years (interquartile range 9.5-16.3). At 15 years after the TCPC, the overall survival rate was comparable (81% ILT vs 89% ECC; P = 0.12). Freedom from late surgical and catheter-based reintervention was higher for patients who had ILT than for those who had ECC (63% vs 44%; P = 0.016). However, freedom from late arrhythmia was lower for patients who had ILT than for those who had ECC (71% vs 85%, P = 0.034). In a subgroup of patients who had the current TCPC technique, when we compared the use of a prosthetic ILT with ≥18-mm ECC, we found no differences in freedom from late arrhythmias (82% vs 86%, P = 0.64) or in freedom from late reinterventions (70% vs 52%, P = 0.14). CONCLUSIONS: A comparison between the updated prosthetic ILT and current ≥18-mm ECC techniques revealed no differences in late arrhythmia-free survival or late reintervention-free survival. Overall, outcomes after the staged TCPC were relatively good and reinterventions occurred more frequently in the ECC group, whereas late arrhythmias were more common in the ILT group.

State of the art of the Fontan strategy for treatment of univentricular heart disease.

In patients with a functionally univentricular heart, the Fontan strategy achieves separation of the systemic and pulmonary circulation and reduction of ventricular volume overload. Contemporary modifications of surgical techniques have significantly improved survival. However, the resulting Fontan physiology is associated with high morbidity. In this review, we discuss the state of the art of the Fontan strategy by assessing survival and risk factors for mortality. Complications of the Fontan circulation, such as cardiac arrhythmia, thromboembolism, and protein-losing enteropathy, are discussed. Common surgical and catheter-based interventions following Fontan completion are outlined. We describe functional status measurements such as quality of life and developmental outcomes in the contemporary Fontan patient. The current role of drug therapy in the Fontan patient is explored. Furthermore, we assess the current use and outcomes of mechanical circulatory support in the Fontan circulation and novel surgical innovations. Despite large improvements in outcomes for contemporary Fontan patients, a large burden of disease exists in this patient population. Continued efforts to improve outcomes are warranted. Several remaining challenges in the Fontan field are outlined.

Long-term outcomes of transatrial-transpulmonary repair of tetralogy of Fallot.

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.