Recurrent Mild Acute Rejections and Donor-specific Antibodies as Risk Factors for Cardiac Allograft Vasculopathy in a National Pediatric Heart Transplant Cohort.

Background: Immune-mediated factors such as acute cellular rejections and donor-specific antibodies (DSAs) are risk factors for cardiac allograft vasculopathy (CAV). We studied a national cohort with a unified setting and thorough protocol endomyocardial biopsy (EMB) data for an association between cellular rejections, especially when mild and recurrent, and DSAs with CAV in pediatric heart transplant (HTx) patients. Methods: This is a retrospective, national cohort study of 94 pediatric HTxs performed between 1991 and 2019 and followed until December 31, 2020. Diagnosis of CAV was based on reevaluation of angiographies. Protocol and indication EMB findings with other patient data were collected from medical records. Associations between nonimmune and immune-mediated factors and CAV were analyzed with univariable and multivariable Cox regression analyses. Results: Angiographies performed on 76 patients revealed CAV in 23 patients (30%). Altogether 1138 EMBs (92% protocol biopsies) were performed on 78 patients (83%). During the first posttransplant year, grade 1 rejection (G1R) appeared in 45 patients (58%), and recurrent (≥2) G1R findings in 14 patients (18%). Pretransplant DSAs occurred in 13 patients (17%) and posttransplant DSAs in 37 patients (39%). In univariable analysis, pretransplant DSAs, appearance and recurrence of G1R findings, and total rejection score during the first posttransplant year, as well as recurrent G1R during follow-up, were all associated with CAV. In multivariable analysis, pretransplant DSAs and recurrent G1R during the first posttransplant year were found to be associated with CAV. Conclusions: Our results indicate that pretransplant DSA and recurrent G1R findings, especially during the first posttransplant year, are associated with CAV after pediatric HTx.

Predictors of blood pressure and hypertension long-term after treatment of isolated coarctation of the aorta in children-a population-based study.

OBJECTIVES: The aim of this study was to assess predictors of BP and hypertension and relations between BP and LV mass in a population-based retrospective study of repaired isolated coarctation of aorta. METHODS: We collected follow-up data until 2018 of 284/304 (93%) patients with coarctation treated by surgery (n = 235) or balloon angioplasty/stent (n = 37/12) in our unit 2000-2012. Systolic hypertension was defined as systolic BP (SBP) z-score ≥+2 standard deviation (SD) or regular use of BP medication. LV hypertrophy was defined as LV mass z-score ≥+2 SD or LV mass index g/m2.7 ≥95th percentile. RESULTS: The median (25-75th percentiles) follow-up time and age at follow-up were 9.7 years (6.9-13.2) and 11.8 years (7.9-16.0), respectively. Age at first procedure (P = 0.011) and systolic arm-leg-gradient (P = 0.007) were positively and transverse arch (P = 0.007) and isthmus diameter (P = 0.001) z-scores at follow-up were negatively associated with SBP z-score adjusted for age at follow-up and need for reintervention for coarctation. Systolic hypertension was present in 53/284 (18.7%) and related with increasing age at first procedure (median 33.2 vs 0.6 months; P < 0.001) and arm-leg-gradient at follow-up (mean ± SD, -0.3 ± 14.6 vs -6.4 ± 11.6 mmHg; P = 0.047) adjusted for reintervention for coarctation and age at follow-up. LV hypertrophy was present in 20/227 (9.3%) and related with SBP z-score. CONCLUSIONS: Higher SBP and hypertension in repaired coarctation of aorta are related with increasing age at first procedure and arm-leg-gradient at follow-up. Transverse arch and isthmus diameters at follow-up are inversely related with SBP.

The incidence of recurrent laryngeal nerve injury resulting in vocal cord paralysis following interventional congenital catheterisation procedures.

BACKGROUND: Recurrent laryngeal nerve injury leading to vocal cord paralysis is a known complication of cardiothoracic surgery. Its occurrence during interventional catheterisation procedures has been documented in case reports, but there have been no studies to determine an incidence. OBJECTIVE: To establish the incidence of left recurrent laryngeal nerve injury leading to vocal cord paralysis after left pulmonary artery stenting, patent ductus arteriosus device closure and the combination of the procedures either consecutively or simultaneously. METHODS: Members of the Congenital Cardiovascular Interventional Study Consortium were asked to perform a retrospective analysis to identify cases of recurrent laryngeal nerve injury after the aforementioned procedures. Twelve institutions participated in the analysis. They also contributed the total number of each procedure performed at their respective institutions for statistical purposes. RESULTS: Of the 1337 patients who underwent left pulmonary artery stent placement, six patients (0.45%) had confirmed vocal cord paralysis. 4001 patients underwent patent ductus arteriosus device closure, and two patients (0.05%) developed left vocal cord paralysis. Patients who underwent both left pulmonary artery stent placement and patent ductus arteriosus device closure had the highest incidence of vocal cord paralysis which occurred in 4 of the 26 patients (15.4%). Overall, 92% of affected patients in our study population had resolution of symptoms. CONCLUSION: Recurrent laryngeal nerve injury is a rare complication of left pulmonary artery stent placement or patent ductus arteriosus device closure. However, the incidence is highest in patients undergoing both procedures either consecutively or simultaneously. Additional research is necessary to determine contributing factors that might reduce the risk of recurrent laryngeal nerve injury.

Development of Human Leukocyte Antigen (HLA) Antibodies Against Vascular Homograft Donor in Pediatric Heart Transplant Recipients.

BACKGROUND The appearance of human leukocyte antigen (HLA) antibodies after solid organ transplantation predisposes recipients to graft dysfunction. In theory, vascular homografts, which are widely used in children with congenital heart defects, may cause allosensitization. MATERIAL AND METHODS In this single-center retrospective study, the presence of pre-existing HLA antibodies in pediatric heart transplant (HTx) recipients with a vascular homograft was evaluated in a cohort of 12 patients. HLA antibodies were screened before and after HTx and positive screening results were confirmed and identified using the Luminex® single antigen bead method. Endomyocardial biopsies (EMB) and coronary angiography studies were re-evaluated to assess the prevalence of acute rejections and coronary artery change in these patients. RESULTS At the time of HTx, 8 patients (67%) had HLA antibodies detected by the Luminex assay, none of which were heart donor specific (DSA). All patients had negative leukocyte crossmatch. One patient developed DSAs against homograft donor prior to HTx. After the HTx, 5 patients (42%) developed DSAs against the heart donor and 4 patients (40%) against the homograft donor. In 2 patients (17%), the antibodies were against both heart and homograft donors. The rejection rate or prevalence of coronary artery vasculopathy did not differ significantly between the homograft cohort and our historical controls. CONCLUSIONS Our results suggest that the prevalence of DSAs against homograft donor prior to HTx is relatively rare. However, almost half of the patients developed DSAs against homograft post-HTx. The clinical importance of these antibodies warrants further studies.

Procedural risk factors, incidence and timing of reintervention after treatment for native coarctation of the aorta in children: a population-based study†.

OBJECTIVES: The aim of the present study was to evaluate procedural risk factors, incidence and timing of reintervention because of recurrent aortic coarctation in children. METHODS: The study cohort consisted of 304 patients with isolated coarctation: 251 underwent surgery and 53 were treated percutaneously (40 balloon angioplasty, 13 stent) at the Helsinki Children's Hospital in 2000-2012. Characteristics, intervention and reintervention data were retrospectively collected from clinical records until 2014 (median follow-up 7.9 years). Age- and sex-matched comparisons between the treatment groups were performed in 86 patients (surgery n = 43, percutaneous n = 43). RESULTS: Forty of the 251 (16%) patients after surgery, 9/40 (23%) patients after balloon angioplasty and 4/13 (31%) patients after stent placement underwent a reintervention after a median time of 3.4, 11.7 and 19.5 months (P < 0.05), respectively. In the surgery group, all reinterventions occurred in children operated on ≤12 months of age and were related to lower body weight and smaller dimensions of the aorta. In the balloon angioplasty group, a higher post-procedure systolic arm-leg blood pressure gradient was associated with reintervention. After stent placement, three-fourths of the reinterventions were performed in a planned postinterventional catheterization. In the age- and sex-matched comparisons (median 5,7 years, range 0,5-17,6), post-procedure blood pressure gradients were higher (mean 10 vs 4 mmHg, P = 0.03), and reinterventions were more common (28%, 95% confidence interval 17-43 vs 2%, 95% confidence interval 0-12) in the percutaneous group compared to the surgery group. CONCLUSIONS: Reinterventions after surgery in neonates were relatively common. In older children, percutaneous treatment carried a higher risk of reinterventions, which were mainly related to residual coarctation after primary treatment.

Right ventricular systolic function in hypoplastic left heart syndrome: A comparison of manual and automated software to measure fractional area change.

BACKGROUND: Quantitative echocardiographic assessment of right ventricular function is important in children with hypoplastic left heart syndrome (HLHS). The aim of this study was to examine the repeatability of different echocardiographic techniques, both manual and automated, to measure fractional area change (FAC) in patients with HLHS and to correlate these measurements with magnetic resonance imaging (MRI)-derived ejection fraction (EF). METHODS: Fifty-one children with HLHS underwent transthoracic echocardiography and cardiac MRI under the same general anesthetic as part of routine inter-stage assessment. FAC was measured from the apical four-chamber view using three different techniques: velocity vector imaging (VVI) (Syngo USWP 3.0; Siemens Healthineers), QLAB (Q-lab R 10.0; Philips Healthcare), and manual endocardial contour tracing (Xcelera, Philips Healthcare). Intra- and inter-observer variability was calculated using intra-class correlation coefficient (ICC). FAC was correlated with MRI EF calculated using a single standard method. RESULTS: Fractional area change had a good correlation with MRI-derived EF with an R value for VVI, QLAB, and manual methods of .7, .6, and .4, respectively. Intra- and inter-observer variability for FAC was good for automated echocardiographic methods (ICC>.85) but worse for manual method particularly inter-observer variability of FAC and end-systolic area. Both automated techniques tended to produce higher FAC values compared with manual measurements (P<.001). CONCLUSION: Automation improves the repeatability of FAC in HLHS. There are some differences between automated software in terms of correlation with MRI-derived EF. Measurement bias and wide limits of agreement mean that the same echocardiographic technique should be used during the follow-up of individual patients.

Fate of fenestration in children treated with fontan operation.

OBJECTIVE: To review the operative history and clinical and catheterization data on patients treated with total cavopulmonary connection (TCPC) with baffle fenestration and to study whether it is possible to predict the fate of fenestration. BACKGROUND: A baffle fenestration may improve postoperative outcomes after Fontan operation but is later associated with cyanosis and thromboembolic risk. Fenestration may close spontaneously or it can be closed percutaneously in patients with favorable hemodynamics. METHODS: Patients were divided into three groups: those with spontaneous closure of fenestration (group S, n = 34) and those with patent fenestration and favorable (group F, n = 36) or unfavorable (group U, n = 20) response to fenestration test occlusion. Clinical records were reviewed for demographic and anatomical characteristics, previous surgeries, and catheterizations. RESULTS: Predominant ventricular morphology was right ventricle (RV)/left ventricle (LV)/undeterminate in 19/14/1 patients in group S, 14/22/0 in group F, and 14/6/0 in group U. No differences were detected between groups in pre-TCPC catheterization data. Type of baffle fenestration was window/tube in 20/14 in group S, 28/8 in group F, and 20/0 in group U. All tube fenestrations either closed spontaneously or could be closed percutaneously. Twenty-nine percent of patients with window-type fenestrations failed the test occlusion. CONCLUSIONS: Spontaneous closure and favorable result in test occlusion are more common in tube than in window fenestrations. Since most preoperative anatomic and hemodynamic factors were similar in all patient groups, we find it difficult to predict the fate of a window-type fenestration and the result of test occlusion. © 2015 Wiley Periodicals, Inc.

Prenatal diagnosis improves the postnatal cardiac function in a population-based cohort of infants with hypoplastic left heart syndrome.

BACKGROUND: Prenatal diagnosis of hypoplastic left heart syndrome (HLHS) enables planning of perinatal care and is known to be associated with more stable preoperative hemodynamics. The impact on postnatal myocardial function is poorly known. The aim of this study was to determine the impact of prenatal diagnosis of HLHS on postnatal myocardial function. METHODS: A consecutively encountered cohort of 66 infants with HLHS born between 2003 and 2010 in Finland was retrospectively reviewed. Twenty-five infants had prenatal diagnoses. Postnatal global and segmental right ventricular fractional area change, strain rate, and myocardial velocity were analyzed from the apical four-chamber view using Velocity Vector Imaging. Preoperative hemodynamic status and end-organ damage measurements were the lowest arterial pH, highest lactate, alanine aminotransferase, and creatinine. Early mortality was studied until 30 days after Norwood procedure. RESULTS: Prenatally diagnosed infants had better cardiac function (fractional area change, 27.9 ± 7.4% vs 21.1 ± 6.3%, P = .0004; strain rate, 1.1 ± 0.6/1.3 ± 1.0 vs 0.7 ± 0.2/0.7 ± 0.3 1/sec, P = .004/.003; myocardial velocity, 1.6 ± 0.6/2.0 ± 1.1 vs 1.3 ± 0.4/1.4 ± 0.4 cm/sec, P = .0035/.0009). Mechanical dyssynchrony was similar in both groups (P > .30). Infants diagnosed prenatally had less acidosis (pH = 7.30 vs 7.25, P = .005) and end-organ dysfunction (alanine aminotransferase, 33 ± 38 vs 139 ± 174 U/L, P = .0001; creatinine, 78 ± 18 vs 81 ± 44 mmol/L, P = .05). No deaths occurred among the prenatally diagnosed infants, but four deaths were recorded among postnatally diagnosed infants (P = .15). CONCLUSIONS: A prenatal diagnosis of HLHS is associated with improved postnatal right ventricular function, reduced metabolic acidosis, and end-organ dysfunction.

Cardiac troponin I in congenital heart defects with pressure or volume overload.

OBJECTIVE: To evaluate the prevalence of cardiac troponin I (cTnI) and autoantibodies to cTn in children with congenital heart defects with volume or pressure overload fulfilling the criteria for treatment, and in healthy children. DESIGN: The study groups comprised 78 children with volume overload caused by an atrial septal defect or a patent ductus arteriosus, and 60 children with pressure overload caused by coarctation of the aorta or stenosis of the aortic or the pulmonary valve, and 74 healthy controls. Serum levels of natriuretic peptides, cTnI, and autoantibodies to cTn were analyzed at baseline, prior to treatment and in 64 patients 6 months after treatment. RESULTS: At baseline, one child with volume overload, 12 children with pressure overload, and one healthy control had positive cTnI. Further analysis of the pressure overload subgroup revealed that the children with positive cTnI were younger than those with negative cTnI, and had higher levels of natriuretic peptides. The pressure gradient at the coarctation site or stenotic valve was higher in those with positive TnI. Six months after treatment, 63 of 64 children examined were cTnI negative. CONCLUSIONS: The cTnI release is more frequently associated with pressure than volume overload which resolves after treatment in most children.

Serum Levels of Natriuretic Peptides in Children before and after Treatment for an Atrial Septal Defect, a Patent Ductus Arteriosus, and a Coarctation of the Aorta-A Prospective Study.

Background and Objectives. We evaluated and compared the influence of treatment for atrial septal defect (ASD), patent ductus arteriosus (PDA), and coarctation of the aorta (CoA) on serum levels of N-terminal proatriopeptide and N-terminal probrain natriuretic peptide. Correlations between peptide levels and echocardiographic measurements were calculated. Patients and Methods. Peptide levels were measured and echocardiography performed before and 6-12 months after treatment in 21 children with ASD, 25 with PDA, 15 with CoA, and 76 control children. Results. ANPN levels were higher than in controls at baseline in all patient groups, and NT-proBNP in patients with ASD and PDA. Both peptide levels were elevated 6 months after treatment and decreased thereafter. Peptide levels were higher in patients with volume than pressure overload. They correlated with echocardiographic measurements. At the 6-month follow-up, dimensions of the originally overloaded ventricle had normalized only in patients with PDA. Conclusions. After intervention, peptide levels decrease but normalization takes over 6 months. The type of correlation between peptide levels and echocardiography varies according to the loading condition. Measurement of peptide levels can be used for monitoring the course of a patient's heart disease.

Serum levels of natriuretic peptides in children with various types of loading conditions.

OBJECTIVES: To evaluate the influence of volume overload of the left (LV) and right ventricle (RV) and pressure overload of LV and restrictive physiology on levels of N-terminal proatriopeptide (ANPN) and N-terminal pro-brain natriuretic peptide (NT-proBNP). DESIGN: We studied 41 children with atrial septal defect (ASD), 35 with patent ductus arteriosus (PDA), 27 with coarctation of the aorta (CoA), 25 with restrictive physiology caused by Mulibrey nanism, and 64 control children. We measured serum concentrations of natriuretic peptides and evaluated ventricular size and function with echocardiography. RESULTS: In patients with ASD, PDA, and Mulibrey nanism, levels of both ANPN and NT-proBNP were higher than in controls but in children with CoA, only ANPN levels were higher. ANPN levels correlated with RV size in ASD and NT-proBNP levels with LV size in PDA. In patients with restriction, NT-proBNP levels correlated negatively with LV size. CONCLUSIONS: Correlation between echo measurements and levels of natriuretic peptides varied according to loading condition. Measurement of natriuretic peptide levels provides a supplemental method for non-invasive haemodynamic evaluation of children's heart disease.

Left ventricular hypertrophy persists after successful treatment for coarctation of the aorta.

OBJECTIVES: To evaluate cardiac size and function in patients with coarctation of the aorta (CoA) before and after treatment. DESIGN: Ventricular size and function were examined by 2- and 3-dimensional echocardiography, and concentrations of natriuretic peptides measured in 15 paediatric patients before repair, and one, 6, and 12 months thereafter. Controls comprised 15 children. RESULTS: Before repair, mitral inflow velocities and left ventricular (LV) size and wall thickness were higher in patients. Thicknesses of interventricular septum and LV posterior wall decreased after repair but increased to initial level one year thereafter. The LV end-diastolic diameter remained larger than in controls despite successful repair. The size of right ventricle increased and levels of natriuretic peptides decreased during follow-up. Levels of natriuretic peptides correlated with the smallest diameter of CoA segment and diastolic indices of LV function. CONCLUSION: LV hypertrophy persists and LV size remains larger than in controls after successful repair even in normotensive patients with normal growth of CoA segment. This may be due to remodelling of ventricles and the aorta caused by CoA.

Hemodynamic improvement is faster after percutaneous ASD closure than after surgery.

OBJECTIVES: Hemodynamic effects of surgical and percutaneous closure of atrial septal defect (ASD) were evaluated. BACKGROUND: ASD causes volume overload of right ventricle (RV) and is associated with distortion and dysfunction of left ventricle (LV). The amount and timing of hemodynamic changes after ASD closure are not well known. METHODS: The study group consisted of 7 children treated surgically and 17 treated in the catheterization laboratory. In the control group, there were 51 healthy children. RV size and LV end-diastolic and systolic dimensions, volumes, and function were examined by two- and three- dimensional echocardiography and serum concentrations of natriuretic peptides measured prior to ASD closure, and 1, 6, and 12 months thereafter. RESULTS: In all children with ASD, during the 1-year follow-up, the z score of RV end-diastolic diameter decreased from a median 5.00 SD to 2.25 SD (P < 0.001). Dilatation of RV did not resolve entirely during 1-year follow-up in either treatment group. End-diastolic LV diameter increased from -1.50 to -0.50 SD (P < 0.001). LV size increased slower in the surgical subgroup but reached control levels in both groups. Concentrations of natriuretic peptides increased during the first month after ASD closure and normalized thereafter in patients treated percutaneously but remained higher than in controls in patients treated surgically. CONCLUSIONS: During 1-year follow-up after ASD closure, RV size decreases but does not normalize in all patients. The size of the LV normalizes after ASD closure but the increase in LV size is slower in patients treated surgically. Serum levels of ANPN and proBNP are elevated prior to ASD closure but decrease thereafter to control levels in patients treated with the percutaneous technique but not in those treated surgically.