The Macrophage Landscape Across the Lifespan of a Human Cardiac Allograft.

BACKGROUND: Much of our knowledge of organ rejection after transplantation is derived from rodent models. METHODS: We used single-nucleus RNA sequencing to investigate the inflammatory myocardial microenvironment in human pediatric cardiac allografts at different stages after transplantation. We distinguished donor- from recipient-derived cells using naturally occurring genetic variants embedded in single-nucleus RNA sequencing data. RESULTS: Donor-derived tissue resident macrophages, which accompany the allograft into the recipient, are lost over time after transplantation. In contrast, monocyte-derived macrophages from the recipient populate the heart within days after transplantation and form 2 macrophage populations: recipient MP1 and recipient MP2. Recipient MP2s have cell signatures similar to donor-derived resident macrophages; however, they lack signatures of pro-reparative phagocytic activity typical of donor-derived resident macrophages and instead express profibrotic genes. In contrast, recipient MP1s express genes consistent with hallmarks of cellular rejection. Our data suggest that recipient MP1s activate a subset of natural killer cells, turning them into a cytotoxic cell population through feed-forward signaling between recipient MP1s and natural killer cells. CONCLUSIONS: Our findings reveal an imbalance of donor-derived and recipient-derived macrophages in the pediatric cardiac allograft that contributes to allograft failure.

Long-term implantable ventricular assist device support in children.

BACKGROUND: In pediatrics, implantable continuous-flow ventricular assist devices (IC-VAD) are often used as a "temporary" support, bridging children to cardiac transplantation during the same hospital admission. METHODS: We conducted a retrospective review of our consecutive patients undergoing IC-VAD support at a tertiary pediatric heart center between 2008 and 2022. RESULTS: We identified 100 IC-VAD implant encounters: HeartWare HVAD (67; 67%), HeartMate II (17; 17%), and HeartMate 3 (16; 16%). The median (range) age, weight, and body surface area at implantation were 14.1 (3.0-56.5) years, 54.8 (13.3-140) kg, and 1.6 (0.6-2.6) m2, respectively. Cardiomyopathy (58; 58%) was the most common etiology, followed by congenital heart disease (37; 37%, including 13 single ventricle). At 6 months of IC-VAD support, 94 (94%) encounters achieved positive outcomes: ongoing support (59; 59%), transplant (33; 33%), and cardiac recovery (2; 2%). Eighty-two encounters (82%) resulted in home discharge with ongoing VAD support, including 38 (46%, out of 82) requiring readmission and 7 (9%, out of 82) resulting in death. There was a clinically significant decrease in morbidity rates before versus after home discharge: bleeding (1.55 vs 0.06), infection (0.84 vs 0.37), and stroke (0.84 vs 0.15 event per patient-year). Overall, 86 encounters (86%) reached positive end points at the latest follow-up (64 transplant, 15 ongoing support, and 7 recovery). Infection (29%; 4 of 14) was the most common cause of negative outcomes, followed by cerebrovascular accident (21%; 3), and unresolved frailty (21%; 3). The estimated overall survival at 1, 2, and 5 years was 90%, 86%, and 77%, respectively. CONCLUSIONS: This study suggests the feasibility of outpatient management of pediatric IC-VAD support. The ability to offer true long-term support maximizes the potential of IC-VAD support, not limited to a temporary bridging tool for heart transplantation.

The Congenital Heart Surgeons' Society Kirklin/Ashburn Fellowship: The Fellows' Perspective.

Since its establishment in 2001, the Congenital Heart Surgeons' Society John W. Kirklin/David Ashburn Fellowship has contributed substantially to the field of congenital heart surgery research while simultaneously training the next generation of surgeon- scientists. To date, ten fellows (and counting) have successfully completed this rigorous training, producing over 40 published articles focused on longitudinal outcomes from the various Congenital Heart Surgeons' Society cohorts. As the Kirklin/Ashburn Fellowship expands and additional fellows matriculate, its legacy, the network of support, and the contribution to congenital heart surgery research will undoubtedly hold strong.

Continuous-Flow Ventricular Assist Device Support in Adult Congenital Heart Disease: A 15-Year, Multicenter Experience of Temporary and Durable Support.

Heart failure (HF) is common in adult congenital heart disease (ACHD) patients; however, use of continuous-flow ventricular assist devices (CF-VADs) remains rare. We reviewed outcomes of patients with congenital heart disease greater than or equal to 18 years of age at the time of CF-VAD implant at the affiliated pediatric and adult institutions between 2006 and 2020. In total, 18 ACHD patients (15 with great anatomical complexity) received 21 CF-VADs. Six patients (median age 34 years) received seven percutaneous CF-VADs with a median duration of support of 20 days (3-44 days) with all patients survived to hospital discharge and two patients were bridged to durable CF-VADs. Fourteen patients (median age 38 years) received durable CF-VADs. Thirteen patients (93%) survived to hospital discharge and the median duration of support was 25.8 months (6.4-52.1 months). Estimated survival on durable CF-VAD at 1, 3, and 5 years was 84%, 72%, and 36%, respectively. Three patients were successfully bridged to transplantation. Device-related complications include cerebrovascular accident (n = 5), driveline infection (n = 3), device infection requiring chronic antibiotic therapy (n = 4), gastrointestinal bleeding (n = 6), and presumed pump thrombosis (n = 5). These results show percutaneous and durable CF-VADs can support ACHD patients with advanced HF.

Retrograde cerebral perfusion for intracardiac air embolism in Fontan procedure.

We report the case of a 5-year-old boy who suffered from an intracardiac air influx with suspected cerebral air embolism during the Fontan procedure. We immediately transformed the cardiopulmonary bypass circuit to perform a retrograde cerebral perfusion, which resulted in successful neuroprotection. He was extubated in the operating room without any neurological defects.

Organizational Culture as a Determinant of Outcome in Teams: Implications for the Pediatric Cardiac Specialist.

Although enormous effort has focussed on how to build an effective culture in the business community, relatively little effort has addressed how to achieve this in the hospital environment, specifically related to the field of congenital heart disease teams. The examination of culture in pediatric cardiac care is particularly important for several key reasons: first, it represents high-stakes medicine, second, there are multiple stakeholders requiring collaboration between cardiologists, surgeons, anaesthesiologists, perfusionists, nursing staff, and allied health care professionals, and finally, both the patient and the family are intimately involved in the care pathway. This review article investigates some of the critical components to building an effective culture, drawing upon similarities in other disciplines, thereby fostering high performance multidisciplinary teams in congenital cardiology care. Strategies to change culture such as Kotter's model of change are also discussed. High performance teams share one common vital characteristic: psychological safety for team members to speak their minds, thereby fostering an open culture, in which creativity can flourish to facilitate major breakthroughs. Adoption of the "Flight Plan" review promotes patient centric care and champions a psychologically safe culture.

Total anomalous pulmonary venous connection: Influence of heterotaxy and venous obstruction on outcomes.

BACKGROUND: Previous studies have demonstrated increased early mortality and pulmonary vein reintervention for patients with total anomalous pulmonary venous connection (TAPVC) and heterotaxy syndrome (HTX+) compared with patients with TAPVC without heterotaxy syndrome (HTX-). We aimed to evaluate the longitudinal risk of pulmonary vein reintervention and mortality in HTX + patients. METHODS: A retrospective review was performed to identify longitudinal interventions in patients with TAPVC seen at a single center from 1995 to 2019. The mean cumulative interventions were described for all patients using the Nelson-Aalen estimator. Survival with TAPVC was described using Kaplan-Meier estimates. RESULTS: A total of 336 patients were identified with TAPVC, of whom 118 (35%) had heterotaxy syndrome. Functional single ventricles were identified in 106 of these 118 HTX + patients (90%) and in 14 of 218 HTX- patients (6%) (P < .001). Obstructed TAPVC (OBS+) was present in 49 of 118 HTX + patients (42%) and in 87 of 218 HTX- patients (40%) (P = .89). The median duration of follow-up was 6.5 years. Five-year survival was 69% for HTX+/OBS + patients, 72% for HTX+/OBS- patients, 86% for HTX-/OBS + patients, and 95% for HTX-/OBS- patients (P < .0001, log-rank test). The mean number of pulmonary vein interventions at the median follow-up time was greater in the HTX+/OBS + patients compared with HTX+/OBS- patients (mean, 2.0 vs 1.1; P = .030), HTX-/OBS + patients (mean, 1.3; P = .033), and HTX-/OBS- patients (mean, 1.3; P = .029). CONCLUSIONS: Among the 4 cohorts, HTX+ was associated with a higher rate of mortality, and HTX+/OBS+ was associated with a greater number of pulmonary vein interventions. This may be due in part to the high prevalence of single ventricle physiology in the HTX + cohort.

Outcomes in Young Adults With Tetralogy of Fallot and Pulmonary Annular Preserving or Transannular Patch Repairs.

BACKGROUND: Early surgical tetralogy of Fallot (ToF) repair involved patching across the pulmonic annulus (transannular patch [TAP] repair), which resulted in severe pulmonic regurgitation. Long-term outcome improvements were anticipated with modifications that preserved the pulmonic annulus (annulus-preserving [AP] repair). The objective of the present study was to evaluate the need for late reintervention in adults with AP repair and those with TAP repair. METHODS: We conducted a retrospective review of adults (born 1981-1996) with childhood intracardiac ToF repairs at a tertiary care center. The primary cardiovascular outcome was need for reintervention after primary intracardiac repair of ToF. Secondary outcomes included a composite of death, heart failure, and ventricular arrhythmias. RESULTS: Two hundred thirty adults were included: 104 with AP repair and 126 with TAP repair. The median age at last follow up was 25 years (interquartile range [IQR] 20-28) and the median follow-up duration was 7.9 years (IQR 3.5-12). Reintervention of any type was significantly more common in the TAP group during both childhood and adulthood (72.2% TAP vs 20.2% AP, HR 5.5, 95% CI 3.4-9.0; P < 0.001). Pulmonary valve replacement (PVR) was almost 6 times more likely in adults with TAP repair (65.1% TAP vs 16.3% AP, HR 5.7, 95% CI 3.4-9.7; P < 0.001). CONCLUSIONS: Patients who had AP ToF repair had significantly fewer late reinterventions compared with TAP repair, with the majority of reinterventions due to PVR. More long-term follow-up is required.

Tricuspid Intervention Following Pulmonary Valve Replacement in Adults With Congenital Heart Disease.

BACKGROUND: Tricuspid regurgitation (TR) is common among adults with corrected tetralogy of Fallot (TOF) or pulmonary stenosis (PS) referred for pulmonary valve replacement (PVR). Yet, combined valve surgery remains controversial. OBJECTIVES: This study sought to evaluate the impact of concomitant tricuspid valve intervention (TVI) on post-operative TR, length of hospital stay, and on a composite endpoint consisting of 7 early adverse events (death, reintervention, cardiac electronic device implantation, infection, thromboembolic event, hemodialysis, and readmission). METHODS: The national Canadian cohort enrolled 542 patients with TOF or PS and mild to severe TR who underwent isolated PVR (66.8%) or PVR+TVI (33.2%). Outcomes were abstracted from charts and compared between groups using multivariable logistic and negative binomial regression. RESULTS: Median age at reintervention was 35.3 years. Regardless of surgery type, TR decreased by at least 1 echocardiographic grade in 35.4%, 66.9%, and 92.8% of patients with pre-operative mild, moderate, and severe insufficiency. In multivariable analyses, PVR+TVI was associated with an additional 2.3-fold reduction in TR grade (odds ratio [OR]: 0.44; 95% confidence interval [CI]: 0.25 to 0.77) without an increase in early adverse events (OR: 0.85; 95% CI: 0.46 to 1.57) or hospitalization time (incidence rate ratio: 1.17; 95% CI: 0.93 to 1.46). Pre-operative TR severity and presence of transvalvular leads independently predicted post-operative TR. In contrast, early adverse events were strongly associated with atrial tachyarrhythmia, extracardiac arteriopathy, and a high body mass index. CONCLUSIONS: In patients with TOF or PS and significant TR, concomitant TVI is safe and results in better early tricuspid valve competence than isolated PVR.

Heart Failure in Adult Congenital Heart Disease: From Advanced Therapies to End-of-Life Care.

There is mounting recognition that some of the most urgent problems of adult congenital heart disease (ACHD) are the prevention, diagnosis, and management of heart failure (HF). Recent expert consensus and position statements not only emphasize a specific and pressing need to tackle HF in ACHD (ACHD-HF) but also highlight the difficulty of doing so given a current sparsity of data. Some of the challenges will be addressed by this review. The authors are from 3 different centres; each centre has an established subspeciality ACHD-HF clinic and is able to provide heart transplant, multiorgan transplant, and mechanical support for patients with ACHD. Appropriate care of this complex population requires multidisciplinary ACHD-HF teams evaluate all possible treatment options. The risks and benefits of nontransplant ACHD surgery, percutaneous structural and electrophysiological intervention, and ongoing conservative management must be considered alongside those of transplant strategies. In our approach, advanced care planning and palliative care coexist with the consideration of advanced therapies. An ethos of shared decision making, guided by the patient's values and preferences, strengthens clinical care, but requires investment of time as well as skilled communication. In this review, we aim to offer practical real-world advice for managing these patients, supported by scientific data where it exists.

Anomalous origins of the coronary arteries: current knowledge and future perspectives.

PURPOSE OF REVIEW: The purpose of this review is to survey the contemporary literature surrounding congenital anomalies of origin of the coronary arteries and to identify remaining gaps in knowledge. RECENT FINDINGS: In recent years, lineage tracing analyses and mechanistic studies in model organisms have enhanced our understanding of the normal embryologic development of the coronary arteries, and how disruption of this intricate process can lead to congenital coronary anomalies. The true incidence of these anomalies remains unknown. Although a majority of cases are believed to be clinically silent, clinical presentation varies widely, from asymptomatic to sudden cardiac death. Cardiac computed tomography angiography and/or magnetic resonance angiography are the mainstay diagnostic modalities. Management of anomalous coronary arteries depends on the morphology and clinical presentation. Surgery is the gold-standard treatment for anomalous left coronary artery arising from the pulmonary artery and anomalous aortic origin of a coronary artery with intramural or interarterial course. SUMMARY: Several large multicenter initiatives are currently underway and should help address some of the numerous knowledge gaps surrounding the evaluation and management of anomalous coronary arteries.

Pulmonary hypertension in patients with a subaortic right ventricle: prevalence, impact and management.

OBJECTIVE: This study sought to determine the prevalence, predictors, prognostic relevance and evolution of pulmonary hypertension (PH) (mean pulmonary artery pressure ≥25 mm Hg) in adult patients with a subaortic right ventricle (RV) in a biventricular circulation (2V-RV). METHODS: We analysed retrospective data from patients with 2V-RV undergoing cardiac catheterisation in our centre between 2000 and 2018. Echocardiographic assessment of subpulmonary ventricular pressures (left ventricular systolic pressure (LVSP)), age and B-type natriuretic peptide (BNP) were assessed as PH screening tools. Kaplan-Meier curves examined time to a composite outcome of death, transplant or ventricular assist device (VAD). Data from repeat catheterisations were analysed to evaluate PH changes over time, including the effects of therapy. RESULTS: A total of 141 patients (median age 39 (IQR 33-45) years, 68% men) underwent 191 cardiac catheterisations. At baseline, 55% had PH (isolated postcapillary 24%, combined precapillary and postcapillary 26% and precapillary 5%). BNP (area under the curve 0.80; 95% CI 0.72 to 0.88; p<0.0001), but not age at catheterisation or echocardiographic estimates of LVSP were associated with the presence of PH. The absence of PH and BNP <100 pg/mL discriminated a subgroup at very low risk during short-term (2.5 (1.3-3.9) years) follow-up (p<0.0001). Diuretics, milrinone and VAD improved haemodynamics over time. CONCLUSION: PH is prevalent in patients with 2V-RV even when asymptomatic. It is difficult to identify by echocardiography and most importantly, is strongly associated with adverse outcomes. PH affects prognosis and transplant options for this patient group and yet is often amenable to treatment. Awareness of these results ought to lower the threshold for invasive haemodynamic assessment and may change the management of failing patients with 2V-RV.

Associations Between Age at Arterial Switch Operation, Brain Growth, and Development in Infants With Transposition of the Great Arteries.

BACKGROUND: Brain injury, impaired brain growth, and long-term neurodevelopmental problems are common in children with transposition of the great arteries. We sought to identify clinical risk factors for brain injury and poor brain growth in infants with transposition of the great arteries undergoing the arterial switch operation, and to examine their relationship with neurodevelopmental outcome. METHODS: The brains of 45 infants with transposition of the great arteries undergoing surgical repair were imaged pre- and postoperatively using magnetic resonance imaging. Brain weight z scores were calculated based on brain volume and autopsy reference data. Brain injury scores were determined as previously described. Neurodevelopment was assessed at 18 months using the Bayley-III scores of infant development. The relationships between clinical variables, brain injury, perioperative brain growth, and 18-month Bayley-III scores were analyzed. RESULTS: On preoperative imaging, moderate or severe white matter injury was present in 10 of 45 patients, whereas stroke was seen in 4 of 45. A similar prevalence of injury was seen on postoperative imaging, and we were unable to identify any clinical risk factors for brain injury. Brain weight z scores decreased perioperatively in 35 of 45 patients. The presence of a ventricular septal defect ( P=0.009) and older age at surgery ( P=0.007) were associated with impaired perioperative brain growth. When patients were divided into those undergoing surgery during the first 2 weeks of life (32/45) versus those being repaired later (13/45), infants repaired later had significantly worse perioperative brain growth (late repair postoperative brain weight z = -1.0±0.90 versus early repair z = -0.33±0.64; P=0.008). Bayley-III testing scores fell within the normal range for all patients, although age at repair ( P=0.03) and days of open chest ( P=0.03) were associated with a lower composite language score, and length of stay was associated with a lower composite cognitive score ( P=0.02). CONCLUSIONS: Surgery beyond 2 weeks of age is associated with impaired brain growth and slower language development in infants with transposition of the great arteries cared for at our center. Although the mechanisms underlying this association are still unclear, extended periods of cyanosis and pulmonary overcirculation may adversely impact brain growth and subsequent neurodevelopment.

Anticoagulation therapy and the risk of perioperative brain injury in neonates with congenital heart disease.

OBJECTIVE: There is considerable variability in anticoagulation use in neonates with transposition of the great arteries (TGA) and single ventricle physiology (SVP) for secondary stroke prevention and primary cardiovascular indications. Leveraging cross-center differences in anticoagulation use, we compared the risk of new postoperative brain injury in neonates with TGA and SVP treated with anticoagulation relative to untreated neonates. METHODS: Two-center observational cohort study of 118 term-born neonates with TGA (n = 83) and SVP (n = 35), undergoing cardiopulmonary bypass surgery and pre- and postoperative brain magnetic resonance imaging. Anticoagulation and antiplatelet therapy details were obtained. Magnetic resonance images were scored for stroke, white matter injury, and hemorrhage. New postoperative injury was compared between neonates with and without anticoagulation for the 2-center cohort, and subsequently stratified by cardiac lesion type and anticoagulation indication. RESULTS: Thirty-six out of 118 neonates (29%) received anticoagulation: 11 (30%) for preoperative stroke, 20 (56%) for preoperative peripheral/intracardiac thrombus, and 5 (14%) for Blalock-Taussig shunt. Five out of 36 neonates (14%) treated with anticoagulation also received antiplatelet therapy. Although no differences were identified for the 2-center cohort or for neonates with TGA separately, significantly more new postoperative parenchymal brain injury (P = .04), particularly stroke, was found in SVP neonates with compared to without anticoagulation (31% vs 5%). In neonates who experienced preoperative stroke, new subdural hemorrhage (36% vs 0%) was more frequent in neonates treated with anticoagulation therapy compared with those without anticoagulation therapy. CONCLUSIONS: In our cohort of neonates with TGA and SVP, anticoagulation for preoperative stroke, preoperative thrombus, and/or Blalock-Taussig shunt did not have the anticipated benefit of preventing new perioperative brain injury. These findings indicate the critical need for rigorous randomized trials on the safety and effectiveness of anticoagulation therapy in this population.

Right ventricular fibrosis is associated with cardiac remodelling after pulmonary valve replacement.

OBJECTIVE: The relationship between right ventricular (RV) fibrosis and right heart reverse remodelling following pulmonary valve replacement (PVR) has not been well studied in adults with repaired tetralogy of Fallot (rTOF). Our aims were to histologically quantify RV fibrosis and to explore the relationship between fibrosis severity and cardiac remodelling post-PVR. METHODS: Adults with rTOF and pre-PVR cardiovascular (CMR) imaging were consented to procurement of RV muscle during PVR. Samples were stained with picrosirius red to quantify collagen volume fraction. Clinical data at baseline and at last follow-up were reviewed. Adverse cardiovascular outcomes included death, sustained arrhythmia and heart failure. RESULTS: Fifty-three patients (male 58%, 38±11 years) were studied. Those with severe fibrosis (collagen volume fraction >11.0%, n=13) had longer aortic cross-clamp times at initial repair compared with the remainder of the population (50 vs 33 min, p=0.018) and increased RV mass:volume ratio pre-PVR (0.20 vs 0.18 g/mL, p=0.028). Post-PVR, the severe fibrosis group had increased indexed RV end-systolic volume index (RVESVi) (74 vs 66 mL/m2, p=0.044), decreased RVESVi change (Δ29 vs Δ45 mL/m2, p=0.005), increased RV mass (34 vs 25 g/m2, p=0.023) and larger right atrial (RA) area (21 vs 17 cm2, p=0.021). A trend towards increased heart failure events was observed in the severe fibrosis group (15% vs 0%, p=0.057). CONCLUSIONS: Severe RV fibrosis was associated with increased RVESVi, RV mass and RA area post-PVR in rTOF. Further study is required to define the impact of fibrosis and persistent right heart enlargement on clinical outcomes.

Phenotype, management and predictors of outcome in a large cohort of adult congenital heart disease patients with heart failure.

OBJECTIVE: Although heart failure (HF) is the leading cause of premature death in adult congenital heart disease (ACHD), little population-specific data exist. This study reports early experience from a dedicated, sub-specialty adult congenital heart disease-heart failure (ACHD-HF) clinic, aiming to identify risk factors for adverse outcome. METHODS: Between 2012 and 2015, 126 patients (57% male) attended the ACHD-HF clinic. Baseline and follow-up data were analysed and compared across 4 anatomical/physiological subgroups: cyanotic ACHD, Fontan circulation (1V), biventricular circulation with a subaortic right ventricle (2V-RV) and biventricular circulation with a subaortic left ventricle (2V-LV). Predictors of the composite primary outcome: death, transplant or ventricular assist device (VAD) were identified using multivariable Cox proportional hazard models. RESULTS: Mean age at first visit was 38±13years. Patients were grouped as follows: cyanotic ACHD 10%, 1V 24%, 2V-RV 29% and 2V-LV 37%. During a median follow-up of 1.7 (IQR 0.8-2.9) years, 38 patients (30%) reached the primary outcome. Event-free survival was 89%, 78% and 63% at 1, 2 and 3years. Forty (31.7%) patients experienced 69 HF hospitalisations. Between-group differences were noted for systolic function, valvular regurgitation, pacing prevalence and invasive hemodynamics. Multivariable analysis revealed 2V-RV subgroup (p=0.001), NYHA class (p=0.002) B-type natriuretic peptide >164pg/ml (p=0.003) and sodium <136mmol/L (p=0.036) as independently associated with death, transplant or VAD. CONCLUSIONS: Our young ACHD-HF patients experienced high adverse event rates during a short period of follow-up. The prognostic markers identified will aid clinicians to stratify short-term risk and thereby guide advanced HF management decisions in ACHD.