Cardiac Allograft Vasculopathy Research Articles

Longitudinal Change and Predictors of Myocardial Flow Reserve by Positron Emission Tomography for the Evaluation of Cardiac Allograft Vasculopathy Following Heart Transplantation

Background: PET myocardial flow reserve (MFR) is a noninvasive method to detect cardiac allograft vasculopathy in heart transplant (HT) recipients. There is limited data on longitudinal change and predictors of MFR following HT. Methods: We conducted a retrospective analysis of HT recipients undergoing PET MPI at an academic center. Multivariable linear and Cox regression models were constructed to identify longitudinal trends, predictors, and prognostic value of MFR after HT. Results: 183 HT recipients underwent 658 PET studies. Average MFR was 2.34 ± 0.70. MFR initially increased in the first three years following HT (+0.12 per year, P = 0.01) before beginning to decline at an annual rate of -0.06 per year (P <0.001). MFR declines preceding acute rejection and improves after treatment. Treatment with mTOR inhibitors (37.2%) slowed the rate of annual MFR decline (P = 0.03). Higher-intensity statin therapy was associated with improved MFR. Longer time post-transplant (p <0.001), hypertension (P <0.001), chronic kidney disease (P < 0.001), diabetes mellitus (P = 0.038), antibody-mediated rejection (P = 0.040), and cytomegalovirus infection (P = 0.034) were associated with reduced MFR. Reduced MFR (HR: 7.6, 95% CI: 4.4-13.4, P <0.001) and PET-defined ischemia (HR: 2.3, 95% CI: 1.4-3.9, P <0.001) was associated with a higher risk of the composite outcome of mortality, retransplantation, heart failure hospitalization, acute coronary syndrome, or revascularization. Conclusion: MFR declines after the third post-transplant year and is prognostic for cardiovascular events. Cardiometabolic risk factor modification and treatment with higher-intensity statin therapy and MTI are associated with a higher MFR.

High sensitivity troponin I as a biomarker for cardiac allograft vasculopathy: Evaluation of diagnostic potential and clinical utility.

Cardiac allograft vasculopathy (CAV) limits long-term survival in heart transplant (HTx) recipients. The use of biomarkers in CAV surveillance has been studied, but none are used in clinical practice. The predictive value of high-sensitivity troponin I (hsTnI) has not been extensively investigated in HTx recipients. HTx patients undergoing surveillance coronary angiograms and enrolled in the Emory Cardiovascular Biobank had plasma hsTnI measured. CAV grade was assessed using ISHLT nomenclature. Multivariable cumulative link mixed modeling was performed to determine association between hsTnI level and CAV grade. Patients were followed for adverse outcomes over a median 10-year period. Kaplan-Meier survival analysis and Cox proportional hazard modeling were performed. Three hundred and seventy-two angiograms were analyzed in 156 patients at a median 8.9years after transplant. hsTnI levels were positively correlated with concurrent CAV grade after adjustment for age, age at transplant, sex, BMI, hypertension, diabetes, hyperlipidemia, estimated glomerular filtration rate, and history of acute cellular rejection (p=.016). In an adjusted Cox proportional hazard model, initial hsTnI level above the median (4.9pg/mL) remained a predictor of re-transplantation or death (hazard ratio 1.82; 95% confidence interval 1.16-2.90; p=.01). An elevated hsTnI level reflects severity of CAV and is associated with poor long-term outcomes in patients with HTx.

Protein Phosphatase 2A Activation Promotes Heart Transplant Acceptance in Mice.

Although heart transplantation is the definitive treatment for heart failure in eligible patients, both acute and chronic transplant rejection frequently occur. Protein phosphatase 2A (PP2A) activity is critical in maintaining tissue and organ homeostasis. In this study, we evaluated the effect of a novel class of small molecule activators of PP2A (SMAPs) on allograft rejection in a mouse heterotopic heart transplantation model. Recipient mice were administered with DT-061 (a pharmaceutically optimized SMAP) or vehicle by oral gavage beginning 1 d after transplantation. Histological and immunofluorescence analyses were performed to examine allograft rejection. Regulatory T cells (Treg) from recipient spleens were subjected to flow cytometry and RNA sequencing analysis. Finally, the effect of DT-061 on smooth muscle cells (SMCs) migration and proliferation was assessed. DT-061 treatment prolonged cardiac allograft survival. SMAPs effectively suppressed the inflammatory immune response while increasing Treg population in the allografts, findings corroborated by functional analysis of RNA sequencing data derived from Treg of treated splenic tissues. Importantly, SMAPs extended immunosuppressive agent cytotoxic T lymphocyte-associated antigen-4-Ig-induced cardiac transplantation tolerance and allograft survival. SMAPs also strongly mitigated cardiac allograft vasculopathy as evidenced by a marked reduction of neointimal hyperplasia and SMC proliferation. Finally, our in vitro studies implicate suppression of MEK/ERK pathways as a unifying mechanism for the effect of PP2A modulation in Treg and SMCs. PP2A activation prevents cardiac rejection and prolongs allograft survival in a murine model. Our findings highlight the potential of PP2A activation in improving alloengraftment in heart transplantation.

Outcomes of untreated subclinical antibody-mediated rejection after heart transplantation

Subclinical antibody-mediated rejection (AMR) is represented by histopathological and/or immunopathological manifestations in the absence of significant cardiac allograft dysfunction. Treatment remains uncertain as there is a lack of data on asymptomatic heart transplant (HT) recipients (HTR) with a positive cardiac biopsy. We sought to determine the impact of untreated subclinical biopsy-proven AMR, regardless of circulating donor-specific antigen (DSA) expression, when diagnosed on surveillance biopsies in the first year after HT. This retrospective case control study evaluated 260 HTR between May 2004 and February 2021. These comprised 231 controls and 29 patients with untreated subclinical AMR. The mortality event rate was higher in controls (2.63 events per 100 person-years) compared to the scAMR Group (1.71 events per 100 person-years), a difference that did not reach statistical significance (hazard ratio 0.66, CI: 0.18–2.36). The combined event rate of cardiac allograft vasculopathy (CAV), graft dysfunction, or mortality was higher in the subclinical AMR group (5.60 events per 100 person-years) than in controls (3.89 events per 100 person-years) but did not reach statistical significance (hazard ratio 1.63, CI: 0.07–40.09). Our results suggest that subclinical AMR diagnosed in the first year after HT on surveillance biopsy is not associated with decreased survival. This may sway the management of subclinical AMR towards a more conservative approach in transplant-capable institutions that currently prioritize treatment, though prospective, randomized studies of such a management strategy are required.

A case of successful orthotopic heart retransplantation in an 11-year-old child

Objective: to present a clinical case of an 11-year-old child who underwent repeat heart transplantation (HT) at Almazov National Medical Research Centre in St. Petersburg, Russia.Materials and methods. A case of successful heart retransplantation in an 11-year-old child with cardiac allograft vasculopathy (CAV) is presented.Results. The postoperative period after heart retransplantation had no significant differences with the postoperative period of primary heart recipients. The complexity of the intraoperative stage was determined by pronounced adhesions. As part of preoperative preparation, the patient underwent chest CT scan, which, in our experience, allows us to evaluate the heart syntopy and, in turn, is an important preparatory stage in planning repeat interventions.Conclusion. Our first experience of cardiac retransplantation in pediatric patients suggests that repeat HT is the most optimal treatment for pediatric patients with CAV and requires more thorough preoperative preparation.

Role of ascorbic acid in cardiac allograft vasculopathy.

Cardiac allograft vasculopathy (CAV) is a progressive fibroproliferative disease which occurs after heart transplantation and is associated with significant long-term morbidity and mortality. Currently available strategies including statins, mammalian target of rapamycin (mTOR) inhibitors, and revascularization, have limited overall effectiveness in treating this pathology once the disease process is established. mTOR inhibitors, while effective when used early in the disease process, are not well tolerated, and hence not routinely used in post-transplant care. Recent work on rodent models have given us a novel mechanistic understanding of effects of ascorbic acid in preventing CAV. TET methyl cytosine dioxygenase2 (TET2) reduces vascular smooth muscle cell (VSMC) apoptosis and intimal thickening. TET2 is repressed by interferon γ (IFNγ) in the setting of CAV. Ascorbic acid has been shown to promote TET2 activity and attenuate allograft vasculopathy in animal models and CAV progression in a small clinical trial. CAV remains a challenging disease process and needs better preventative strategies. Ascorbic acid improves endothelial dysfunction, reduces reactive oxygen species, and prevents development of intimal hyperplasia by preventing smooth muscle cell apoptosis and hyperproliferation. Further large-scale randomized control studies of ascorbic acid are needed to establish the role in routine post-transplant management.

Medium-term Outcomes in Pediatric Heart Transplant Recipients Managed Using a Steroid Avoidance Immune Suppression Protocol.

Short-term outcomes using steroid avoidance immune suppression are encouraging in pediatric heart transplant (HT) recipients at low risk of antibody-mediated rejection. We assessed medium-term outcomes in pediatric HT recipients initiated on a steroid avoidance protocol at our institution using surveillance biopsies. All primary HT recipients during 2006-2020 who did not have a donor-specific antibody were eligible for immune suppression consisting of 5-d Thymoglobulin/steroid induction followed by a tacrolimus-based, steroid-free regimen. We assessed freedom from graft failure (death or retransplant), acute rejection, posttransplant lymphoproliferative disease, and cardiac allograft vasculopathy. Overall, 150 of 181 primary HT recipients were eligible for steroid avoidance regimen. Their median age was 8.7 y, 41% had congenital heart disease, 23% were sensitized, and 35% were on a mechanical support. The median follow-up was 6.1 y. Eleven patients (8%) were on maintenance steroids at discharge and 13% at 1 y. Graft survival was 94% at 1 y and 87% at 5 y. Freedom from rejection was 73% at 1 y and 64% at 5 y. Freedom from posttransplant lymphoproliferative disease was 96% at 1 y and 95% at 5 y. Freedom from moderate cardiac allograft vasculopathy was 94% at 5 y. Eight patients developed diabetes. Estimated glomerular filtration rate was <60 mL/min/1.73 m2 in 5% of the cohort at 5 y. Pediatric HT recipients at low risk of antibody-mediated rejection have excellent medium-term survival and relatively low incidence of posttransplant morbidities when managed using a steroid avoidance immune suppression protocol.

Outcomes of Heart Transplant Donation After Circulatory Death

BackgroundHeart transplantation using donation after circulatory death (DCD) allografts is increasingly common, expanding the donor pool and reducing transplant wait times. However, data remain limited on clinical outcomes. ObjectivesWe sought to compare 6-month and 1-year clinical outcomes between recipients of DCD hearts, most of them recovered with the use of normothermic regional perfusion (NRP), and recipients of donation after brain death (DBD) hearts. MethodsWe conducted a single-center retrospective observational study of all adult heart-only transplants from January 2020 to January 2023. Recipient and donor data were abstracted from medical records and the United Network for Organ Sharing registry, respectively. Survival analysis and Cox regression were used to compare the groups. ResultsDuring the study period, 385 adults (median age 57.4 years [IQR: 48.0-63.7 years]) underwent heart-only transplantation, including 122 (32%) from DCD donors, 83% of which were recovered with the use of NRP. DCD donors were younger and had fewer comorbidities than DBD donors. DCD recipients were less often hospitalized before transplantation and less likely to require pretransplantation temporary mechanical circulatory support compared with DBD recipients. There were no significant differences between groups in 1-year survival, incidence of severe primary graft dysfunction, treated rejection during the first year, or likelihood of cardiac allograft vasculopathy at 1 year after transplantation. ConclusionsIn the largest single-center comparison of DCD and DBD heart transplantations to date, outcomes among DCD recipients are noninferior to those of DBD recipients. This study adds to the published data supporting DCD donors as a safe means to expand the heart donor pool.

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

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

An agent-based model of cardiac allograft vasculopathy: toward a better understanding of chronic rejection dynamics.

Cardiac allograft vasculopathy (CAV) is a coronary artery disease affecting 50% of heart transplant (HTx) recipients, and it is the major cause of graft loss. CAV is driven by the interplay of immunological and non-immunological factors, setting off a cascade of events promoting endothelial damage and vascular dysfunction. The etiology and evolution of tissue pathology are largely unknown, making disease management challenging. So far, in vivo models, mostly mouse-based, have been widely used to study CAV, but they are resource-consuming, pose many ethical issues, and allow limited investigation of time points and important biomechanical measurements. Recently, agent-based models (ABMs) proved to be valid computational tools for deciphering mechanobiological mechanisms driving vascular adaptation processes at the cell/tissue level, augmenting cost-effective in vivo lab-based experiments, at the same time guaranteeing richness in observation time points and low consumption of resources. We hypothesize that integrating ABMs with lab-based experiments can aid in vivo research by overcoming those limitations. Accordingly, this work proposes a bidimensional ABM of CAV in a mouse coronary artery cross-section, simulating the arterial wall response to two distinct stimuli: inflammation and hemodynamic disturbances, the latter considered in terms of low wall shear stress (WSS). These stimuli trigger i) inflammatory cell activation and ii) exacerbated vascular cell activities. Moreover, an extensive analysis was performed to investigate the ABM sensitivity to the driving parameters and inputs and gain insights into the ABM working mechanisms. The ABM was able to effectively replicate a 4-week CAV initiation and progression, characterized by lumen area decrease due to progressive intimal thickening in regions exposed to high inflammation and low WSS. Moreover, the parameter and input sensitivity analysis highlighted that the inflammatory-related events rather than the WSS predominantly drive CAV, corroborating the inflammatory nature of the vasculopathy. The proof-of-concept model proposed herein demonstrated its potential in deepening the pathology knowledge and supporting the in vivo analysis of CAV.

Cardiac allograft vasculopathy and survival in pediatric heart transplant recipients transitioned to adult care

Cardiac allograft vasculopathy (CAV) is an important cause of mortality after pediatric heart transplantation (HT) but there is a paucity of data regarding its incidence and impact on survival in pediatric recipients transitioned to adult care. We conducted a retrospective review of consecutive pediatric HT patients from 1989-2017 at the Hospital for Sick Children who transitioned to adult care at ≥18 years at Toronto General Hospital. We evaluated the incidence of ISHLT CAV grade ≥1 using competing risk models. We assessed the association between all-cause mortality and CAV using Cox proportional hazards and used Kaplan Meier methods to evaluate all-cause mortality stratified by CAV and transplant era (1989-2001, 2002-2017). 96 patients were transitioned to adult care by 01/2022, of which 53 underwent repeat coronary angiography as adults. CAV was newly diagnosed in 49% patients after transition to adult care. The overall incidence of CAV was 3.9 cases per 100 person-years. There was no difference in the adjusted incidence of CAV according to transplant era (SHR = 1.17, 95% CI 0.54-2.66). CAV was associated with a higher risk of death in the early era (HR 10.29, 95% CI 2.16-49.96), but not in the recent era (HR 1.61, 95% 0.35-7.47). There is a role for continued CAV surveillance after the transition to adult care. The implications of diagnosing CAV after the transition to adult care requires further study, particularly because the risk of death in pediatric HT recipients diagnosed with CAV in the more recent era may be attenuated compared to the earlier HT era.

Assessing Donor-Recipient Size Mismatch in Pediatric Heart Transplantation: Lessons Learned From Over 7,500 Transplants

BackgroundTo date, no studies have identified an optimal metric to match donor-recipient (D-R) pairs in pediatric heart transplantation (HT). ObjectivesThis study sought to identify size mismatch metrics that predicted graft survival post-HT. MethodsD-R pairs undergoing HT in Pediatric Heart Transplant Society database from 1993 to 2021 were included. Effects of size mismatch by height, weight, body mass index, body surface area, predicted heart mass, and total cardiac volume (TCV) on 1- and 5-year graft survival and morbidity outcomes (rejection and cardiac allograft vasculopathy) were evaluated. Cox models with stepwise selection identified size metrics that independently predicted graft survival. ResultsOf 7,715 D-R pairs, 36.0% were well matched (D-R ratio: −20% to +20%) by weight, 39.0% by predicted heart mass, 50.0% by body surface area, 57.0% by body mass index, 71.0% by height, and 93.0% by TCV. Of all size metrics, only D-R mismatch by height and TCV predicted graft survival at 1 and 5 years. Effects of D-R size mismatch on graft survival were nonlinear. At both 1 and 5 years post-HT, D-R undersizing and oversizing by height led to increased graft loss, with graft loss observed more frequently with undersizing. Moderately undersized donors by height (D-R ratio: <−30%) frequently experienced rejection post-HT (P < 0.001). Assessing D-R size matching by TCV, minimal donor undersizing was protective, while oversizing up to 25% was not associated with increased graft loss. ConclusionsIn pediatric HT, D-R appear most optimally matched using TCV. Only D-R size mismatch by TCV and height independently predicts graft survival. Standardizing size matching across centers may reduce donor discard.

Lower platelet count following induction therapy with anti-thymocyte globulin is associated with a lower incidence of cardiac allograft vasculopathy

Lower platelet count following induction therapy with anti-thymocyte globulin is associated with a lower incidence of cardiac allograft vasculopathy

Effect of renal function under left ventricular assist device support on the cardiac function and clinical events after heart transplantation.

We investigated the effects of pre-transplantation renal dysfunction under left ventricular assisted device (LVAD) support on post-transplantation cardiac function, and patient prognosis after heart transplantation (HTx). All patients who were bridged by LVAD and underwent HTx at our hospital between 2007 and 2022 were included in this study. Patients were classified into two groups based on estimated glomerular filtration rate (eGFR) before HTx: renal dysfunction (RD) group (eGFR<60mL/min/1.73m2 ) and non-renal dysfunction (NRD) group. A total of 132 patients were analyzed, of whom 48 were classified into the RD group and 84 into the NRD group (RD group, 47.9±10.1years; NRD group, 38.4±11.9years, p<.0001). Under LVAD support before HTx, the RD group tended to have a history of right ventricular failure (RD group, nine (19%); NRD group, seven (8%); p=.098). After HTx, the echocardiographic parameters did not differ between the two groups in the long term. Furthermore, more concise hemodynamic parameters, exemplified by right heart catheterization, were not significantly different between the two groups. Regarding graft rejection, no significant differences were foundin acute cellular rejection and cardiac allograft vasculopathy following HTx. In contrast, patients with RD before HTx had significantly increased mortality in the chronic phase after HTx and initiation of maintenance dialysis, without any overt changes in cardiac function. Pre-transplantation renal dysfunction under LVAD support significantly affected clinical course after HTx without any overt changes in graft cardiac function.

Use of Intravascular Ultrasound and Coronary Angiography to Measure the Prevalence of Myocardial Bridge in Heart Transplant Patients

Myocardial bridge (MB) detection rates vary across methods and most studies that have assessed MB include symptomatic patients. Intravascular ultrasound (IVUS) is a sensitive tool for MB detection and donor hearts may serve as a surrogate measure of asymptomatic patients. We used IVUS and coronary angiography to measure MB prevalence in heart transplant patients during routine follow-up invasive coronary assessments. This was a retrospective, single-center study of heart transplant patients who received follow-up coronary assessments at the University of Chicago Heart and Vascular Center between December 2014 and December 2021. A single experienced interventional cardiologist assessed incidental findings of MB in IVUS and coronary angiography. Detection rates were compared with meta-analysis-reported prevalence. Of 129 patients, IVUS-detected MB in 87 patients (67.4%), whereas coronary angiography detected 41 (31.8%). All MB found by coronary angiography were detected by IVUS. Some level of cardiac allograft vasculopathy was found in 92 patients (71.3%). Our IVUS-detected MB prevalence was greater than meta-analysis-reported pooled prevalence across all methods: autopsy, computed tomography angiography, and coronary angiography (67.4% [95% confidence interval [CI] 59.4 to 75.5] vs 42% [95% CI 30 to 55]; 22% [95% CI 18 to 25]; 6% [95% CI 5 to 8], p≤0.005). The difference between our observed IVUS-detected MB prevalence and meta-analysis autopsy reported MB prevalence was 1.25 (95% CI 1.11 to 1.40). In conclusion, the high prevalence of MB recorded in donor hearts emphasizes the need to further investigate the causes of chest pain in patients who are found to have MB.

Conversion between sirolimus and everolimus in heart transplant recipients.

Sirolimus and everolimus are mechanistic target of rapamycin inhibitors (mTORi) that may be included in immunosuppression regimens for orthotopic heart transplant (OHT) recipients. mTORi play a role in slowing progression of cardiac allograft vasculopathy; however, they have poor tolerability, sometimes necessitating a change between agents or therapies. The literature surrounding a conversion between mTORi are incongruent, thus this study was designed to assess the concentration/dose ratio for each medication around the time of conversion to provide guidance for a conversion strategy between mTORi. We conducted a retrospective study of adult OHT recipients who were maintained on both sirolimus- and everolimus-based immunosuppression regimens. The primary outcome was the concentration/dose (C/d) ratio of sirolimus to everolimus. Secondary outcomes included changes in hematologic and lipid labs and patient-reported intolerances. The C/d ratio of sirolimus was 4.42, whereas the everolimus ratio was 2.23, resulting in a sirolimus: everolimus ratio of 1.98. Secondarily, after converting between mTORi, 93% of patients who reported intolerance(s) to one agent had a resolution of that intolerance. In our patient population, everolimus appeared better tolerated than sirolimus, with significantly more patients having no reported intolerances and significantly fewer patients experiencing edema. Other lab values were similar between patients receiving sirolimus and everolimus, except for an increased hemoglobin level in those receiving everolimus. The conversion ratio of 1:2 observed in our population suggests OHT recipients may require an increased dose of EVL compared with SRL to maintain the same goal trough levels. A conversion between mTORi appeared to improve tolerability and did not lead to clinically significant worsening of any measured lab value.

Heart transplantation and human immunodeficiency virus–navigating drug-drug interactions: a case report

BackgroundAntiretroviral therapy (ART) has led to a decline in human immunodeficiency virus (HIV)-related mortality, but comorbidities, including organ dysfunction, are increasingly the focus of care. Heart transplant (HT) is a very effective therapeutic strategy for end-stage heart failure (HF); however, clinicians may be hesitant due to concerns of complex drug-drug interactions (DDIs) between ART and HT immunosuppressive regimens and the potential impact of ART on long-term HT outcomes. In this report, we describe long-term (76-month) follow-up of a patient with HIV-positive status who underwent orthotopic HT with special emphasis on complex drug interactions.Case presentationA 58-year-old man with HIV-1 developed ischemic cardiomyopathy, progressed to end-stage HF and underwent orthotopic HT. To avoid DDIs with planned immunosuppressive therapies, the ART regimen was modified to consist of lamivudine, tenofovir disoproxil fumarate, rilpivirine, and raltegravir. Following HT, the patient’s immunosuppression consisted of tacrolimus and mycophenolate mofetil. He has had normal cardiac function and no opportunistic infections and was subsequently switched to tenofovir alafenamide, emtricitabine, and bictegravir in combination for convenience. Serial HIV-1 RNA blood levels were constantly below the limit of quantification, and his CD4 count remained above 200 cells/mm3 (30–35%). Several DDIs were identified and addressed; however, his long-term post-HT complications included one episode of asymptomatic acute cellular rejection, adenocarcinoma of the prostate, basal cell carcinoma, cardiac allograft vasculopathy, and peripheral neuropathy.ConclusionThe clinical outcome of this case supports the conclusion of previously published reports, summarized here within, demonstrating that HIV-1 positive status should not preclude HT in carefully selected individuals. Both addressing potential DDIs prior to HT and long-term monitoring for routine post-transplant complications and secondary and incidental malignancies are imperative.

Abstract P1124: Immunosuppression Drug Mediated Cardiovascular Effects

Heart transplantation continues to be a life-saving therapy for patients with end-stage heart failure; yet the average long-term graft survival remains at only 12.5 years. Cardiac allograft vasculopathy (CAV) and cardiac graft dysfunction are both key contributors to long-term morbidity and mortality in the heart transplant population. Studies have suggested that immunosuppressive agents may modulate cardiovascular function, yet the mechanisms for this modulation is incompletely understood. The primary classes of immunosuppressive agents utilized post-heart transplantation are mammalian target of rapamycin inhibitors (e.g. sirolimus), calcineurin inhibitors (e.g. tacrolimus), and purine synthesis inhibitors (e.g. mycophenolate mofetil). Our prior findings indicate no discernible change to cell contraction or viability, but increased fibrosis and adverse remodeling in response to tacrolimus treatment. Using cardiac organoids; composed of human induced pluripotent stem cells (hiPSCs) derived cardiomyocytes, endothelial cells, and cardiac fibroblasts; we investigated the effects of these agents on the cardiovascular system using RNA-sequencing and proteomic analysis. Proteomic analysis of cardiac organoids was done using Luminex bead-array assay. Treatment with MPA coincided with a significant reduction of proinflammatory cytokines including the various interleukin-families and TNF-alpha/beta. Tacrolimus yielded mixed results on proteins associated with cardiac remodeling but indicated significant upregulation of proteins that have been implicated in CAV progression. In addition, RNA-sequencing findings revealed significant upregulation of genes associated with cardiac fibrosis and remodeling with tacrolimus treatment in comparison to sirolimus treatment. These findings correlate with functional profile observed on treatment of cardiac organoids. Our results provider further insight into the pathways by which differential immunosuppression drugs influence cardiovascular remodeling.

Atypical infiltrates on endomyocardial biopsy are associated with adverse outcomes in pediatric heart transplantation

The significance of atypical infiltrates (eosinophils or plasma cells) on endomyocardial biopsy (EMB) after pediatric heart transplant (HTx) is not known. We hypothesized that atypical infiltrates are associated with worse post-HTx outcomes. We performed a retrospective cohort study of consecutive patients <21 years old who underwent primary HTx between 2013 and 2017. Multiorgan transplants were excluded. The presence of atypical infiltrates and burden of atypical infiltrates (rare vs predominant) on EMB were recorded. Primary outcome was a composite of cardiac allograft vasculopathy, graft failure (relisting or retransplant), or death. Presence of atypical infiltrates was evaluated: (1) overall using Cox regression with time-dependent covariates and (2) if present by 1 year post-HTx using Kaplan-Meier analysis. Atypical infiltrates were present in 24 out of 95 patients (25%) and were associated with a higher likelihood of reaching the composite outcome (hazard ratio (HR) 6.22, 95% confidence interval (CI) 2.60-14.89, p<0.0001). This persisted when controlling for rejection in multivariable analysis. There was also a greater risk of the composite outcome if ≥2 nonconsecutive EMBs had atypical infiltrates (HR 11.80, 95%CI 3.17-43.84, p=0.0002) or if atypical infiltrates were the predominant feature on EMB (HR 30.58, 95%CI 9.34-100.06, p<0.0001). Patients with atypical infiltrates by 1-year post-HTx had a 5-year freedom from the composite outcome of 48%, compared to 90% if no atypical infiltrates had been present by this timepoint (log rank p=0.002). The presence of atypical infiltrates on EMB is associated with significantly worse outcomes in children following HTx. These patients require closer follow-up to assess for developing graft dysfunction.

Early optical coherence tomography evaluation of donor-transmitted atherosclerosis and cardiac allograft vasculopathy: insights from a prospective, single-center study

The impact of donor transmitted atherosclerosis as assessed by intravascular ultrasound on development and progression of cardiac allograft vasculopathy (CAV) after heart transplantation (HT) remains poorly defined in contemporary practice. In this exploratory analysis, we sought to assess the prognostic role of early qualitative assessment of donor artery morphology using optical coherence tomography (OCT) as a more sensitive imaging modality. HT recipients were prospectively enrolled for baseline OCT imaging of the left anterior descending coronary artery. OCT findings were classified as normal, homogeneous intimal thickening, and advanced plaque characteristics. The endpoint was a composite of cardiac death, myocardial infarction, or new angiographically detectable CAV stratified by the International Society of Heart and Lung Transplantation criteria up to 4 years of follow-up. A total of 35 patients underwent baseline OCT of whom 51.4% had normal OCT, 14.3% had homogenous plaque, and 34.3% had advanced characteristics. There were no significant differences in baseline demographics between patients with and without normal morphology. During a mean follow-up of 3.3±0.4 years, the endpoint occurred in 11 patients including 1 death, 7 CAV1, 3 CAV2, and 1 CAV3. Kaplan-Meier analysis revealed a significantly higher event rate in patients with advanced characteristics (log-rank p=0.010). In multivariate analysis, OCT-based plaque morphology was an independent predictor of clinical events (adjusted hazard ratio 4.57, 95% confidence interval 1.50-13.92, p=0.008) while maximal intimal thickness ≥0.5mm was not. Early qualitative OCT assessment of donor coronary artery morphology appears to be a reliable marker for predicting future cardiovascular events in HT recipients. Our findings warrant more careful study in a larger cohort.