Kevin P. Daly

Effect of inhaled iloprost on the exercise function of Fontan patients: A demonstration of concept

BACKGROUND Exercise capacity following Fontan surgery is often depressed. An inability to reduce pulmonary vascular resistance appropriately during exercise may contribute to this phenomenon. The aim of this study was to determine whether administration of iloprost, a selective pulmonary vasodilator, would improve exercise function after Fontan procedure. METHODS Double-blind, randomized, placebo controlled, crossover trial. Patients performed two cardiopulmonary exercise tests (CPX) separated by <1 month. A single nebulizer treatment (iloprost or placebo) was administered before each CPX. RESULTS 18 patients aged 12-49 (median 17) years were recruited. Mild throat discomfort developed in 10/18 patients during iloprost administration; all but 1 were able to complete treatment. No symptoms developed during placebo treatments (p<0.001). Two additional patients did not complete CPX: one with atrial flutter; another with developmental issues that precluded adequate CPX. In the 15 remaining subjects oxygen pulse (a surrogate for forward stroke volume) at peak exercise was higher following iloprost (median increase 1.2 ml/beat; p<0.001). Peak VO2 also rose (median increase 1.3 ml/kg/min; p<0.04). Nine patients had peak VO2 <30 ml/kg/min; each of these patients had higher peak VO2 following iloprost. Only 3/6 patients with peak VO2 >30 ml/kg/min had higher peak VO2 following iloprost (p<0.04). CONCLUSIONS Iloprost improves the peak oxygen pulse and peak VO2 of patients with Fontan physiology and appears to be particularly beneficial among patients with impaired exercise function. Treatment is associated with minor side effects. These findings support the concept of pulmonary vasodilator therapy in Fontan patients with limited functional capacity.

ENDOMYOCARDIAL BIOPSY AND SELECTIVE CORONARY ANGIOGRAPHY ARE LOW RISK PROCEDURES IN PEDIATRIC HEART TRANSPLANT RECIPIENTS: RESULTS OF A MULTICENTER EXPERIENCE

BACKGROUND No prior reports documenting the safety and diagnostic yield of cardiac catheterization and endomyocardial biopsy (EMB) in heart transplant recipients include multicenter data. METHODS Data on the safety and diagnostic yield of EMB procedures performed in heart transplant recipients were recorded in the Congenital Cardiac Catheterization Outcomes Project database at 8 pediatric centers during a 3-year period. Adverse events (AEs) were classified according to a 5-level severity scale. Generalized estimating equation models identified risk factors for high-severity AEs (HSAEs; Levels 3-5) and non-diagnostic biopsy samples. RESULTS A total of 2,665 EMB cases were performed in 744 pediatric heart transplant recipients (median age, 12 years [interquartile range, 4.8, 16.7]; 54% male). AEs occurred in 88 cases (3.3%), of which 28 (1.1%) were HSAEs. AEs attributable to EMB included tricuspid valve injury, transient complete heart block, and right bundle branch block. Amongst 822 cases involving coronary angiography, 10 (1.2%) resulted in a coronary-related AE. There were no myocardial perforations or deaths. Multivariable risk factors for HSAEs included fewer prior catheterizations (p = 0.006) and longer case length (p < 0.001). EMB yielded sufficient tissue for diagnosis in 99% of cases. Longer time since heart transplant was the most significant predictor of a non-diagnostic biopsy sample (p < 0.001). CONCLUSIONS In the current era, cardiac catheterizations involving EMB can be performed in pediatric heart transplant recipients with a low AE rate and high diagnostic yield. Risk of HSAEs is increased in early post-transplant biopsies and with longer case length. Longer time since heart transplant is associated with non-diagnostic EMB samples.

Key Features of the Intragraft Microenvironment that Determine Long-Term Survival Following Transplantation

In this review, we discuss how changes in the intragraft microenvironment serve to promote or sustain the development of chronic allograft rejection. We propose two key elements within the microenvironment that contribute to the rejection process. The first is endothelial cell proliferation and angiogenesis that serve to create abnormal microvascular blood flow patterns as well as local tissue hypoxia, and precedes endothelial-to-mesenchymal transition. The second is the overexpression of local cytokines and growth factors that serve to sustain inflammation and, in turn, function to promote a leukocyte-induced angiogenesis reaction. Central to both events is overexpression of vascular endothelial growth factor (VEGF), which is both pro-inflammatory and pro-angiogenic, and thus drives progression of the chronic rejection microenvironment. In our discussion, we focus on how inflammation results in angiogenesis and how leukocyte-induced angiogenesis is pathological. We also discuss how VEGF is a master control factor that fosters the development of the chronic rejection microenvironment. Overall, this review provides insight into the intragraft microenvironment as an important paradigm for future direction in the field.

VEGF-C, VEGF-A and related angiogenesis factors as biomarkers of allograft vasculopathy in cardiac transplant recipients.

BACKGROUND Cardiac allograft vasculopathy (CAV), the major cause of late allograft loss after cardiac transplantation, results from donor-directed cellular and humoral alloimmune responses. Graft vascular endothelial cells (EC) are primary targets of these destructive responses, suggesting that factors associated with endothelial injury and repair could serve as biomarkers of CAV. METHODS Using a protein profiler array platform, we measured the levels of 55 angiogenesis-related proteins in sera from 33 adult heart transplant recipients, including 17 with angiographically documented CAV and 16 age- and gender-matched controls without CAV. All patients were >2 years after heart transplant. RESULTS The study population was 75% male with a mean age of 62 ± 11 years. On average, patients were 12 ± 5 years after heart transplantation. We found that vascular endothelial growth factor (VEGF)-C, VEGF-A, angiopoietin-2, artemin, urokinase-type plasminogen activator and vasohibin were strongly associated with established CAV (all p < 0.01). Multivariable modeling identified VEGF-C, VEGF-A and platelet factor-4 (PF-4) as significant independent biomarkers of CAV. Furthermore, receiver-operating characteristic curve analysis demonstrated that the combination of all 3 molecules provided outstanding performance for the diagnosis of CAV (area under the curve [AUC] = 0.98; p < 0.001). CONCLUSIONS Serum levels of VEGF-C, VEGF-A and PF-4 demonstrate strong associations with established CAV and, together with related angiogenesis factors, may serve as a reliable, non-invasive diagnostic test for CAV in cardiac transplant recipients.

Multicenter Analysis of Immune Biomarkers and Heart Transplant Outcomes: Results of the Clinical Trials in Organ Transplantation‐05 Study

Identification of biomarkers that assess posttransplant risk is needed to improve long‐term outcomes following heart transplantation. The Clinical Trials in Organ Transplantation (CTOT)‐05 protocol was an observational, multicenter, cohort study of 200 heart transplant recipients followed for the first posttransplant year. The primary endpoint was a composite of death, graft loss/retransplantation, biopsy‐proven acute rejection (BPAR), and cardiac allograft vasculopathy (CAV) as defined by intravascular ultrasound (IVUS). We serially measured anti‐HLA‐ and auto‐antibodies, angiogenic proteins, peripheral blood allo‐reactivity, and peripheral blood gene expression patterns. We correlated assay results and clinical characteristics with the composite endpoint and its components. The composite endpoint was associated with older donor allografts (p < 0.03) and with recipient anti‐HLA antibody (p < 0.04). Recipient CMV‐negativity (regardless of donor status) was associated with BPAR (p < 0.001), and increases in plasma vascular endothelial growth factor‐C (OR 20; 95%CI:1.9–218) combined with decreases in endothelin‐1 (OR 0.14; 95%CI:0.02–0.97) associated with CAV. The remaining biomarkers showed no relationships with the study endpoints. While suboptimal endpoint definitions and lower than anticipated event rates were identified as potential study limitations, the results of this multicenter study do not yet support routine use of the selected assays as noninvasive approaches to detect BPAR and/or CAV following heart transplantation.

Antibody depletion for the treatment of crossmatch-positive pediatric heart transplant recipients.

Sensitization to HLA is a risk factor for adverse outcomes after heart transplantation. Requiring a negative prospective CM results in longer waiting times and increased waitlist mortality. We report outcomes in a cohort of sensitized children who underwent transplant despite a positive CDC CM+ using a protocol of antibody depletion at time of transplant, followed by serial IVIG administration. All patients <21 yrs old who underwent heart transplantation at Boston Childrens Hospital from 1/1998 to 1/2011 were included. We compared freedom from allograft loss, allograft rejection, and serious infection between CM+ and CM− recipients. Of 134 patients in the cohort, 33 (25%) were sensitized prior to transplantation and 12 (9%) received a CM+ heart transplant. Serious infection in the first post‐transplant year was more prevalent in the CM+ patients compared with CM− patients (50% vs. 16%; p = 0.005), as was HD‐AMR (50% vs. 2%; p < 0.001). There was no difference in freedom from allograft loss or any rejection. At our center, children transplanted despite a positive CM had acceptable allograft survival and risk of any rejection, but a higher risk of HD‐AMR and serious infection.

Use of [18F]FDG Positron Emission Tomography to Monitor the Development of Cardiac Allograft Rejection.

Background Positron emission tomography (PET) has the potential to be a specific, sensitive and quantitative diagnostic test for transplant rejection. To test this hypothesis, we evaluated 18F-labeled fluorodeoxyglucose ([18F]FDG) and 13N-labeled ammonia ([13N]NH3) small animal PET imaging in a well-established murine cardiac rejection model. Methods Heterotopic transplants were performed using minor major histocompatibility complex-mismatched B6.C-H2bm12 donor hearts in C57BL/6(H-2b) recipients. C57BL/6 donor hearts into C57BL/6 recipients served as isograft controls. [18F]FDG PET imaging was performed weekly between posttransplant days 7 and 42, and the percent injected dose was computed for each graft. [13N]NH3 imaging was performed to evaluate myocardial perfusion. Results There was a significant increase in [18F]FDG uptake in allografts from day 14 to day 21 (1.6% to 5.2%; P < 0.001) and uptake in allografts was significantly increased on posttransplant days 21 (5.2% vs 0.9%; P = 0.005) and 28 (4.8% vs 0.9%; P = 0.006) compared to isograft controls. Furthermore, [18F]FDG uptake correlated with an increase in rejection grade within allografts between days 14 and 28 after transplantation. Finally, the uptake of [13N]NH3 was significantly lower relative to the native heart in allografts with chronic vasculopathy compared to isograft controls on day 28 (P = 0.01). Conclusions PET imaging with [18F]FDG can be used after transplantation to monitor the evolution of rejection. Decreased uptake of [13N]NH3 in rejecting allografts may be reflective of decreased myocardial blood flow. These data suggest that combined [18F]FDG and [13N]NH3 PET imaging could be used as a noninvasive, quantitative technique for serial monitoring of allograft rejection and has potential application in human transplant recipients.

What Is the Role of Developmental Disability in Patient Selection for Pediatric Solid Organ Transplantation

The National Organ Transplant Act stipulates that deceased donor organs should be justly and wisely allocated based on sound medical criteria. Allocation schemes are consistent across the country, and specific policies are publicly vetted. Patient selection criteria are largely in the hands of individual organ transplant programs, and consistent standards are less evident. This has been particularly apparent for patients with developmental disabilities (DDs). In response to concerns regarding the fairness of transplant evaluations for patients with DDs, we developed a transplant centerwide policy using a multidisciplinary, community‐based approach. This publication details the particular policy of our center. All patients should receive individualized assessments using consistent standards; disability should be neither a relative nor an absolute contraindication to transplantation. External review can increase trust in the selection process. Patients in persistent vegetative states should not be listed for transplantation.

Anatomical Significance in Aortoiliac Occlusive Disease

Aortoiliac occlusive disease is a subset of peripheral arterial disease involving an atheromatous occlusion of the infrarenal aorta, common iliac arteries, or both. The disease, as it is known today, was described by the French surgeon René Leriche as a thrombotic occlusion of the end of the aorta. Leriche successfully linked the anatomic location of the occlusion with a unique triad of symptoms, including claudication, impotence, and decreased peripheral pulses. The anatomical location of the atheromatous lesions also has a direct influence on classification of the disease, as well as choice of treatment modality. Considering its impact on diagnosis and treatment, we aimed to provide a detailed understanding of the anatomical structures involved in aortoiliac occlusive disease. Familiarity with these structures will aid the physician in interpretation of radiologic images and surgical planning. Clin. Anat. 27:1264–1274, 2014.

SUDDEN DEATH AFTER PEDIATRIC HEART TRANSPLANTATION: Analysis of data from the Pediatric Heart Transplant Study Group

BACKGROUND Sudden death is a well-recognized complication of heart transplantation. Little is known about the incidence and risk factors for sudden death after transplant in children. The purpose of this study was to determine the incidence of and risk factors for sudden death. METHODS This retrospective multicenter cohort study used the Pediatric Heart Transplant Study Group (PHTS) database, an event-driven registry of children aged <18 at listing undergoing heart transplantation between 1993 and 2007. Standard Kaplan-Meier and parametric analyses were used for survival analysis. Multivariate analysis in the hazard-function domain was used to identify risk factors for sudden death after transplant. RESULTS Of 604 deaths in 2,491 children who underwent heart transplantation, 94 (16%) were classified as sudden. Freedom from sudden death was 97% at 5 years, and the hazard for sudden death remained constant over time at 0.01 deaths/year. Multivariate risk factors associated with sudden death included black race (hazard ratio [HR], 2.6; p < 0.0001), United Network of Organ Sharing (UNOS) status 2 at transplant (HR, 1.8; p = 0.008), older age (HR, 1.4/10 years of age; p = 0.03), and an increased number of rejection episodes in the first post-transplant year (HR, 1.6/episode; p = 0.03). CONCLUSION Sudden death accounts for 1 in 6 deaths after heart transplant in children. Older recipient age, recurrent rejection within the first year, black race, and UNOS status 2 at listing were associated with sudden death. Patients with 1 or more of these risk factors may benefit from primary prevention efforts.