Antibody responses to dietary antigens are accompanied by specific plasma cells in the infant thymus.

BACKGROUND: Human infants develop IgG responses to dietary antigens during the first 2 years of life. Yet, the source of these antibodies is unclear. In previous studies we reported on the thymus as a unique functional niche for plasma cells (PCs) specific to environmental antigens. OBJECTIVE: We sought to examine whether PCs specific to dietary antigens are detected in the infant thymus. METHODS: We tested IgG reactivity to 112 food antigens and allergens in the serum of 20 neonates and infants using microarrays. The presence of PC-secreting IgG specific to the most prominent antigens was then assessed among thymocytes in the same cohort. Using an LC-MS proteomics approach, we looked for traces of these antigens in the thymus. RESULTS: Our studies first confirmed that cow's milk proteins are prevalent targets of serum IgG in early life. Subjects with the highest serum IgG titers to cow's milk proteins also harbored IgG-producing PCs specific to the same antigens in the thymic niche. Furthermore, we detected multiple peptide fragments of cow's milk antigens in the thymus. Lastly, we verified that both serum IgG and IgG secreted by thymic PCs recognized the peptide epitopes found in the thymus. CONCLUSIONS: Our studies reveal the presence of antibody-secreting PCs specific to common dietary antigens in the infant thymus. The presence of these antigens in the thymus suggested that activation and differentiation of specific PCs occurred in this organ. Further studies are now warranted to evaluate the possible implication of these cells in tolerance to dietary antigens.

Storage, preservation, and rehabilitation of living heart valves to treat congenital heart disease.

Heart valve disease patients undergo multiple surgeries to replace structurally degraded valve prostheses, highlighting the need for valve replacements with growth and self-repair capacity. Given allogeneic valve transplantation's promise in meeting these goals by delivering a living valve replacement, we propose a framework for preserving and rehabilitating living valves ex vivo.

Long-term autograft dilation and durability after the Ross procedure are similar in infants, children, and adolescents with primary aortic stenosis.

BACKGROUND: Autograft durability and remodeling are thought to be superior in younger pediatric patients after the Ross operation. We sought to delineate the fate of autografts across the pediatric age spectrum in patients with primary aortic stenosis (AS). METHODS: We retrospectively reviewed patients age ≤18 years with primary AS who underwent the Ross operation between 1993 and 2020. Patients were categorized by age. The primary endpoint was autograft dimensional change, and secondary endpoints were severe neo-aortic insufficiency (AI) and autograft reintervention. RESULTS: A total of 119 patients underwent the Ross operation, including 37 (31.1%) in group I (age <18 months), 24 (20.2%) in group II (age 18 months-8 years), and 58 (48.7%) in group III (age 8-18 years). All groups exhibited similar annular growth rates within the first 5 postoperative years, followed by a collective decrease in annulus growth rates from year 5 to year 10. Group III experienced rapid sinus dilation in the first 5 years, followed by stabilization of the sinus z-score from year 5 to year 10, whereas groups I and II demonstrated stable sinus z-scores over 10 years. There were 4 early deaths (3.4%) and 2 late deaths (1.7%) at a median follow-up of 8.1 years (range, 0.01-26.3 years). At 15 years, the incidences of severe neo-AI (0.0 ± 0.0% vs 0.0 ± 0.0% vs 3.9 ± 3.9%; P = .52) and autograft reintervention (8.4 ± 6.0% vs 0.0 ± 0.0% vs 2.4 ± 2.4%; P = .47) were similar in the 3 groups. CONCLUSIONS: Age at the time of Ross operation for primary AS does not influence long-term autograft remodeling or durability. Other physiologic or technical factors are likely greater determinants of autograft fate.

Rare coronary artery variants are associated with increased mortality and reinterventions following the arterial switch operation.

OBJECTIVE: To determine the influence of coronary anatomy on long-term outcomes of the arterial switch operation (ASO). METHODS: We retrospectively reviewed patients with transposition of the great arteries or Taussig-Bing anomaly who underwent ASO at our institution between 1992 and 2022. The primary endpoint was freedom from a composite of death, transplantation, and coronary reintervention. RESULTS: A total of 632 patients (median age, 5.0 days; interquartile range [IQR], 4.0-7.0 days) underwent ASO. Coronary anatomy included the following categories: usual (n = 411; 65%), circumflex (Cx) from sinus 2 (n = 89; 14%), inverted (n = 55; 9%), single sinus (n = 46; 7%), and intramural (n = 31; 5%). Overall operative mortality was 3% (n = 16) and highest in patients with intramural cardiac anatomy (n = 3; 10%), although it dropped to 0% in this group in the most recent decade. The median duration of follow-up was 14.5 years (IQR, 6.0-20.3 years). Twenty-year freedom from the primary endpoint was 95 ± 1% for usual anatomy, 99 ± 1% for Cx from sinus 2, 90 ± 4% for inverted, 91 ± 4% for single sinus, and 80 ± 9% for intramural (P < .001). Intramurals had the highest 20-year incidence of coronary reintervention (11 ± 8%). Cox modeling identified intraoperative coronary revision (hazard ratio [HR], 20.1; 95% confidence interval [CI], 9.4-53.9; P < .001), Taussig-Bing anomaly (HR, 4.9; 95% CI, 2.2-10.9; P < .001), and an intramural coronary artery (HR, 2.9; 95% CI, 1.0-8.2; P = .04) to be risk factors for the composite endpoint. CONCLUSIONS: Rare coronary artery variants-particularly intramural-are associated with increased mortality and coronary reinterventions after ASO. A low threshold for unroofing intramurals is likely associated with declining mortality and improved outcomes. Additional investigations are needed to determine the long-term fate of the coronary arteries after ASO.

Single ventricle palliation in congenitally corrected transposition of the great arteries: An international multicenter study.

BACKGROUND: Single ventricle palliation may be performed in patients with congenitally corrected transposition of the great arteries due to hypoplasia of 1 ventricle or anatomic complexity rendering biventricular repair unfeasible. There have been only a few small studies of the outcomes of single ventricle palliation in the setting of congenitally corrected transposition of the great arteries. METHODS: A multicenter, international, retrospective cohort study of patients with congenitally corrected transposition of the great arteries undergoing single ventricle palliation was conducted in 29 tertiary hospitals in 6 countries from 1990 to 2018. RESULTS: A total of 194 patients with congenitally corrected transposition of the great arteries underwent single ventricle palliation. A functionally univentricular heart was present in 62.4% (121/194). Patients with 2 good-sized ventricles had more laterality defects (50.7% vs 28.1%, P = .002). Fontan completion was achieved in 80.3% (155/194). A tricuspid valve surgery was performed in 9.3% (18/194). Survival was 97.4% (95% CI, 92.1-99.2) at 15 years in the univentricular cohort and 89.8% (95% CI, 78.0-95.5) at 15 years in those with 2 adequate ventricles (P = .05). At last follow-up, 11.5% of patients had heart failure, whereas 6.0% had moderate or greater systemic right ventricle dysfunction and 8.4% exhibited moderate or greater tricuspid regurgitation. In multivariable analysis, aortic coarctation or hypoplasia (hazard ratio, 7.7; P = .005) was associated with mortality. CONCLUSIONS: Single ventricle palliation in patients with congenitally corrected transposition of the great arteries is associated with excellent long-term survival and low rates of heart failure and atrioventricular valve failure. In patients who would require complex surgery to achieve a biventricular repair, single ventricle palliation appears to be a good alternative.

Designing Biocompatible Tissue Engineered Heart Valves In Situ: JACC Review Topic of the Week.

Valvular heart disease is a globally prevalent cause of morbidity and mortality, with both congenital and acquired clinical presentations. Tissue engineered heart valves (TEHVs) have the potential to radically shift the treatment landscape for valvular disease by functioning as life-long valve replacements that overcome the current limitations of bioprosthetic and mechanical valves. TEHVs are envisioned to meet these goals by functioning as bioinstructive scaffolds that guide the in situ generation of autologous valves capable of growth, repair, and remodeling within the patient. Despite their promise, clinical translation of in situ TEHVs has proven challenging largely because of the unpredictable and patient-specific nature of the TEHV and host interaction following implantation. In light of this challenge, we propose a framework for the development and clinical translation of biocompatible TEHVs, wherein the native valvular environment actively informs the valve's design parameters and sets the benchmarks by which it is functionally evaluated.

The Commando procedure for pediatric patients: A case series.

Objective: The Commando procedure involves division of the intervalvular fibrous body, mitral valve replacement, and aortic valve replacement. It is considered a technically challenging procedure and traditionally has had high mortality. Methods: Five pediatric patients with combined left ventricular inflow and outflow obstruction were included in this study. Results: There were no early or late deaths during follow-up, and no pacemakers were implanted. None of the patients required reoperation during follow-up, and none developed a clinically significant gradient across the mitral valve or aortic valve. Conclusions: The risks of this operation for patients with congenital heart disease undergoing multiple redo operations should be weighed against the benefits of normal-size mitral and aortic annular diameters and dramatically improved hemodynamics.

Aortic root translocation (Nikaidoh) procedure for complex transposition of the great arteries with left ventricular outflow tract obstruction.

Background: Several surgical techniques have been developed for the management of complex transposition of the great arteries with ventricular septal defect and left ventricular outflow tract obstruction (TGA/VSD/LVOTO). Aortic root translocation, or the Nikaidoh operation, offers the most anatomic biventricular repair in these patients. However, the Nikaidoh operation commonly has been limited to patients with "typical" anatomy, including a conoventricular VSD and usual coronary anatomy. We sought to describe a single surgeon's experience with aortic root translocation for complex TGA/VSD/LVOTO. Methods: We present a series of 12 patients with complex anatomy who underwent the Nikaidoh operation over the last 13 years. Results: We report good mid- to long-term results, excellent performance of the reconstructed left ventricular outflow tract, aortic valve competence, and no coronary insufficiency. Conclusions: Our experience suggests that the Nikaidoh operation is a valid option even for patients with complex TGA/VSD/LVOTO.

Outcomes of surgical management of Ebstein anomaly and tricuspid valve dysplasia in critically ill neonates and infants.

Objective: To describe the surgical outcomes in neonates and infants who had surgery for Ebstein anomaly (EA) and tricuspid valve dysplasia (TVD). Methods: Retrospective chart review for all patients who underwent surgery for EA or TVD during the index hospitalization after birth at our institution from January 2005 to February 2023. Results: Fifteen symptomatic neonates and infants who had surgery for EA or TVD were included, 8 with EA and 7 with TVD. Eleven patients (73%) and 3 patients (20%) required preoperative inotropes and extracorporeal membrane oxygenation, respectively. Nine patients (60%) had a Starnes procedure and 6 patients (40%) had tricuspid valve repair (TVr). Mortality at last follow-up was 27% overall (n = 4/15), 22% after Starnes (n = 2/9) and 33% after TVr (n = 2/6), without a significant difference despite a greater-risk profile in the Starnes group. Postoperative day 1 lactate level was associated with mortality on Cox regression (hazard ratio, 1.45; P = .01). Three of 9 patients who had a Starnes procedure were or will be converted to a cone repair (1.5/2-ventricle repair). Conclusions: Mortality after surgery for EA or TVD during the index hospitalization after birth is still significant in the current era and is associated with a greater lactate level at postoperative day 1. The Starnes procedure and TVr had comparable outcomes despite a greater-risk profile in the Starnes group. An initial single-ventricle approach does not preclude conversion to biventricular or 1.5-ventricle repair.

Transcatheter Cardiac Interventions in the Newborn: JACC Focus Seminar.

For neonates with critical congenital heart disease requiring intervention, transcatheter approaches for many conditions have been established over the past decades. These interventions may serve to stabilize or palliate to surgical next steps or effectively primarily treat the condition. Many transcatheter interventions have evidence-based records of effectiveness and safety, which have led to widespread acceptance as first-line therapies. Other techniques continue to innovatively push the envelope and challenge the optimal strategies for high-risk neonates with right ventricular outflow tract obstruction or ductal-dependent pulmonary blood flow. In this review, the most commonly performed neonatal transcatheter interventions will be described to illustrate the current state of the field and highlight areas of future opportunity.

Pericardial lymphangioma: a rare benign albeit variably symptomatic tumefactive lesion.

Primary pericardial-based tumefactive lesions include pericardial cysts, mature teratomas, and lymphangiomas, and while benign they may result in clinical symptomatology that leads to their radiologic detection. We present the case of a 5-year-old boy with a heart murmur who was otherwise healthy and without significant medical history. Transthoracic echocardiogram, computed tomography, and magnetic resonance imaging studies revealed a pericardial multicystic mass imparting compression upon the right atrium and ventricle. The case proceeded to surgery in which complete resection of the mass was performed without complication, and the patient was discharged three days after. Pathology examination of the lesion determined it to be a pericardial lymphangioma with characteristic histologic features of sequestered vascular channels lined by endothelium that specifically expressed lymphatic-specific podoplanin (also known as D2-40), and with associated adipose tissue, smooth muscle bundles, and reactive lymphoid aggregates. Although a rare underlying etiology for mediastinal and specifically pericardial tumors, lymphangiomas should be considered in the differential of tumefactive lesions in this anatomic location.

Familial Recurrence Patterns in Congenitally Corrected Transposition of the Great Arteries: An International Study.

BACKGROUND: Congenitally corrected transposition of the great arteries (ccTGA) is a rare disease of unknown cause. We aimed to better understand familial recurrence patterns. METHODS: An international, multicentre, retrospective cohort study was conducted in 29 tertiary hospitals in 6 countries between 1990 and 2018, entailing investigation of 1043 unrelated ccTGA probands. RESULTS: Laterality defects and atrioventricular block at diagnosis were observed in 29.9% and 9.3%, respectively. ccTGA was associated with primary ciliary dyskinesia in 11 patients. Parental consanguinity was noted in 3.4% cases. A congenital heart defect was diagnosed in 81 relatives from 69 families, 58% of them being first-degree relatives, including 28 siblings. The most prevalent defects in relatives were dextro-transposition of the great arteries (28.4%), laterality defects (13.6%), and ccTGA (11.1%); 36 new familial clusters were described, including 8 pedigrees with concordant familial aggregation of ccTGA, 19 pedigrees with familial co-segregation of ccTGA and dextro-transposition of the great arteries, and 9 familial co-segregation of ccTGA and laterality defects. In one family co-segregation of ccTGA, dextro-transposition of the great arteries and heterotaxy syndrome in 3 distinct relatives was found. In another family, twins both displayed ccTGA and primary ciliary dyskinesia. CONCLUSIONS: ccTGA is not always a sporadic congenital heart defect. Familial clusters as well as evidence of an association between ccTGA, dextro-transposition of the great arteries, laterality defects and in some cases primary ciliary dyskinesia, strongly suggest a common pathogenetic pathway involving laterality genes in the pathophysiology of ccTGA.

The Ross procedure in children: a systematic review.

BACKGROUND: The Ross procedure involves autograft transplantation of the native pulmonary valve into the aortic position and reconstruction of the right ventricular outflow tract (RVOT) with a homograft. The operation offers the advantages of a native valve with excellent hemodynamic performance, the avoidance of anticoagulation, and growth potential. Conversely, the operation is technically demanding and imposes the risk of turning single-valve disease into double-valve disease. This systematic review reports outcomes of pediatric patients undergoing the Ross procedure. METHODS: An electronic search identified studies reporting outcomes on pediatric patients (mean age <18 years, max age <21 years) undergoing the Ross procedure. Long-term outcomes, including early mortality, late mortality, sudden unexpected unexplained death, reoperation due to failure of the pulmonary autograft or RVOT reconstruction, thromboembolic events, bleeding events, and endocarditis-related complications, were evaluated. RESULTS: Upon review of 2,035 publications, 30 studies and 3,156 pediatric patients were included. Patients had a median age of 9.5 years and median follow-up period of 5.7 years. Early mortality rates varied from 0.0 to 17.0% and were increased in the neonatal population. Late mortality rates were much lower (0.04-1.83%/year). Reoperation due to pulmonary autograft failure occurred at rates of 0.37-2.81%/year and reoperation due to RVOT reconstruction failure was required at rates of 0.34-4.76%/year. Thromboembolic, bleeding, and endocarditis events were reported to occur at rates of 0.00-0.58, 0.00-0.39, and 0.00-1.68%/year, respectively. CONCLUSIONS: The Ross operation offers a durable aortic valve replacement (AVR) option in the pediatric population that offers favorable survival, excellent hemodynamics, growth potential, decreased risk of complications, and avoidance of anticoagulation. Larger multi-institutional registries focusing on pediatric patients are necessary to provide more robust evidence to further support use of the Ross procedure in this population.

Intrathymic differentiation of natural antibody-producing plasma cells in human neonates.

The thymus is a central lymphoid organ primarily responsible for the development of T cells. A small proportion of B cells, however, also reside in the thymus to assist negative selection of self-reactive T cells. Here we show that the thymus of human neonates contains a consistent contingent of CD138+ plasma cells, producing all classes and subclasses of immunoglobulins with the exception of IgD. These antibody-secreting cells are part of a larger subset of B cells that share the expression of signature genes defining mouse B1 cells, yet lack the expression of complement receptors CD21 and CD35. Data from single-cell transcriptomic, clonal correspondence and in vitro differentiation assays support the notion of intrathymic CD138+ plasma cell differentiation, alongside other B cell subsets with distinctive molecular phenotypes. Lastly, neonatal thymic plasma cells also include clones reactive to commensal and pathogenic bacteria that commonly infect children born with antibody deficiency. Thus, our findings point to the thymus as a source of innate humoral immunity in human neonates.

Arterial switch for transposition with left outflow tract obstruction: outcomes and risk analysis.

BACKGROUND: The long-term results and indications of the arterial switch operation (ASO) for transposition of the great arteries (TGA) and anatomic left ventricular outflow tract obstruction (LVOTO) remain undetermined. The aims of this study were to determine long-term outcomes and prognostic factors in this specific population. METHODS: Between 1986 and 2011, 55 patients with TGA and anatomic LVOTO underwent ASO. Anatomic LVOTO was defined as an echocardiographic peak LVOT gradient exceeding 20 mm Hg associated with an anatomic narrowing. Forty-three patients had a ventricular septal defect. Median follow-up was 7.9 ± 6.5 years (maximum, 25 years). Univariate and multivariate risk analyses for late LVOTO, aortic regurgitation, LVOT reintervention, and death were performed. RESULTS: The early mortality rate was 11% (n = 6); 2 deaths were LVOTO-related. At the latest follow-up, 3 patients (5%) had a LVOTO, 7 (13%) had moderate aortic regurgitation, and 4 (7%) had LVOT reoperation. Actuarial freedom from LVOT reoperation was 90% ± 5% at 10 and 15 years. The mean LVOT peak gradient was 3 ± 9 mm Hg at the latest follow-up. A preoperative pulmonary valve z-score of less than -1.7 (odds ratio, 19; p = 0.02) and an atrioventricular valve-related LVOTO (odds ratio, 15; p = 0.02) are independent predictors of recurrent LVOTO. A preoperative pulmonary valve z-score of less than -1.8 is an independent predictor of LVOT reoperation (odds ratio, 17; p = 0.03). The LVOT gradient per se and the presence of ventricular septal defect or a bicuspid valve do not influence outcomes. CONCLUSIONS: Long-term outcomes of ASO for patients with TGA and anatomic LVOTO are satisfactory in selected patients. A lower preoperative pulmonary valve z-score and complex multilevel atrioventricular valve-related LVOTO are independent predictors of recurrent LVOTO and LVOT reoperation. TGA/LVOTO patients with pulmonary valve z-score exceeding -1.8 and resectable valvular or subvalvular LVOTO, or both, should be candidates for ASO, regardless of the severity of the LVOT peak gradient.

Tetralogy of Fallot with an abnormal coronary artery: surgical options and prognostic factors.

OBJECTIVES: The objectives were to determine in patients with Tetralogy of Fallot (ToF) and abnormal coronary artery (ACA): the long-term outcomes of different surgical strategies; the risk factors for right ventricular outflow tract (RVOT) obstruction, reoperation, heart failure and mortality. To date, the surgical strategies and prognostic factors for repair of ToF with an ACA, crossing the RVOT and avoiding a classic repair, have not been evaluated in a large series using a multivariate analysis. METHODS: A retrospective study (1986-2011) included 72 patients. The mean follow-up was 9.6 ± 6.8 years. Median age at surgery was 1.5 years (0.2-11.3). The main surgical techniques were 'tailored' right ventriculotomy and patch of the RVOT (63%; n = 45), implantation of a conduit between the right ventricle (RV) and the pulmonary artery (PA; 25%; n = 18) and a transatrial ± transpulmonary approach (11%; n = 8). Univariate and multivariate logistic regression analyses were performed. RESULTS: Intrahospital mortality was 2.7%. Actuarial freedom from reoperation and actuarial survival at 15 years were 77% (confidence interval [CI]: 70-83%) and 94% (CI: 90-97%), respectively. Reoperations occurred more frequently after conduit implantation (50%) than after patch reconstruction (17%) or transatrial ± transpulmonary approach (0%; P = 0.002). The transatrial ± transpulmonary approach was significantly less complicated, with a long-term RVOT obstruction of 0% compared with the other surgical techniques (45.4%; P = 0.03). Implantation of a RV-PA conduit was an independent risk factor for RVOT obstruction (odds ratio [OR]: 31; P < 0.001) and reoperation (OR: 20; P = 0.02). An immediate postoperative right ventricle/left ventricle (RV/LV) pressure ratio >0.5 was independently associated with a long-term RV/LV pressure ratio >0.5 (OR: 14; P = 0.001), but was not a risk factor for reoperation (P = 0.8). Postoperative electric ischaemic signs independently increased the risk of long-term heart failure (OR: 22; P = 0.04). CONCLUSIONS: The transatrial ± transpulmonary approach displays the best long-term outcomes, by reducing the risks for RVOT obstruction and reoperation, but does not improve the patient survival. A RV-PA conduit was an independent risk factor for RVOT obstruction and reoperation. An immediate postoperative RV/LV pressure ratio >0.5 was not a risk factor for reoperation. The transatrial ± transpulmonary approach should be preferred to the implantation of a conduit or a tailored right ventriculotomy whenever possible.