Incidence Of Cardiac Allograft Vasculopathy Research Articles

Abstract Tu031: Immunosuppression Drug Modulation of Endothelial Cell Function

Heart transplantation is a life-saving therapy for patients with end-stage heart failure with over 4,000 transplants occurring per year. The use of immunosuppression drugs is necessary in post transplantation to prevent graft rejection. Proliferation signal inhibitors have previously been shown to effectively reduce the incidence of cardiac allograft vasculopathy (CAV) compared to calcineurin inhibitors but the differential mechanisms that drive this benefit and differences in vascular profile of immunosuppression drugs remain incompletely understood. In this study, we examined the direct effect of immunosuppressive agents on endothelial function to define cellular mechanisms that may contribute to differential vascular phenotypes. We used endothelial cells derived from human induced pluripotent stem cells (iPSCs) and treated them with calcineurin inhibitor (tacrolimus), mTOR inhibitor (sirolimus), or vehicle for 5 days with daily media changes. We examined endothelial function using scratch wound assay, tube formation assay, and LDL uptake. We also examined metabolic changes using Seahorse assay owing to metabolic changes induced by immunosuppression drugs in other organs. Our results indicate mTOR inhibitor (sirolimus) resulted in a reduction in endothelial cell proliferation and migration using the scratch wound assay and tube formation assay compared to vehicle or calcineurin inhibitor (tacrolimus)-treated cells. Sirolimus also reduced LDL uptake in iPSC-derived endothelial cells compared to vehicle or tacrolimus-treated cells. Tacrolimus was associated with a trend towards altered endothelial energetics. Tacrolimus and sirolimus exert differential endothelial cell functional profiles that do not fully explain the clinical outcomes observed suggesting a need to explore the drug endothelial profiles in the context of vascular injury and inflammation.

Comparison of cardiac allograft vasculopathy incidence between simultaneous multiorgan and isolated heart transplant recipients in the United States

BackgroundPrior studies have shown reduced development of cardiac allograft vasculopathy (CAV) in multi-organ transplant recipients. The aim of this study was to compare the incidence of CAV between isolated heart transplants and simultaneous multi-organ heart transplants in the contemporary era. MethodsWe utilized the Scientific Registry of Transplant Recipients to perform a retrospective analysis of first-time adult heart transplant recipients between January 1, 2010 and December 31, 2019 in the United States. The primary endpoint was the development of angiographic CAV within 5 years of follow-up. ResultsAmong 20,591 patients included in the analysis, 1,279 (6%) underwent multi-organ heart transplantation (70% heart-kidney, 16% heart-liver, 13% heart-lung, and 1% triple-organ) and 19,312 (94%) were isolated heart transplant recipients. The average age was 53 years and 74% were male. There were no significant between-group differences in cold ischemic time between the groups. The incidence of acute rejection during the first year after transplant was significantly lower in the multi-organ group (18% vs. 33%, p<0.01). The 5-year incidence of CAV was 33% in the isolated heart group and 27% in the multi-organ group (p<0.0001); differences in CAV incidence were seen as early as 1 year after transplant and persisted over time. In multivariable analysis, multi-organ heart transplant recipients had a significantly lower likelihood of CAV at 5 years (hazard ratio=0.76, 95% confidence interval: 0.66-0.88, p<0.01). ConclusionsSimultaneous multi-organ heart transplantation is associated with significantly lower long-term risk of angiographic CAV compared with isolated heart transplantation in the contemporary era.

(386) - Lower Platelet Count Following Induction with Antithymocyte Globulin is Associated with a Lower Incidence of Cardiac Allograft Vasculopathy

(386) - Lower Platelet Count Following Induction with Antithymocyte Globulin is Associated with a Lower Incidence of Cardiac Allograft Vasculopathy

Cardiac allograft vasculopathy in heart transplant recipients from hepatitis C viremic donors.

Recent studies suggest the transplantation of Hepatitis C (HCV) hearts from viremic donors is associated with comparable 1 year survival to nonviremic donors. Though HCV viremia is a known risk factor for accelerated atherosclerosis, data on cardiac allograft vasculopathy (CAV) outcomes are limited. We compared the incidence of CAV in heart transplant recipients from HCV viremic donors (nucleic acid amplification test positive; NAT+) compared to non-HCV infected donors (NAT-). We retrospectively reviewed annual coronary angiograms with intravascular ultrasound from April 2017 to August 2020 at two large cardiac transplant centers. CAV was graded according to ISHLT guidelines. Maximal intimal thickness (MIT) ≥ 0.5mm was considered significant for subclinical disease. Among 270 heart transplant recipients (mean age 54; 77% male), 62 patients were transplanted from NAT+ donors. CAV ≥ grade 1 was present in 8.8% of the NAT+ versus 16.8% of the NAT- group at 1 year, 20%versus 28.8% at 2 years, and 33.3%versus 41.5% at 3 years. After adjusting for donor age, donor smoking history, recipient BMI, recipient, hypertension, and recipient diabetes, NAT+ status did not confer increased risk of CAV (HR.80; 95% CI.45-1.40, p=0.43) or subclinical IVUS disease (HR.87; 95% CI.58-1.30, p=0.49). Additionally, there was no difference in the presence of rapidly progressive lesions on IVUS. Our data show that NAT+ donors conferred no increased risk for early CAV or subclinical IVUS disease following transplantation in a cohort of heart transplant patients who were treated for HCV, suggesting the short-term safety of this strategy to maximize the pool of available donor hearts.

Cardiac PET Myocardial Blood Flow Quantification Assessment of Early Cardiac Allograft Vasculopathy

BackgroundPositron emission tomography (PET) has demonstrated utility for diagnostic and prognostic assessment of cardiac allograft vasculopathy (CAV) but has not been evaluated in the first year after transplant. ObjectivesThe authors sought to evaluate CAV at 1 year by PET myocardial blood flow (MBF) quantification. MethodsAdults at 2 institutions enrolled between January 2018 and March 2021 underwent prospective 3-month (baseline) and 12-month (follow-up) post-transplant PET, endomyocardial biopsy, and intravascular ultrasound examination. Epicardial CAV was assessed by intravascular ultrasound percent intimal volume (PIV) and microvascular CAV by endomyocardial biopsy. ResultsA total of 136 PET studies from 74 patients were analyzed. At 12 months, median PIV increased 5.6% (95% CI: 3.6%-7.1%) with no change in microvascular CAV incidence (baseline: 31% vs follow-up: 38%; P = 0.406) and persistent microvascular disease in 13% of patients. Median capillary density increased 30 capillaries/mm2 (95% CI: −6 to 79 capillaries/mm2). PET myocardial flow reserve (2.5 ± 0.7 vs 2.9 ± 0.8; P = 0.001) and stress MBF (2.7 ± 0.6 vs 2.9 ± 0.6; P = 0.008) increased, and coronary vascular resistance (CVR) (49 ± 13 vs 47 ± 11; P = 0.214) was unchanged. At 12 months, PET and PIV had modest correlation (stress MBF: r = −0.35; CVR: r = 0.33), with lower stress MBF and higher CVR across increasing PIV tertiles (all P < 0.05). Receiver-operating characteristic curves for CAV defined by upper-tertile PIV showed areas under the curve of 0.74 for stress MBF and 0.73 for CVR. ConclusionsThe 1-year post-transplant PET MBF is associated with epicardial CAV, supporting potential use for early noninvasive CAV assessment. (Early Post Transplant Cardiac Allograft Vasculopahty [ECAV]; NCT03217786)

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.

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

Graft function and incidence of cardiac allograft vasculopathy in donation after circulatory-determined death heart transplant recipients

Experience in donation after circulatory-determined death (DCD) heart transplantation (HTx) is expanding. There is limited information on the functional outcomes of DCD HTx recipients. We sought to evaluate functional outcomes in our cohort of DCD recipients. We performed a single-center, retrospective, observational cohort study comparing outcomes in consecutive DCD and donation after brain death (DBD) HTx recipients between 2015 and 2019. Primary outcome was allograft function by echocardiography at 12 and 24 months. Secondary outcomes included incidence of cardiac allograft vasculopathy, treated rejection, renal function, and survival. Seventy-seven DCD and 153 DBD recipients were included. There was no difference in left ventricular ejection fraction at 12 months (59% vs 59%, P = .57) and 24 months (58% vs 58%, P = .87). There was no significant difference in right ventricular function at 12 and 24 months. Unadjusted survival between DCD and DBD recipients at 5 years (85.7% DCD and 81% DBD recipients; P = .45) was similar. There were no significant differences in incidence of cardiac allograft vasculopathy (odds ratio 1.59, P = .21, 95% confidence interval 0.77-3.3) or treated rejection (odds ratio 0.60, P = .12, 95% confidence interval 0.32-1.15) between DBD and DCD recipients. Post-transplant renal function was similar at 1 and 2 years. In conclusion, cardiac allografts from DCD donors perform similarly to a contemporary population of DBD allografts in the medium term.

Primary Graft Dysfunction Is Associated With Development of Early Cardiac Allograft Vasculopathy, but Not Other Immune-mediated Complications, After Heart Transplantation.

We investigated associations between primary graft dysfunction (PGD) and development of acute cellular rejection (ACR), de novo donor-specific antibodies (DSAs), and cardiac allograft vasculopathy (CAV) after heart transplantation (HT). A total of 381 consecutive adult HT patients from January 2015 to July 2020 at a single center were retrospectively analyzed. The primary outcome was incidence of treated ACR (International Society for Heart and Lung Transplantation grade 2R or 3R) and de novo DSA (mean fluorescence intensity >500) within 1 y post-HT. Secondary outcomes included median gene expression profiling score and donor-derived cell-free DNA level within 1 y and incidence of cardiac allograft vasculopathy (CAV) within 3 y post-HT. When adjusted for death as a competing risk, the estimated cumulative incidence of ACR (PGD 0.13 versus no PGD 0.21; P = 0.28), median gene expression profiling score (30 [interquartile range, 25-32] versus 30 [interquartile range, 25-33]; P = 0.34), and median donor-derived cell-free DNA levels was similar in patients with and without PGD. After adjusting for death as a competing risk, estimated cumulative incidence of de novo DSA within 1 y post-HT in patients with PGD was similar to those without PGD (0.29 versus 0.26; P = 0.10) with a similar DSA profile based on HLA loci. There was increased incidence of CAV in patients with PGD compared with patients without PGD (52.6% versus 24.8%; P = 0.01) within the first 3 y post-HT. During the first year after HT, patients with PGD had a similar incidence of ACR and development of de novo DSA, but a higher incidence of CAV when compared with patients without PGD.

Molecular Signature of Antibody-Mediated Chronic Vasculopathy in Heart Allografts in a Novel Mouse Model

Cardiac allograft vasculopathy (CAV) limits the long-term success of heart transplants. Generation of donor-specific antibodies (DSAs) is associated with increased incidence of CAV clinically, but mechanisms underlying development of this pathology remain poorly understood. Major histocompatibility complex-mismatched A/J cardiac allografts in B6.CCR5-/- recipients have been reported to undergo acute rejection with little T-cell infiltration, but intense deposition of C4d in large vessels and capillaries of the graft accompanied by high titers of DSA. This model was modified to investigate mechanisms of antibody-mediated CAV by transplanting A/J hearts to B6.CCR5-/- CD8-/- mice that were treated with low doses of anti-CD4 monoclonal antibody to decrease T-cell-mediated graft injury and promote antibody-mediated injury. Although the mild inhibition of CD4 T cells extended allograft survival, the grafts developed CAV with intense C4d deposition and macrophage infiltration by 14 days after transplantation. Development of CAV correlated with recipient DSA titers. Transcriptomic analysis of microdissected allograft arteries identified the Notch ligand Dll4 as the most elevated transcript in CAV, associated with high versus low titers of DSA. More importantly, these analyses revealed a differential expression of transcripts in the CAV lesions compared with the matched apical tissue that lacks large arteries. In conclusion, these findings report a novel model of antibody-mediated CAV with the potential to facilitate further understanding of the molecular mechanisms promoting development of CAV.

Impact Of Recipient CMV Serological Status On Outcomes After Heart Transplantation In Contemporary Prophylactic Treatment Era

Background Cytomegalovirus (CMV) infection can limit the long term success of heart transplantation (HT) by promoting cardiac allograft vasculopathy (CAV). Moreover, prophylactic treatment of HT recipients with ganciclovir and/or CMV hyperimmune globulin reduces the incidence of CAV. We aimed to determine the prognostic impact of CMV serostatus of the donor and recipient and its effect on survival, graft failure and drug treated rejection in the contemporary prophylactic treatment era. Methods We identified adult patients who underwent HT between 2000 and 2018 in the Scientific Registry of Transplant Recipients. These patients were categorized as per recipient and donor CMV serological status. We compared survival with the Kaplan-Meier method. We constructed Cox proportional hazards regression models to determine the risk-adjusted influence of CMV serostatus on survival. Results Out of 34,279 HT recipients, 46.3 % had dissimilar (8028 with -/+ and 7840 with +/-) and 53.7% had similar (n=5417 with -/- and 12,994 with+/+) CMV serostatus. Compared to dual negative CMV serostatus, recipients with other CMV serostatuses had significantly higher 1-, 3- and 5-year mortality (Figure & Table 1). Surprisingly, while CMV +/- had an increased prevalence of graft failure, CMV -/+ had a decreased prevalence of graft failure when compared to the dual negative serotype. There was no significant difference for drug treated rejection between groups (Table 2). Conclusion Recipient and donor CMV seronegative status is associated with best post-HT survival and decreased graft failure. Despite prophylactic treatment CMV positive serostatus impacts post HT outcomes. This observation warrants further investigation into developing strategies to improve outcomes in this large HT cohort. Cytomegalovirus (CMV) infection can limit the long term success of heart transplantation (HT) by promoting cardiac allograft vasculopathy (CAV). Moreover, prophylactic treatment of HT recipients with ganciclovir and/or CMV hyperimmune globulin reduces the incidence of CAV. We aimed to determine the prognostic impact of CMV serostatus of the donor and recipient and its effect on survival, graft failure and drug treated rejection in the contemporary prophylactic treatment era. We identified adult patients who underwent HT between 2000 and 2018 in the Scientific Registry of Transplant Recipients. These patients were categorized as per recipient and donor CMV serological status. We compared survival with the Kaplan-Meier method. We constructed Cox proportional hazards regression models to determine the risk-adjusted influence of CMV serostatus on survival. Out of 34,279 HT recipients, 46.3 % had dissimilar (8028 with -/+ and 7840 with +/-) and 53.7% had similar (n=5417 with -/- and 12,994 with+/+) CMV serostatus. Compared to dual negative CMV serostatus, recipients with other CMV serostatuses had significantly higher 1-, 3- and 5-year mortality (Figure & Table 1). Surprisingly, while CMV +/- had an increased prevalence of graft failure, CMV -/+ had a decreased prevalence of graft failure when compared to the dual negative serotype. There was no significant difference for drug treated rejection between groups (Table 2). Recipient and donor CMV seronegative status is associated with best post-HT survival and decreased graft failure. Despite prophylactic treatment CMV positive serostatus impacts post HT outcomes. This observation warrants further investigation into developing strategies to improve outcomes in this large HT cohort.

Cardiac Allograft Vasculopathy in Heart Transplant Recipients from Hepatitis C Viremic Donors, Data from Two Large Academic Transplant Centers

<h3>Purpose</h3> Heart transplantation from Hepatitis C (HCV) viremic donors is an increasingly utilized strategy, though long-term outcomes with respect to cardiac allograft vasculopathy (CAV) are unknown. HCV is implicated as a potent trigger of the inflammatory cascade and may be associated with CAV. We report the incidence of CAV and subclinical disease in recipients of HCV-viremic donors (nucleic amplification test positive: NAT+) vs non-viremic donors (nucleic amplification test negative: NAT-) <h3>Methods</h3> We retrospectively reviewed coronary angiograms with intravascular ultrasound (IVUS) of patients who received NAT+ and NAT- hearts between January 2014 and July 2020 at two large academic institutions. Donor-derived acute HCV infection was treated with a direct-acting antiviral agent per site protocol. CAV was graded according to ISHLT guidelines. Maximal intimal thickness (MIT) of the left main and left anterior descending artery was measured by IVUS. MIT ≥ 0.5mm was considered significant subclinical disease. Two-sample t tests were performed for continuous variables. Chi-square or Fisher's exact test were used for categorical variables. <h3>Results</h3> Among 178 patients, 65 received NAT+ donor hearts. Average recipient age was 58 and 55 years in the NAT+ and NAT- groups respectively and 15% vs 27% were female. NAT- donors were older (42 vs 36 years), but with no significant difference in cardiac risk factors including tobacco use, hypertension, and diabetes. CAV ≥ grade 1 was present in 9.1% of the NAT+ vs 18.8% of the NAT- group at 1 year (p=0.16), and 19.4% vs 21.0% at 2 years (p=1). Rates of significant IVUS disease were 53.7% in NAT+ vs 70.5% in NAT- at 1 year (p=0.068), and 72.2% vs 78.3% at 2 years (p=0.3). <h3>Conclusion</h3> Among heart transplant recipients from HCV viremic donors our data show no difference in rates of angiographic CAV or subclinical disease by IVUS at 1 or 2 years. While these results are encouraging, longer follow up is needed to assess CAV risk in this population.

Carbohydrate Metabolism Disorders in Relation to Cardiac Allograft Vasculopathy (CAV) Intensification in Heart Transplant Patients According to the Grading Scheme Developed by the International Society for Heart and Lung Transplantation (ISHLT).

BackgroundCardiac allograft vasculopathy (CAV) is the leading complication limiting the long-term survival of heart transplant (HTx) patients. The goal of this study was to assess carbohydrate metabolism disorders in relation to CAV intensification in heart transplant patients according to the ISHLT grading scheme.Material/MethodsThis retrospective study involved 477 HTx recipients undergoing angiographic observation for up to 20 years after transplantation. The patients were assigned to 4 groups on the basis of their carbohydrate metabolism status: without diabetes, with type 2 diabetes prior to HTx, with new-onset diabetes after transplantation, and with transient hyperglycemia.ResultsIn the study, 62.7% (n=299) of the patients manifested no diabetes after HTx, while 14.3% (n=68) of patients had type II diabetes prior to HTx and 18.4% (n=88) developed new-onset diabetes after transplantation. In total, 1442 coronary angiograms were taken in the specified control periods. CAV incidence increased over time after transplantation, reaching 11% after 1 year, 57% after 10 years, and 50% after 20 years. The longest survival time was observed for patients who had developed type II diabetes prior to HTx, but the difference was not statistically significant. The multivariate analysis failed to identify an independent risk factor for developing cardiac allograft vasculopathy.ConclusionsDespite the relatively high rates of CAV and carbohydrate metabolism disorders in heart transplant patients, our retrospective analysis revealed no statistically significant link between these 2 diseases.

Abstract 13704: Early Trends in Cardiac Allograft Vasculopathy After Implementation of the New 2018 Donor Heart Allocation Protocol in the United States

Introduction: The new donor heart allocation policy implemented in October 2018 prioritizes hemodynamically unstable patients with the greatest need for urgent transplantion. The impact of this policy change on the incidence of cardiac allograft vasculopathy (CAV) has not been described. Methods: We performed a retrospective analysis of adult (≥ 18 years) heart transplant recipients registered in the UNOS database between 10/18/2015 - 11/25/2019 to evaluate the effect of the new allocation system on angiographic CAV at 1 year. Recipients undergoing first-time single organ heart transplant with 1 year follow-up were stratified based on the old (10/18/2015 - 10/17/2018) or new (10/18/2018 - 11/25/2019) allocation system. Recipient and donor demographic and cardiovascular risk factors, wait-list factors, and transplant factors with a p-value &lt; 0.10 in univariable analysis were included in multivariable logistic regression models to identify independent predictors of accelerated CAV. Results: Of 8,724 transplant recipients (mean age 54 ± 13 years, 73% male), 6,661 (76%) and 2,063 (24%) were listed in the old and new allocation systems, respectively. The old cohort consisted of 4,409 (66%) classified as Status 1A, while the new cohort consisted of 168 (8%) classified as Status 1 and 944 (46%) as Status 2. The incidence of accelerated CAV was 520 (7.8%) in the old allocation cohort compared with 130 (6.3%) in the new allocation cohort (p=0.02). In adjusted analyses, the new allocation system was significantly associated with a reduction in CAV (OR=0.72, 95% CI: 0.59-0.89, p=0.002; Table). This association persisted even after restricting the cohort to the highest acuity patients—Status 1A (old) and Status 1 or 2 (new) (OR=0.75, 95% CI: 0.57-0.99, p=0.04). Conclusions: The new donor heart allocation system is significantly associated with lower rates of accelerated angiographic CAV at 1 year, including among recipients requiring the most urgent transplants.

Abstract 13053: Cardiac Allograft Vasculopathy Following Donation After Circulatory-Determined Death Heart Transplantation

Introduction: Cardiac allograft vasculopathy (CAV) remains a major problem for heart transplant (HTx) recipients, limiting their long-term survival. Our centre has performed the world’s largest series of donation after circulatory-determined death (DCD) HTx. Five-year survival is equivalent to donation after brainstem-determined death (DBD) HTx. However, there is no information on CAV in DCD HTx recipients. We sought to evaluate the incidence of CAV in our cohort of DCD HTx recipients. Methods: All DCD HTx recipients at our centre between February 2015 and December 2019 who had undergone CAV screening were included. They were compared with all DBD recipients during the same period who had undergone CAV screening. Angiograms were retrospectively assigned an ISHLT CAV grade by two independent observers. Results: Thirty-six DCD and 70 DBD HTx recipients were included in the study. Median time to first imaging of coronary arteries was 621 days and 572 days for DCD and DBD cohorts respectively. There was a higher proportion of male donors in the DCD cohort (p= 0.03) but no other significant differences between donor baseline characteristics. DCD recipients had a lower median pre-transplant pulmonary vascular resistance (p=0.03) but there were no other significant differences in recipient baseline characteristics. The two cohorts had similar rates of pre-operative durable LVAD use, post-transplant mechanical circulatory support and post-transplant immunosuppression regimes. There was no significant difference in the rates of CAV between the DBD and DCD groups (p=0.41) (Figure 1). When adjusted for standard risk factors for development of CAV (including donor factors, CMV status and rejection) there remained no significant difference between rates of CAV between groups (OR 1.48, p=0.41, 95% CI 0.58-3.78). Conclusions: DCD HTx recipients have similar rates of CAV when compared to a contemporary population of DBD HTx recipients.

The effects of donor-specific antibody characteristics on cardiac allograft vasculopathy.

Cardiac allograft vasculopathy (CAV) causes late graft dysfunction and post-transplant mortality. Currently, the effects of different donor-specific antibodies (DSA) on the severity of CAV remain unclear. We evaluated 526 adult heart transplant recipients at a single center between January 2010 and August 2015. Subjects were divided into those with DSA (n = 142) and those without DSA (n = 384, control). The DSA group was stratified into persistent DSA (n = 34), transient DSA (n = 105), 1:8 dilution DSA (n = 45), complement-binding (C1q) DSA (n = 36), Class I DSA (n = 37), and Class II DSA (n = 105). The primary outcome was the incidence of moderate-to-severe CAV (CAV 2/3) at 5-year follow-up. Subjects with persistent DSA, 1:8 dilution DSA, and C1q DSA had higher incidence of CAV 2/3 compared the control group (17.6%, 13.3%, and 16.7% vs. 3.1%, respectively; P≤ .001). The incidence of CAV 2/3 between subjects with transient DSA and the control group was similar (2.8% vs. 3.1%; P = .888). Subjects with Class II DSA also had higher incidence of CAV 2/3 (7.6% vs. 3.1%; P = .039). DSA that are persistent, 1:8 dilution positive, C1q positive, and Class II are associated with more severe grades of CAV. These DSA characteristics may prognosticate disease and warrant consideration for treatment.

Early aspirin use, allograft rejection, and cardiac allograft vasculopathy in heart transplantation

Early aspirin (ASA) use after orthotopic heart transplantation (OHT) has been associated with lower rates of cardiac allograft vasculopathy (CAV). We hypothesized that the inverse association between ASA use and CAV incidence may be most pronounced in patients with allograft rejection. Patients receiving OHT at a single center 2004-2010 (n=120) were categorized by early ASA use post-transplant (ASA use for>6 months in the first year) and the presence of biopsy-defined acute cellular rejection (ACR) and/or antibody-mediated rejection (AMR) during 5-year follow-up. Propensity scores for ASA treatment were estimated using boosting models and applied by inverse probability of treatment weighting. The association between ASA use and time to moderate/severe CAV (ISHLT ≥ 2) was investigated. Among patients with ACR or AMR, ASA therapy was associated with significantly lower rates of CAV≥ 2 (3.3vs. 30.1%; P=.001; HRadj .07; 95% CI .01-.52), whereas ASA therapy was not associated with lower rates of CAV in patients with no rejection (5.6vs. 5.3%; P=.90; HRadj 1.26; 95% CI .08-20.30; pinteraction =.09). Early ASA use after OHT was associated with lower rates of moderate to severe CAV only in those patients with episodes of allograft rejection.

Low-Density Lipoprotein Cholesterol Trends and the Development of Cardiac Allograft Vasculopathy after Heart Transplantation

<h3>Purpose</h3> The relationship between low-density lipoprotein cholesterol (LDL-C) and cardiac allograft vasculopathy (CAV) is unclear. The objectives of this study were to characterize lipid profiles early after heart transplant (HT), and to evaluate the relationship between early serum LDL-C and the development of CAV. <h3>Methods</h3> We retrospectively reviewed consecutive adults who underwent HT at the University of Ottawa Heart Institute (Ottawa, Canada) and Toronto General Hospital (Toronto, Canada) from 2010-2018. The primary outcome was the incidence of CAV (ISHLT grade 1-3). The relationship between LDL-C and CAV was assessed using Cox proportional hazards and logistic regression models adjusted <i>a priori</i> for clinically important covariates including recipient and donor age, recipient sex, ischemic time and pre-HT diabetes. <h3>Results</h3> 386 patients followed for 4.4 (2.8-6.8) years were included. LDL-C at baseline (2.11±0.86 mmol/L) and at 1-year after HT (2.20±0.88 mmol/L) was similar (p=0.21) but was significantly lower at the end of study follow-up (1.89±0.74 mmol/L) (p<0.01). Of 309 patients who underwent angiography, 54% developed CAV. The risk of CAV did not vary according to baseline, 1-year or change from baseline to 1-year pre-specified LDL-C thresholds (Figure). The odds of CAV at 1-year was equally likely across LDL-C values (adjusted OR 1.00, 95% CI: 0.61-1.63 for baseline and adjusted OR 1.25, 95% CI: 0.74-2.10 for 1-year LDL-C). <h3>Conclusion</h3> There was no relationship between early LDL-C and the development of CAV after HT. Our findings do not support targeting a specific LDL-C for patients who do not otherwise meet criteria for non-HT guideline recommended LDL-C targets. Randomized studies are warranted to determine if lipid-lowering to a specific LDL-C target decreases the development and progression of CAV.

The Effects of Donor-Specific Antibody Characteristics on Cardiac Allograft Vasculopathy

Purpose Cardiac allograft vasculopathy (CAV) is a major cause of late graft dysfunction and mortality after heart transplantation. The pathophysiology of CAV consists of a complex interplay between donor risk factors, recipient comorbidities, and immune-mediated processes. Despite many studies showing a correlation between donor-specific antibodies (DSA) and CAV, the effects of different DSA types on the severity of CAV remains elusive. This study investigates the characteristics of DSA amongst different CAV severity groups. Methods We evaluated 526 adult heart transplant recipients at a single tertiary medical center between January 2010 and August 2015. Subjects were screened for DSA at the time of transplant, 1 month, 3 months, 6 months, 1 year, and then annually thereafter. CAV screening was performed with annual angiography. Subjects were divided into those with DSA (n= 143) and those without DSA (control group, n =383). Subjects with DSA were further categorized into those with persistent DSA (n=34), transient DSA (n=106), 1:8 dilution positive DSA (n=45), complement-binding (C1q) DSA (n=36), Class I DSA (n=36), and Class II DSA (n=106). The mean duration of follow up was 3.6 years. The outcomes are the incidence of CAV based on the ISHLT grading scale. Results Subjects with persistent DSA were found to have higher incidence of moderate-to-severe CAV (CAV2/3) compared the control group (p= Subjects with 1:8 dilution positive DSA and C1q positive DSA also had a higher incidence of CAV2/3 when compared those without DSA (p=0.001, p= Conclusion DSA that are persistent, 1:8 dilution positive, C1q positive, and Class II are associated with more severe grades of CAV. Given CAV2/3 is linked with higher mortality post-transplantation, these DSA characteristics may serve as prognostic markers of disease and may warrant consideration for treatment.

Risk factors for early development of cardiac allograft vasculopathy by intravascular ultrasound.

Cardiac allograft vasculopathy (CAV) is the leading cause of late graft loss. While there are numerous post-transplant factors which may increase the risk of the development of CAV, there is a paucity of data on the impact of donor-derived atherosclerosis (DA), early discontinuation of prednisone, and early initiation of proliferation signal inhibitors (PSI) as assessed by intravascular ultrasound (IVUS). Retrospective single-center study of all adult transplant patients (2008-2017) with serial IVUS at baseline and annually for 5years. DA was defined as a baseline maximal intimal thickness (MIT) ≥0.5mm, and CAV development was defined as MIT ≥1mm or an increase in MIT ≥0.5mm at year 1 compared with baseline or an increase in 0.3mm annually thereafter. Clinical risk factors for CAV were identified using multivariable hazard regression. Separate multistate models were applied to assess the association of prednisone discontinuation and PSI initiation and CAV. Of 282 patients screened, 186 patients had a 1-year angiogram. The mean age of those included in the cohort was 51±11years, 70% were male, 58% were Caucasian, and 27% were supported by a left ventricular assist device. Donor atherosclerosis was present in 40%. The cumulative incidence of CAV at 5years is 41% in DA- vs. 59% in DA + (p=.012). Donor age was a strong predictor of DA (p=.016). Significant risk factors for CAV included male sex (HR=4.141, p=.001), non-Caucasian race (HR=1.98, p=.011), BMI<18kg/m2 (HR=4.596, p=.042), longer ischemic time (HR=1.374, p=.028), older donor age (HR=1.158, p=.009), and rejection with hemodynamic compromise within the first year (HR=2.858, p=.043). Prednisone discontinuation within 1year was associated with a lower risk of CAV (HR 0.58 p=.047). Initiation of proliferation signal inhibitors (PSI) within 2years resulted in fewer cases of CAV (HR 0.397 p<.001). In patients with an angiogram at 1year, those with DA were significantly more likely to develop CAV. Lower incidence of CAV by IVUS was seen in patients who discontinued prednisone in the first year or had initiation of a PSI within two years of transplantation. Knowledge of early IVUS may allow a more tailored approach to patient management.