Integrated multi-omic characterization of congenital heart disease.

The heart, the first organ to develop in the embryo, undergoes complex morphogenesis that when defective results in congenital heart disease (CHD). With current therapies, more than 90% of patients with CHD survive into adulthood, but many suffer premature death from heart failure and non-cardiac causes1. Here, to gain insight into this disease progression, we performed single-nucleus RNA sequencing on 157,273 nuclei from control hearts and hearts from patients with CHD, including those with hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot, two common forms of cyanotic CHD lesions, as well as dilated and hypertrophic cardiomyopathies. We observed CHD-specific cell states in cardiomyocytes, which showed evidence of insulin resistance and increased expression of genes associated with FOXO signalling and CRIM1. Cardiac fibroblasts in HLHS were enriched in a low-Hippo and high-YAP cell state characteristic of activated cardiac fibroblasts. Imaging mass cytometry uncovered a spatially resolved perivascular microenvironment consistent with an immunodeficient state in CHD. Peripheral immune cell profiling suggested deficient monocytic immunity in CHD, in agreement with the predilection in CHD to infection and cancer2. Our comprehensive phenotyping of CHD provides a roadmap towards future personalized treatments for CHD.

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 kidney outcomes in pediatric continuous-flow ventricular assist device patients.

BACKGROUND: Continuous-flow ventricular assist devices (CF-VADs) are used increasingly in pediatric end-stage heart failure (ESHF) patients. Alongside common risk factors like oxidant injury from hemolysis, non-pulsatile flow constitutes a unique circulatory stress on kidneys. Post-implantation recovery after acute kidney injury (AKI) is commonly reported, but long-term kidney outcomes or factors implicated in the evolution of chronic kidney disease (CKD) with prolonged CF-VAD support are unknown. METHODS: We studied ESHF patients supported > 90 days on CF-VAD from 2008 to 2018. The primary outcome was CKD (per Kidney Disease Improving Global Outcomes (KDIGO) criteria). Secondary outcomes included AKI incidence post-implantation and CKD evolution in the 6-12 months of CF-VAD support. RESULTS: We enrolled 134 patients; 84/134 (63%) were male, median age was 13 [IQR 9.9, 15.9] years, 72/134 (54%) had preexisting CKD at implantation, and 85/134 (63%) had AKI. At 3 months, of the 91/134 (68%) still on a CF-VAD, 34/91 (37%) never had CKD, 13/91 (14%) developed de novo CKD, while CKD persisted or worsened in 49% (44/91). Etiology of heart failure, extracorporeal membrane oxygenation use, duration of CF-VAD, AKI history, and kidney replacement therapy were not associated with different CKD outcomes. Mortality was higher in those with AKI or preexisting CKD. CONCLUSIONS: In the first multicenter study to focus on kidney outcomes for pediatric long-term CF-VAD patients, preimplantation CKD and peri-implantation AKI were common. Both de novo CKD and worsening CKD can happen on prolonged CF-VAD support. Proactive kidney function monitoring and targeted follow-up are important to optimize outcomes.

Labyrinthine cor triatriatum sinister in fetal hypoplastic left heart syndrome is associated with poor outcomes.

OBJECTIVES: A subset of hypoplastic-left-heart-syndrome (HLHS) fetuses have a complex cor-triatriatum sinister that we named "labyrinthine-cor (L-cor)". We sought to determine the prevalence of L-cor in HLHS fetuses and hypothesized that it is associated with increased mortality. METHODS: This single-center retrospective cohort study included all HLHS fetuses from January 2010-December 2020. Fetuses with other hypoplastic-left-heart variants, inadequate images, lack of follow-up and fetal atrial-septal interventions were excluded. RAS was defined as the ratio of pulmonary-vein forward-to-reverse velocity-time-integral (VTI) ≤ 5 and severe-RAS defined as VTI-ratio <3. Kaplan-Meier survival-analysis was performed for the primary outcome of transplant-free survival for 62 weeks after gestational-age of 30 weeks (∼1 year). RESULTS: Of the 156 consecutive fetuses with HLHS, 11 (7.7%) had L-cor and 8/11 (72.7%) of these had RAS. When compared to HLHS-RAS without L-cor, fetuses with HLHS-RAS and L-cor were less likely to survive to 28 days (87% vs. 62.5%, p = 0.017) and to 1 year (69.6% vs. 25%, p = 0.029). When comparing by survival analysis, fetuses with severe-RAS with L-cor had lower survival compared severe-RAS without L-cor (p = 0.020). CONCLUSION: L-cor in fetal HLHS is associated with increased mortality. Recognition of this finding is important for prognostication and atrial-septal-intervention planning.

Atrial tachyarrhythmias after lung transplantation in children: A common occurrence.

BACKGROUND: Atrial arrhythmia's (AA) following lung transplant in adults are a well-described clinical finding. In pediatrics, however, there are limited data with some reports suggesting that arrhythmias are rare. METHODS: We performed a single-center retrospective review of lung transplant recipients from January 2013 to June 2020. A detailed evaluation of clinical characteristics, presence of arrhythmias, and outcomes was completed. Arrhythmias were documented based on inpatient telemetry or remote Holter monitoring. Analyses assessing risk factors for arrhythmias and associations with clinical outcomes were performed. RESULTS: Ninety-one lung transplants were performed in 90 patients. Post-operative AA occurred following 19% transplants. Ectopic atrial tachycardia was seen in 14%, atrial flutter in 2%, and a combination in 2%. The majority of these arrhythmias occurred within the first 45 days post-operatively. Antiarrhythmic treatment was required in 59%, but none required ablation or electrical cardioversion. In patients followed for a year or more, 88% had resolution of their arrhythmia. Arrhythmias were not associated with mortality. In further analysis, however, the presence of arrhythmia was associated with an increased length of ICU stay (median of 12 days (IQR 6, 23) versus 5 days (IQR 4, 9); p = .019) and overall length of hospital stay (median of 26 days (IQR 19, 36) versus 17 days (IQR 19, 36); p = .043). CONCLUSIONS: Atrial tachyarrhythmias after lung transplantation are common in the pediatric population and usually occur early. Although they frequently require medical therapy and are associated with longer stays, there is no associated increased mortality. In addition, the arrhythmias typically self-resolve.

Ventricular assist device support for children with chemotherapy-induced cardiomyopathy and advanced heart failure: Perspectives gained from a single-center experience.

BACKGROUND: Guidance and data on ventricular assist device (VAD) support for children with chemotherapy-induced cardiomyopathy, particularly within the first 2 years after chemotherapy, are limited. METHODS: We performed a single-center retrospective case series, reviewing medical records of children <18 years of age with chemotherapy-induced cardiomyopathy and advanced heart failure (HF) who received durable VAD support. RESULTS: Six patients met inclusion criteria-5 HeartWare™ HVAD, 1 Berlin Heart EXCOR® . Median age at cancer diagnosis was 6 years (IQR 4.5-10 years). Median dose of anthracycline received was 540 mg/m2 (IQR 450-630 mg/m2 ). All patients developed HF within 1 year after initiation of cancer treatment (median 8 months, IQR 6-11.5 months) and were initiated on durable VAD support at a median of 8 months after completion of cancer treatment (IQR 3.3-43.5 months). Four patients had significant right ventricular dysfunction needing oral pulmonary vasodilator therapy, one patient had a major bleeding complication, and two patients had thromboembolic strokes while on VAD support. Median duration of VAD support was 7.5 months (IQR 3-11.3 months). Two patients underwent VAD explant due to recovery of LV function, one died due to cancer progression, and three underwent heart transplantation. CONCLUSIONS: Durable VAD support should be considered as a therapeutic option for children who have advanced HF due to chemotherapy-induced cardiomyopathy, even within 2 years of completing cancer treatment. A multi-disciplinary approach is essential for appropriate patient selection prior to implant and to ensure comprehensive care throughout the duration of VAD support.

Bivalirudin or Unfractionated Heparin for Anticoagulation in Pediatric Patients on Continuous Flow Ventricular Assist Device Support: Single-Center Retrospective Cohort Study.

OBJECTIVES: Bivalirudin is a direct thrombin inhibitor that is being increasingly used for anticoagulation in children after ventricular assist device (VAD) implantation. While the data on bivalirudin use in pulsatile flow VADs are growing, reports on its use in patients on continuous flow (CF) VAD as well as comparisons of associated outcomes with unfractionated heparin (UFH) remain limited. DESIGN: Retrospective cohort study. SETTING: Single tertiary-quaternary referral center. PATIENTS: All patients less than 21 years old on CF-VAD support who received bivalirudin or UFH for anticoagulation between the years 2016 and 2020. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: Clinical characteristics compared between the cohorts included time to target range of anticoagulation, markers of hemolysis, and prevalence of hemocompatibility-related adverse events such as major hemorrhagic complications, ischemic stroke, and pump thrombosis. In 42 unique patients (41 HeartWare HVAD [Medtronic, Minneapolis, MN], one HeartMate 3 LVAD [Abbott Laboratories, Abbott Park, IL]) during the study period, a total of 67 encounters of IV anticoagulation infusions (29 UFH and 38 bivalirudin) were retrospectively reviewed. In comparison with use of UFH, bivalirudin was associated with lesser odds of major bleeding complications (odds ratio [OR], 0.29; 95% CI, 0.09-0.97; p = 0.038). We failed to identify any difference in odds of major thrombotic complications (OR, 2.53; 95% CI, 0.47-13.59; p = 0.450). Eight of the patients (28%) on UFH were switched to bivalirudin due to hemorrhagic or thrombotic complications or inability to achieve therapeutic anticoagulation, while two of the patients (5%) on bivalirudin were switched to UFH due to hemorrhagic complications. Bivalirudin was used for a "washout" in eight cases with concern for pump thrombosis-six had resolution of the pump thrombosis, while two needed pump exchange. CONCLUSIONS: Use of bivalirudin for anticoagulation in patients on CF-VAD support was associated with lesser odds of hemorrhagic complications compared with use of UFH. Bivalirudin "washout" was successful in medical management of six of eight cases of possible pump thrombosis.

Mitral valve perforation, a hole-in-one for 3-dimensional echocardiography.

Mitral valve perforation is an uncommon aetiology of mitral regurgitation in the paediatric population. We present a case where 3-dimensional echocardiography assisted in the diagnosis of the source of mitral regurgitation and the surgical correlation.

Central venoarterial extracorporeal life support in pediatric refractory septic shock: a single center experience.

OBJECTIVE: Venoarterial extracorporeal membrane oxygenation (VA ECMO) is recognized as a potential support therapy for pediatric patients with refractory septic shock (RSS). This review aims to report our experience with central VA cannulation in pediatric patients with RSS, and to compare this with peripheral VA ECMO cannulations for this condition at our institution. DESIGN: Retrospective case series. SETTING: Pediatric and cardiac intensive care units in an academic pediatric hospital. PATIENTS: All patients 0-18 years old meeting criteria of RSS placed on VA ECMO between January 2011 and December 2018. INTERVENTIONS: None. MEASUREMENTS: Demographics, relevant clinical variables, ECMO run details, and outcomes were collected. RESULTS: Between 2011 and 2018, 14 children were placed on VA ECMO for RSS. Nine were cannulated centrally, with the rest placed on peripheral VA ECMO. Overall survival to hospital discharge was 57.1% (8/14), with 66.7% of the central cannulation cohort surviving versus 40% in the peripheral cannulation (p = 0.34). Median ECMO duration was 147.1 hours (IQR: 91.9-178.6 hours), with survivors having a median length of 147.1 (IQR: 138.5-185.7) versus non survivors 114.7 hours (IQR: 63.7-163.5), p = 0.48. Overall median ICU length of stay (LOS) was 19 days (IQR: 10.5-42.2). The median % maximum flow achieved on VA ECMO was higher in the central cannulation group at 179.6% (IQR: 154.4-188.1) versus the peripheral with 133.5% (98.1-149.1), p = 0.01. Functional status scale (FSS) was used to capture morbidity. All survivors had a mean increase in their FSS from baseline. In the centrally cannulated group, 50% (4/8) received mediastinal exploration, but none developed mediastinitis. In terms of blood product utilization, the central cannulation received more platelets compared to the peripherally cannulated group (median 15.6 vs 3.3 mL/kg/day, p = 0.03). CONCLUSION: A central approach to VA ECMO cannulation is feasible and has potential for good patient outcomes in selected patients.

Hospital outcomes for pediatric heart transplant recipients undergoing tracheostomy: A multi-institutional analysis.

Tracheostomy is associated with increased mortality and resource utilization in children with CHD. However, the prevalence and hospital outcomes of tracheostomy in children with HTx are not known. We describe the prevalence and compare the post-HTx hospital outcomes of pediatric patients with Pre-TT and Post-TT to those without tracheostomy. A multi-institutional retrospective cohort study was performed using the Pediatric Health Information System database. Hospital mortality, mediastinitis, LOS, and costs were compared among patients with Pre-TT, Post-TT, and no tracheostomy. Pre-TT was identified in 29 (1.1%) and Post-TT was identified in 41 (1.6%) of 2603 index HTx hospitalizations. Patients with Pre-TT were younger and more likely to have CHD, a non-cardiac birth defect, or an airway anomaly compared to those without Pre-TT. Pre-TT was not independently associated with increased post-HTx in-hospital mortality. Age at HTx < 1 year, CHD, and Post-TT were associated with increased in-hospital mortality. Pre-TT that occurred during the HTx hospitalization and Post-TT were associated with increased resource utilization. Tracheostomy was not associated with mediastinitis.

Mechanical Support for The Failing Single Ventricle at Pre-Fontan Stage: Current State of The Field and Future Directions.

With the substantial growth of pediatric ventricular assist device (VAD) support, there has been an expansion of the target population towards more complex patients, including congenital heart disease (CHD) with single ventricle (SV) physiology. The outcomes of Stage I and Stage II SV-CHD patients on VAD support from the Pedimacs database are poor, with less than 50% survival on VAD by the 3-month mark in both. The primary objective of this article is to describe the current state of VAD support for the failing Stage I and II SV-CHD circulation, to provide insight into potential areas of outcome improvement. We reviewed the published literature in the form of database and registry reports as well as single-center studies to discuss the outcomes of Stage I and Stage II SV-CHD patients on VAD support. Registry-based studies suggest that VAD support for the failing Stage I and Stage II SV-CHD circulations is challenging. However, the more promising outcomes in several single-institutional reports for both Stage I and Stage II SV-VAD indicate that the grim picture from the databases does not reflect the best outcomes that are possible to be achieved, potentially at experienced centers with higher volumes. Areas of future study and potential improvement including timely initiation of VAD support in the cohort of patients expected to not be a candidate for standard SV palliations, pump selection and the benefits of continuous-flow devices, and the decision-making for setting up the optimum circulation for VAD support, be it Fontan completion if feasible or takedown to shunt physiology.

Mechanical Circulatory Support for the Failing Sub-Aortic Right Ventricle in Adults.

Patients with ccTGA or d-TGA managed via atrial switch (Mustard or Senning operations) have biventricular circulations with a sub-aortic right ventricle (2V-RV). Other than in a tiny percentage of ccTGA patients, premature heart failure (HF) is common, driven by chronic RV dilatation and dysfunction and/or tricuspid regurgitation. These patients are different from the general HF population in that they are younger, more heterogeneous, are predisposed to pulmonary hypertension and present unique and complex surgical challenges. Despite their young age, they experience disproportionately poor access to advanced therapies and are often disqualified for transplant by pulmonary hypertension, HLA sensitization, program risk-tolerance and psychosocial issues. Mechanical support of the subaortic RV with ventricular assist device (subaortic RVAD, also known as SVAD), although technically challenging, can be an effective alternative to palliative care and offers high likelihood of bridging patients to heart transplant candidacy. In addition, temporary trans-catheter SVAD Impella support has been advantageous for stabilization of decompensated 2V-RV patients or as bridge to durable SVAD support. Improved awareness of and access to specialist ACHD-HF teams offering mechanical support (and transplantation) for 2V-RV patients is increasingly urgent for this aging population, and will improve options and outcomes for these patients as HF emerges.

Smaller right pulmonary artery is associated with longer survival time without scimitar vein repair.

INTRODUCTION: The optimal management of scimitar syndrome remains incompletely defined. We (1) evaluated the impact of aortopulmonary collateral (APC) occlusion, (2) compared outcomes according to surgical approach for patients who underwent surgery, and (3) identified anatomic factors associated with longer survival time without scimitar vein repair. METHODS: We conducted a single center, retrospective study of 61 patients diagnosed with scimitar syndrome between 1995 and 2019. Right pulmonary artery to total pulmonary artery cross-sectional area (RPA:PA CSA) quantitatively assessed right pulmonary artery size. Anatomical features were analyzed for association with longer survival time without scimitar vein repair. RESULTS: Median follow-up time was 6 years (Q1-Q3, 2-12), with 96% 5-year survival. Twenty-three patients underwent APC occlusion, which significantly decreased symptoms of overcirculation (100%-46%; p = .001) and systolic pulmonary artery pressure (median, 34-29 mmHg; p = .004). Twenty-three patients underwent scimitar vein repair; 5-year freedom from scimitar vein stenosis was 90% among patients who underwent a reimplantation compared with 42% in patients with baffle repair (p = .1). Three patients underwent surgery before the first year of age, with lower 5-year freedom from scimitar vein stenosis (0% vs. 84%; p < .001). On multivariate analysis, a lower RPA:PA CSA was associated with longer survival time without scimitar vein repair (p = .003). CONCLUSIONS: APC occlusion improves the clinical status of young and hemodynamically unstable patients. Repair at an early age is associated with an increased risk of scimitar vein stenosis. Scimitar vein repair might be avoided in patients with a smaller right pulmonary artery.

The intraoperative use of recombinant activated factor VII in arterial switch operations.

BACKGROUND: The rate of bleeding complications following arterial switch operation is too low to independently justify a prospective randomised study for benefit from recombinant factor VIIa. We aimed to evaluate factor VIIa in a pilot study. METHODS: We performed a retrospective cohort study of patients undergoing arterial switch operation from 2012 to 2017. Nearest-neighbour propensity score matching on age, gender, weight, and associated cardiac defects was used to match 27 controls not receiving recombinant factor VIIa to 30 patients receiving recombinant factor VIIa. Fisher's exact test was performed to compare categorical variables. Wilcoxon's rank-sum test was used to compare continuous variables between cohorts. RESULTS: Post-operative thrombotic complications were not associated with factor VIIa administration (Odds Ratio (OR) 0.28, 95% CI 0.005-3.77, p = 0.336), nor was factor VIIa administration associated with any re-explorations for bleeding. No intraoperative transfusion volumes were different between the recombinant factor VIIa cohort and controls. Post-operative prothrombin time (10.8 [10.3-12.3] versus 15.9 [15.1-17.2], p < 0.001) and international normalised ratio (0.8 [0.73-0.90] versus 1.3 [1.2-1.4], p < 0.001]) were lower in recombinant factor VIIa cohort relative to controls. CONCLUSIONS: In spite of a higher post-bypass packed red blood cell transfusion requirement, patients receiving recombinant factor VIIa had a similar incidence of bleeding post-operatively. With no difference in thrombotic complications, and with improved post-operative laboratory haemostasis, a prospective randomised study is warranted to evaluate recombinant factor VIIa.

Midterm outcomes of pulmonary artery sling repair with and without tracheoplasty.

OBJECTIVE: Review a single-centre experience with pulmonary artery sling repair and evaluate risk factors for re-intervention. METHODS: Patients with surgically repaired pulmonary artery sling at a single institution between 1996 and 2018 were retrospectively reviewed. A univariate Cox regression analysis was used to evaluate variables for association with freedom from re-intervention. RESULTS: Eighteen patients had pulmonary artery sling repair. At operation, median age and weight were 6.9 months (interquartile range 4.1-18.1) and 9.5 kg (interquartile range 6.5-14.5), respectively. A median hospital length of stay was 12 days (interquartile range 5.8-55.3). Twelve patients (67%) had complete tracheal rings, of whom six (50%) underwent tracheoplasty (five concurrently with pulmonary artery sling repair). Airway re-intervention was required in five (83%) of the six patients who underwent tracheoplasty. One patient had intraoperative diagnosis and repair of pulmonary artery sling during unrelated lesion repair and required tracheoplasty 24 days post-operatively. One patient died 55 days after pulmonary artery sling repair and tracheoplasty following multiple arrests and re-interventions. Median post-operative follow-up for surviving patients was 6.3 years (interquartile range 11 months-13 years), at which time freedom from re-intervention was 61%. When controlling for patient and tracheal size, initial tracheoplasty was associated with decreased freedom from re-intervention (hazard ratio 21.9, 95% confidence interval 1.7-284.3, p = 0.018). CONCLUSIONS: In patients with pulmonary artery sling, tracheoplasty is associated with decreased freedom from re-intervention. In select patients with pulmonary artery sling and complete tracheal rings, conservative management without tracheoplasty is feasible. Further study is necessary to delineate objective indications for tracheoplasty.

Application of transcatheter valves for aortic valve replacement in pediatric patients: A case series.

OBJECTIVES: To describe our initial experience with pediatric transcatheter aortic valve replacement. BACKGROUND: Transcatheter aortic valve replacement (TAVR) has been approved and used to treat calcific aortic stenosis in adult patients. Select pediatric patients with congenital heart disease (CHD) who are poor candidates for conventional surgical aortic valve replacement can benefit from TAVR. METHODS: A retrospective review was performed to identify and describe pediatric patients with CHD who underwent transcatheter or hybrid aortic valve replacement using a Melody Valve (Medtronic, Minneapolis, MN), or Sapien S3/XT valve (Edwards Life sciences LLC, Irvine, CA). Patients in whom transcatheter valves were implanted on cardiopulmonary bypass were included. Imaging data, procedural elements, and clinical follow-up data were collected to evaluate acute and short-term results. RESULTS: A total of eight pediatric patients underwent treatment of aortic valvular disease using balloon expandable valves and delivery systems. Two patients had Melody valve implantation and six received a Sapien valve (one XT/five S3). In one patient, a Melody valve was placed surgically, failed, and was replaced with a Sapien valve 2 years later. Two patients were treated using a standard transfemoral route, four had the valve delivered on cardiopulmonary bypass via a median sternotomy, one was placed with a transapical approach, and one via a carotid cut down. Patients were followed for an average 16 months (range 1-208 weeks). There were no early or late deaths in this cohort. There were no embolic events, and all valves worked well in the immediate postoperative period. Both Melody implants developed moderate to severe regurgitation at 2 years and 4 years, respectively, and both required replacement at that time. One Sapien 3 valve developed a paravalvular leak that required reintervention within 6 months of implantation. CONCLUSIONS: Transcatheter valves offer a reasonable alternative to traditional surgical aortic valve replacement in certain pediatric patients who are suboptimal surgical candidates. Hybrid approaches and valve delivery on cardiopulmonary bypass has been used in smaller patients. Long-term performance of these valves in young patients has not been studied.

Pulmonary Artery Banding for Children With Dilated Cardiomyopathy: US Experience.

Pulmonary artery band placement is a recently described therapeutic strategy for dilated cardiomyopathy with preserved right ventricular function, originally reported from Germany.1 We present the results of the multicenter retrospective study of pulmonary artery band experience in the United States, with comparison to the German experience. Five centers contributed a total 14 patients (median age 5 months, interquartile range 3.5-10). Mechanical ventilation was required in 9/12 (75%) patients and inotropes were used in 13/14 (93%) patients preoperatively. Ultimately, 4 (29%) patients experienced cardiac recovery, 8 (57%) were bridged to cardiac transplantation (6 with ventricular assist device placement), and 2 (14%) died. Although both the US and Germany series demonstrated high prevalence of achieving patients' individual target (either cardiac recovery or transplant), the mode of success was different (recovery rate: <1/3 in the United States and >2/3 in Germany). Lower recovery rate may be a reflection of sicker preoperative status, and thereby a more advanced stage of heart failure (preoperative intubation: >2/3 in the United States vs <1/3 in Germany). Further studies would be warranted to gain more insight into patient selection as well as optimal timing for the intervention.

Current status of pediatric mechanical circulatory support.

PURPOSE OF REVIEW: The field of pediatric mechanical circulatory support has experienced exponential evolution in recent decades. With favorable complication profiles, implantable continuous-flow ventricular assist devices (VADs) have become a standard option in children, as has been seen in the adult counterpart. Nevertheless, there still exists room for further advances, not just for survival, but throughout the whole trajectory of treatment courses. With reviewing the current state of pediatric VAD support, including existing challenges, we aim to highlight the targets clinicians should focus on for further improvement of pediatric VAD support. RECENT FINDINGS: The field of pediatric VAD has been steadily growing, as evidenced by an increasing number of total VAD implants, particularly with continuous-flow VAD. Currently, HeartWare HVAD (Medtronic Inc., Mounds View, MN) is the most widely used continuous-flow VAD in children with excellent performance. However, only half of the children with HVAD are discharged home, which is drastically different from adult patients, suggesting that the pediatric field is still in the process of maturation. Additionally, outcomes of VAD support for complex congenital heart defect, particularly single ventricle physiology, remain suboptimal, despite an increasing number of such patients. SUMMARY: With the ongoing advancement, the field of pediatric VAD support is undergoing a rapid maturation process. This will eventually lead to further paradigm changes, including the use of VAD as permanent therapy.

Antithrombin Population Pharmacokinetics in Pediatric Ventricular Assist Device Patients.

OBJECTIVES: Describe the pharmacokinetics of antithrombin in pediatric patients undergoing ventricular assist device therapy and provide dosing recommendations for antithrombin in this population. DESIGN: A retrospective population pharmacokinetic study was designed. SETTING: Large tertiary care children's hospital Subject inclusion criteria consisted of less than 19 years old. PATIENTS: Subjects less than 19 years old undergoing therapy with a HeartWare ventricular assist device (HeartWare, Framingham, MA) or Berlin EXCOR ventricular assist device (Berlin GmbH, Berlin, Germany), who received a dose of antithrombin with a postdose antithrombin activity level from January 1, 2011, to June 30, 2017. INTERVENTIONS: Population pharmacokinetic analysis and simulation using NONMEM v.7.4 (Icon, PLC, Dublin, Ireland). MEASUREMENTS AND MAIN RESULTS: A total of 41 patients met study criteria (median age, 5.8 years [interquartile range, 1.6-9.9 yr]), and 53.7% underwent therapy with the pulsatile Berlin EXCOR pediatric ventricular assist device (Berlin Heart GmbH, Berlin, Germany). All patients received unfractionated heparin continuous infusion at a mean ± SD dose of 29 ± 14 U/kg/hr. A total of 181 antithrombin doses (44.1 ± 24.6 U/kg/dose) were included, and baseline antithrombin activity levels were 77 ± 12 U/dL. Antithrombin activity levels were drawn a median 19.9 hours (interquartile range, 8.8-41.6 hr) after antithrombin dose. A one-compartment proportional error model best fit the data, with allometric scaling of fat-free mass providing a better model fit than actual body weight. Unfractionated heparin and baseline antithrombin were identified as significant covariates. A 50 U/kg dose of antithrombin had a simulated half-life 13.2 ± 6.6 hours. CONCLUSIONS: Antithrombin should be dosed on fat-free mass in pediatric ventricular assist device patients. Unfractionated heparin dose and baseline antithrombin activity level should be considered when dosing antithrombin in pediatric ventricular assist device patients.

Reoperation after isolated subaortic membrane resection.

BACKGROUND: The resection of a subaortic membrane remains far from a curative operation. We sought to examine factors associated with reoperation and the degree of aortic valve regurgitation as a potential long-term source for reoperation. METHODS: All patients who underwent resection of an isolated subaortic membrane between 1995 and 2018 were included. Patients who underwent other procedures were excluded. Paired categorical data were compared using McNemar's test. Univariate time-to-event analyses were performed using Kaplan-Meier methods with log-rank tests for categorical variables and univariate Cox models for continuous variables. RESULTS: A total of 84 patients (median age 6.6, 31% females) underwent resection of isolated subaortic membrane. At a median follow-up of 9.3 years (interquartile range 0.6-22.5), 12 (14%) patients required one reoperation and 1 patient required two reoperations. Median time to first reoperation was 4.6 years. The degree of aortic valve regurgitation improved post-operatively from pre-operatively (p = 0.0007); however, the degree of aortic valve regurgitation worsened over the course of follow-up (p = 0.010) to equivalence with pre-operative aortic valve regurgitation (p = 0.18). Performance of a septal myectomy was associated with longer freedom from reoperation (p = 0.004). CONCLUSIONS: In patients with isolated subaortic membranes, performance of a septal myectomy can minimise risk for reoperation. Patients should be serially monitored for degradation of the aortic valve, even if aortic regurgitation is not present post-operatively.