Transplant Coronary Artery Disease Research Articles

Mid-term and long-term outcomes following heart transplantation with prolonged cold ischemia

Objective: comparative analysis of long-term outcomes following heart transplantation (HT) with prolonged and short cold ischemia.Materials and methods. We analyzed the data of 29 orthotopic HT with >4 hours of cold ischemia. The transplant surgery was performed at Meshalkin National Medical Research Center between 2013 and the present time. Organs were obtained from donors from other regions. The control group consisted of 29 HTs with cold ischemia <4 hours, performed in the same period. The minimum distance between the transplant center and the donor base was about 250 km (Barnaul); the maximum distance was about 850 km (Krasnoyarsk). Recipient survival and postoperative peculiarities were analyzed.Results. In-hospital survival in the prolonged cold ischemia group was 89.7% (n = 26) with 3 deaths (10.3%). In the second group (<240 min), in-hospital survival was 79.3% (n = 23) with 6 (20.7%) deaths. The Kaplan-Meier survival analysis showed no difference between the groups (Log-Rank Test, P 1/4 0.59). In addition, cold ischemia time did not increase the risk of graft rejection and the risk of transplant coronary artery disease (TCAD).Conclusion. HT with cold ischemia >4 hours did not have worse outcomes than in short graft ischemia. This provides grounds for further accumulation of experience in the use of heart donors from remote locations.

Lung transplant and severe coronary artery disease: results from a single-centre experience.

The management of severe coronary artery disease at the time of a lung transplant remains a challenge. We analysed the short- and long-term outcomes of lung transplant recipients with severe coronary artery disease. Records of adult patients who received transplants at our institution between April 2010 and February 2021 were reviewed retrospectively. Severe coronary artery disease was defined as coronary stenosis ≥70% (main stem ≥50%) seen on the coronary angiographic scans performed before or at the time of listing. Patient characteristics, perioperative and long-term outcomes were compared between patients with and without severe coronary artery disease. Among 896 patients who received lung transplants who had undergone coronary angiography before the transplant, 77 (8.5%) had severe coronary artery disease; the remaining 819 (91.5%) did not. Patients with severe coronary artery disease were older (p < 0.0001), more often male (p < 0.0001) and received transplants more often for pulmonary fibrosis (p = 0.0007). The median (interquartile range) follow-up was 46 (20-76) months. At the Cox multivariable analysis, severe coronary artery disease was not associated with death. Patients with pretransplant percutaneous transluminal coronary angioplasty and patients with coronary artery bypass graft surgery concomitant to a transplant had survival equivalent to that of patients without severe coronary artery disease (p = 0.513; p = 0.556). Severe coronary artery disease was not associated with decreased survival after a lung transplant. Concomitant coronary artery bypass graft surgery and pretransplant percutaneous transluminal coronary angioplasty can be used for revascularization.

Abstract 55: Statin Type Does Matter: Decreasing Incorrect Statin Administration For Hospitalized Heart Transplant Patients

Background: Statin therapy has been shown to prevent the development of transplant coronary artery disease (TCAD) in heart transplant (HT) patients. Pravastatin is used in HT patients as it does not depend on CYP3A4 metabolism. Other widely used statins, such as simvastatin, have significant drug-drug interactions with the calcineurin inhibitors, which are used as standard immunosuppression therapy for all HT patients. Objective: Our goal was to increase correct statin administration for HT patients from 41-43% to 80% by June 2021 through electronic medical record (EMR) modification and interprofessional communication with the pharmacy department. Methods: Previous to our intervention, the EMR would recommend ordering simvastatin when ordering pravastatin, due to simvastatin being the hospital formulary preferred statin. The EMR did not cross reference HT status, and that pravastatin should be ordered instead. Our intervention was to remove the EMR notification for HT patients recommending simvastatin, as well as working with the clinical heart transplant pharmacists to mediate communication with primary teams. Monthly data was obtained through retrospective chart review. Results: Following our intervention in March 2021, pravastatin was ordered for 67%, 78%, and 81% of heart transplant readmissions in April, May, and June 2021, respectively (Table 1). Conclusion: Our intervention of EMR modification as well as interprofessional communication has almost doubled the correct administration of pravastatin in HT admissions from 41% to 81% over the course of seven months. Prescribing the proper statin for HT patients prevents unwanted toxicities, as well as TCAD - a major limitation to longevity amongst HT patients. Further educational interventions will be implemented for providers to achieve 100% correct statin administration to patients with heart transplant.

Alterations to the Intestinal Microbiome Are Associated with Post-Heart Transplant Outcomes in Children

<h3>Purpose</h3> Alterations to the intestinal microbiome are associated with mortality after stem cell transplant in adults. We hypothesize that alterations to the intestinal microbiome occur in children after pediatric heart transplant (HTx) and are associated with post-HTx outcomes. <h3>Methods</h3> Pre-HTx and post-HTx stool specimens were prospectively collected from 9/2018 - 7/2020. Bacterial DNA was extracted and processed through an Illumina MiSeq 16S sequencing pipeline. Separate regions of the 16S rRNA gene, V1V3 and V4, were targeted for sequencing. Resulting raw sequences were analyzed utilizing the UPARSE algorithm for clustering of sequences into operational taxonomic units (OTUs) and the SILVA v123 database for taxonomic classification of each OTU. The outcome was a composite "event" (infection, graft rejection, or transplant coronary artery disease) at the time of stool collection. <h3>Results</h3> There were 316 stool specimens (138 pre-HTx, 178 post-HTx) collected from 105 patients, including from 28 patients with sequential samples who underwent HTx during the study period. There are compositional differences between pre-HTx vs post-HTx patients (Fig 1A), most notably in the abundance of <i>Bacteroides, Enterococcus</i>, and <i>Akkermansia</i> species, and compositional shifts depending on time elapsed from HTx (Fig 1B). There were also specific compositional differences among patients with post-HTx events (most notably in the abundance of <i>Clostridium and Ruminococcus</i> species<i>;</i> Fig 1C) and among patients with post-HTx rejection (most notably in <i>Enterococcus, Bifidobacterium, and Akkermansia</i> species; Fig 1D). <h3>Conclusion</h3> Compositional alterations to the intestinal microbiome occur in children undergoing HTx. Specific differences were observed in children experiencing post-HTx composite events, including specific compositional changes among children with post-HTx rejection. Whether these compositional alterations are a cause or effect, or if they can be reversed, remains to be elucidated.

Analysis of survival and risk factors in recipients with coronary artery disease of a heart transplant

Objective: to conduct a comparative analysis of survival rate and development of heart transplant coronary artery disease risk factors during early and late post-transplantation periods. Materials and methods: a retrospective analysis of 58 patients with was conducted in S.V. Ochapovsky Region Clinical Hospital № 1, Krasnodar. Inclusion criteria were patients with vasculopathy; group № 1 — recipients with heart transplant coronary artery disease up until 3 years after heart transplantation; group № 1 — recipients with heart transplant coronary artery desease 3 years after heart transplantation. Endomyocardial biopsy, coronary angiography and immunological examination were used for monitoring heart recipients. Results: survival rate in group № 1 — 51,9%; in group № 2 — 64,5%. During studying the influence of age category on survival rate it was discovered that belonging to the age category influences on the survival rate in group № 1, p – 0,023. Death risk in group №1 is 1,7 (0,59 – 4,85) times higher in comparison with group № 2. When combined heart transplant coronary artery desease with cellular and humoral rejection in group №1 death risk is reliably 2,75 (1,58 – 4,78) times higher (p = 0,010). The frequency of heart transplant coronary artery desease recurrence does not have a meaningful impact on the survival rate of the recipients with heart transplant coronary artery desease n both groups. One of the meaningful risk factors in two groups, which affects heart transplant coronary artery desease development is cytomegalovirus infection. Cellular rejection is also a fact which influences lethal outcome.

Heart transplantation in diabetic recipients

Introduction . Heart transplantation (HT) in patients with preexisting type 2 diabetes (T2D) is associated with high risk of infectious and non-infectious complications (renal dysfunction, multifocal atherosclerosis, transplant coronary artery disease, etc.) that can negatively affect recipient survival in the early and late periods after HT. Objective: to assess the effect of pre-transplant T2D on early and long-term outcomes of HT based on a singlecenter retrospective study. Materials and methods . The study enrolled 891 recipients who underwent HT within the period 2011 to 2018, and were divided into two groups: main group (T2D) – recipients with pretransplant T2D (n = 80, 9.0%) and the control group (T2D-free) – recipients without T2D (n = 811, 91.0%). Recipients from both groups did not differ in terms of HT urgency (UNOS status) and the need for pre-transplant mechanical circulatory support (MCS). Results . At the time of the HT, recipients from the T2D group were older than the T2D-free recipients (54 [46; 59] years vs 48 [35; 56] years, p &lt; 0.001), they had a higher weight (p &lt; 0.001) and body mass index (p &lt; 0.001), coronary heart disease was more often their main disease (65.0% vs 36.5%, p &lt; 0.001), they had higher transpulmonary gradient (10.0 [7.0; 12.0] mm Hg vs 9.0 [6.0; 12.0] mm Hg, p = 0.024) and pulmonary vascular resistance (2.9 [2.2; 4.0] Wood units vs 2.5 [1.8; 3.4] Wood units, p = 0.038). In the pre-transplant period, the T2D group had pronounced manifestations of renal dysfunction and increased comorbidity. Recipients in both groups did not differ in terms of cardiac donor parameters, graft ischemia time, cardiopulmonary bypass time, and incidence of severe early heart graft dysfunction requiring MCS (12.5% vs 10.7%, p = 0.74). In the early post-transplant period, the T2D group had high requirements (100% vs 28.0%, p &lt; 0.001) and higher doses of insulin therapy. More pronounced manifestations of renal dysfunction and a greater need for renal replacement therapy (51.4% vs 27.9%, p = 0.003) did not affect artificial ventilation and ICU duration (6 [5; 10] days vs 6 [5; 10] days, p = 0.098), as well as hospital mortality ( 8.8% vs 8.5%, p = 0.895). The presence of pre-transplant T2D had no negative effect on the incidence of acute cardiac graft rejection, progression of transmissible coronary atherosclerosis, incidence and severity of cardiac graft vasculopathy, structure and severity of distant infectious and non-infectious complications, and post-transplant survival. Conclusion . With correct selection of recipients and choice of optimal tactics for their post-transplant management, the presence of pre-transplant T2D has no negative effect on early and long-term outcomes of HT.

Outcomes of mechanical support for cardiogenic shock associated with late cardiac allograft failure.

Late graft failure (LGF) is an unresolved issue after orthotopic heart transplant (OHT). In this study, we report characteristics and outcomes of severe LGF requiring mechanical circulatory support (MCS). All patients undergoing OHT from 2000 to 2018 at our center were reviewed. Patients re-admitted to the hospital for late graft failure (>3 months after initial discharge) and developing cardiogenic shock requiring MCS were identified. Outcomes and mortality were evaluated. Twenty-six patients were identified. Median age was 37.3 years (interquartile range: 28.2-47.6) and 69% were male. Median time from initial transplant to MCS was 2.9 years. Etiology of graft failure was rejection in 19 patients (73%), transplant coronary artery disease (tCAD) in 3 (12%), with mixed tCAD or rejection in 4 (15%).

Pre-Liver Transplant Coronary Artery Disease Workup for Low-Risk Patients.

Coronary artery disease (CAD) is a leading cause of mortality following orthotopic liver transplant, yet there is no standardized protocol for pre-liver-transplant coronary artery disease assessment. The main objective of this study was to determine the agreement between 2 methods of cardiac risk assessment: dobutamine stress echocardiogram (DSE) and coronary calcium score (CCS) and to determine which test was best able to predict coronary calcification in low-risk patients. A retrospective study was performed using the medical records of 436 patients who received cardiac clearance for a liver transplant. A total of 152 patients' medical records were included based on the inclusion of patients who had received both DSE and CCS. A kappa coefficient was calculated to determine the agreement between the DSE and CCS results. In addition, the positive predictive values (PPVs) of both the CCS and DSE along with cardiac catheterization indicating abdominal occlusion were analyzed to compare the accuracy of the 2 tests. It was determined that there was a 12% agreement between DSE results and CCS. It was found that the DSE had a PPV of 56% and the CCS had a PPV of 80%. From this data, it was concluded that there was no agreement between the results of the CCS and the DSE. While neither the CCS nor the DSE presents an optimal method of risk assessment, the CCS had a much higher PPV and was therefore determined to be the more accurate test.

Impact of Induction Immunosuppression on Post-Transplant Outcomes of Patients Bridged with Contemporary Left Ventricular Assist Devices.

For patients bridged to transplant (BTT) with left ventricular assist devices (LVAD), data regarding the use of induction immunosuppressive therapy remain limited. The objectives of the current study were to describe the current trends and clinical consequences of IT in patients BTT with LVAD. The United Network of Organ Sharing database was queried to identify adult, single-organ heart transplant recipients who were BTT with LVAD between 2008 and 2018. Propensity score matching was then used to balance clinical covariates between those patient who did and did not receive IT. The primary outcomes of interest were graft survival, hospitalization for rejection and infection, and freedom from transplant coronary artery disease (TCAD). In the overall cohort, 49.1% (n = 3,978) received IT, with basiliximab being the most commonly used agent followed by antithymocyte globulin. After propensity score matching, 4,388 patients (2,194 without induction and 2,194 with induction) were identified. Between those who did and did not receive IT, there was no significant difference in graft survival, freedom from hospitalization for rejection, and freedom from hospitalization for infection. Patients who received IT experienced increased freedom from TCAD (p = 0.004) with unadjusted hazard ratio of 0.81 (95% Cardiac Index: 0.70-0.93). For freedom from TCAD, antithymocyte globulin was associated with better outcomes than basiliximab (80.2% vs. 73.1% at 5 years, log rank p value = 0.004). In a sensitivity analysis, there was no significant increase in hospitalization for infection in those patients with an infected LVAD before transplant. Use of induction therapy in patients BTT with LVAD appears to be safe and feasible, without a significant increase in the risk of infection or rejection, even in those patients with pretransplant device-related infections. IT, particularly antithymocyte globulin, was associated with increased time to development of TCAD. Routine use of IT in patients BTT with LVAD may be considered, and further randomized control trials are warranted to further support these data.

THE ROLE OF LOCAL ENDOTHELIAL SHEAR STRESS (ESS) IN THE DEVELOPMENT OF CORONARY ARTERY DISEASE IN CARDIAC TRANSPLANT PATIENTS: POSSIBLE MAGNIFICATION OF ESS PATHOBIOLOGIC EFFECT RELATED TO IMMUNOLOGIC FACTORS OF REJECTION

Transplant (tplant) coronary artery disease (TCAD) is an immunologic phenomenon and a major cause of morbidity/mortality after heart tplant. Low ESS drives plaque behavior in native CAD, but its role in TCAD, with its prominent immunologic environment, has not been studied. We studied 21 pts (av

Understanding the Correlation Between DSA, Complement Activation, and Antibody-Mediated Rejection in Heart Transplant Recipients.

Donor-specific HLA antibodies (DSA) are associated with increased rates of rejection and of graft failure in cardiac transplantation. The goal of this study was to determine the association of preformed and posttransplant development of newly detected DSA (ndDSA) with antibody-mediated rejection (AMR) and characterize the clinical relevance of complement-activating DSA in heart allograft recipients. The study included 128 adult and 48 pediatric heart transplant patients transplanted between 2010 and 2013. Routine posttransplant HLA antibody testing was performed by IgG single-antigen bead test. The C3d single-antigen bead assay was used to identify complement-activating antibodies. Rejection was diagnosed using International Society for Heart and Lung Transplantation criteria. In this study, 22 patients were transplanted with preexisting DSA, and 43 patients developed ndDSA posttransplant. Pretransplant (P < 0.05) and posttransplant (P < 0.001) ndDSA were associated with higher incidence of AMR. Patients with C3d + DSA had significantly higher incidence of AMR compared with patients with no DSA (P < 0.001) or patients with C3d-DSA (P = 0.02). Nine (36%) of 25 patients with AMR developed transplant coronary artery disease compared with 17 (15.9%) of 107 patients without AMR (P < 0.05). Among the 47 patients who received ventricular assistant device (VAD), 7 of 9 VAD+ patients with preformed DSA experienced AMR compared with 7 of 38 VAD+ patients without preformed DSA, indicating presensitization to donor HLA significantly increased the risk of AMR (P < 0.01). Preformed and posttransplant ndDSA were associated with AMR. C3d + DSA correlates with complement deposition on the graft and higher risk of AMR which may permit the application of personalized immunotherapy targeting the complement pathway.

Longer Ischemic Time is Associated with Increased Ventricular Stiffness as Measured by Pressure-Volume Loop Analysis in Pediatric Heart Transplant Recipients.

The purpose of this study was to investigate the associations between clinical factors and cardiac function as measured by pressure-volume loops (PVLs) in a pediatric heart transplant cohort. Patients (age<20years) who underwent heart transplantation presenting for a clinically indicated catheterization were enrolled. PVLs were recorded using microconductance catheters (CD Leycom®, Zoetermeer, Netherlands). Demographic data, serum B-type natriuretic peptide (BNP), time from transplant, ischemic time, presence of transplant coronary artery disease, donor-specific antibodies, and history of rejection were recorded at the time of catheterization. PVL data included contractility indices: end-systolic elastance and preload recruitable stroke work; ventricular-arterial coupling index; ventricular stiffness constant, Beta; and isovolumic relaxation time constant, tau. Associations between PVL measures and clinical data were investigated using non-parametric statistical tests. A total of 18 patients were enrolled. Median age was 8.7years (IQR 5-14years). There were ten males and eight females. Six patients had a history of rejection and ten had positive donor-specific antibodies. There was no transplant coronary artery disease. Median BNP was 100pg/mL (IQR 46-140). Time from transplant to PVL obtained during catheterization procedure was 4.1years (IQR 1.7-7.8year). No single clinical characteristic was statistically significant when correlated with PVL data. However, longer ischemic time was associated with worse Beta (r=0.49, p=0.05). Our study found that longer ischemic times are associated with increased left ventricular stiffness. No other single clinical variable is associated with cardiac dysfunction as determined by PVL analysis.

Drug-Eluting Balloons–A New Tool in the Treatment of Cardiac Allograft Vasculopathy: A Case Series

Percutaneous coronary intervention in patients with cardiac allograft vasculopathy is burdened with a lot of difficulties. Although they have allowed significant progress in comparison with plain balloon angioplasty and bare metal stents, drug-eluting stents have not fully overcome problems of diffuse lesions and small-vessel disease that are so common in transplant coronary artery disease. There is growing evidence that drug-eluting balloons might be a better choice for patients with small vessel atherosclerotic coronary disease and yet there is no experience with this technology in patients with cardiac allograft vasculopathy. Herein we report a case series of successful percutaneous coronary interventions in patients with cardiac allograft vasculopathy.

Relationship between ventricular pressure and coronary artery disease in asymptomatic adult heart transplant recipients.

The association between data of right heart catheterization and cardiac allograft vasculopathy (CAV) in adult heart transplant (HTx) recipients remains to be determined. This is an observational, retrospective study, including all consecutive asymptomatic HTx patients undergoing routine right and left catheterization. The independent predictive power of pulmonary capillary wedge pressure (PCWP) to predict CAV (classified according to working formulation of a standardized nomenclature for CAV-2010) was the primary end point. Seventy-one patients were included, with a mean time from HTx to procedure of 19 ± 25 months. At coronary angiography first degree of CAV was found in eight patients (11.2%), second degree of CAV in two patients (2.8%), and third in two (2.8%). PCWP values were significantly higher in patients with CAV compared with patients without CAV (17.5 ± 7.5 vs. 10.4 ± 5.6, P < 0.001) and values of 15 mmHg or greater had an AUC of 0.71 (0.48-0.92), with a sensitivity of 71% and a specificity of 73% in predicting CAV, with an independent relationship confirmed at logistic regression analysis (odds ratio 1.28, IC 1.06-1.53; P = 0.008). A significantly elevated PCWP at the time of the diagnosis of transplant coronary artery disease may be considered as an early marker of CAV, especially in asymptomatic HTx recipients.

(912) - Coronary Vasospasm After Heart Transplantation: Does It Portend Poor Outcome?

Coronary vasospasm (CV) may present after heart transplant (HTx) and is characterized by reversible luminal narrowing during coronary angiography. It is a potential marker for the development of transplant coronary artery disease (TCAD) and may be related to pre-existing TCAD. We sought to assess the post-HTx prevalence of CV in patients (pts) and its concurrent and subsequent development of TCAD and poor outcome at our center.

Prevalence and Severity of Anemia in Children Hospitalized with Acute Heart Failure.

Anemia is common among adult heart failure patients and is associated with adverse outcomes, but data are lacking in children with heart failure. The purpose of this study was to determine the prevalence of anemia in children hospitalized with acute heart failure and to evaluate the association between anemia and adverse outcomes. Review of the medical records of 172 hospitalizations for acute heart failure. Single, tertiary children's hospital. All acute heart failure admissions to our institution from 2007 to 2012. None. Composite endpoint of death, mechanical circulatory support deployment, or cardiac transplantation. Patients ages ranged in age from 4 months to 23 years, with a median of 7.5 years, IQR 1.2, 15.9. Etiologies of heart failure included: dilated cardiomyopathy (n = 125), restrictive cardiomyopathy (n = 16), transplant coronary artery disease (n = 18), ischemic cardiomyopathy (n = 7), and heart failure after history of congenital heart disease (n = 6). Mean hemoglobin concentration at admission was 11.8 g/dL (±2.0 mg/dL). Mean lowest hemoglobin prior to outcome was 10.8 g/dL (±2.2 g/dL). Anemia (hemoglobin <10 g/dL) was present in 18% of hospitalizations at admission and in 38% before outcome. Anemia was associated with increased risk of death, transplant, or mechanical circulatory support deployment (adjusted odds ratio 1.79, 95% confidence interval = 1.12-2.88, P = .011). For every 1 g/dL increase in the patients' lowest hemoglobin during admission, the odds of death, transplant, or mechanical circulatory support deployment decreased by 18% (adjusted odds ratio = 0.82, 95% confidence interval = 0.74-0.93, P = 0.002). Anemia occurs commonly in children hospitalized for acute heart failure and is associated with increased risk of transplant, mechanical circulatory support, and inhospital mortality.

(528) - The Clinical Application of Non-Invasive Assessment of Coronary Flow Reserve via Rubidium PET in Heart Transplant Patients

Coronary flow reserve (CFR) has been measured through a flow wire and more recently with the use of nuclear imaging. The advantage of nuclear imaging is that the entire heart is being assessed as opposed to a single coronary artery through the use of the flow wire. Reduction of CFR has implied an abnormal microcirculation in the donor heart due to small vessel transplant coronary artery disease. We have been assessing our patients in a cross-sectional study using Rubidium PET scans to assess CFR. It is not known whether an abnormal CFR (<2.0) is correlated to cardiac function and hemodynamics. Between 2010 and 2014 we assessed 93 heart transplant patients who had undergone Rubidium PET scanning to exclude significant transplant coronary artery disease (TCAD). Patients with abnormal CFR (<2.0) and normal CFR (≥2.0) were compared for the presence of coronary ischemia, LVEF at rest and with stress, end diastolic volume index (EDVI) at rest and stress and % left ventricular (LV) enlargement. Subsequent 1-year survival and development of new cardiac allograft vasculopathy (CAV) were also recorded. Those patients with abnormal CFR (<2.0) compared to those with normal CFR (≥2.0) had lower LVEF at rest and with stress, higher average end diastolic volume index (EDVI) at rest and stress and increased % left ventricular (LV) enlargement (see table). There was no difference in 1-year subsequent survival and development of new CAV. (See table) Patients with abnormal CFR (<2.0) have abnormal cardiac function and hemodynamics and may be at risk for poor outcome. Longer follow-up is required to assess for prognostic significance of an abnormal CFR.Tabled 1EndpointsCFRCFR > 2.0 (n=66)P-Value1-Year Subsequent Actual Survival96.2%97.6%0.5321-Year Subsequent Actual Freedom from CAV100.0%96.8%0.517Average LVEF Rest, Mean ± SD56.4 ± 15.8862.9 ± 11.180.028Average LVEF Post Stress, Mean ± SD60.5 ± 17.1067.4 ± 11.830.029Average EDVI Rest, Mean ± SD50.8 ± 30.3741.4 ± 14.060.044Average EDVI Post Stress, Mean ± SD55.3 ± 34.5145.2 ± 13.760.045% LV Enlargement (%)14.8% (4/27)1.5% (1/66)0.024 Open table in a new tab

(768) - Proliferation Signal Inhibitors Prevent Donor-Specific Antibody Production in Sensitized Patients after Heart Transplantation

Everolimus and sirolimus are proliferation signal inhibitors (PSI) reported to decrease incidence and progression of transplant coronary artery disease, incidence of cardiac rejection, and development of de novo circulating antibodies (Abs) in the 1st year after heart transplant (Htx). Donor-specific Abs (DSA) appear to be a main factor associated with poor outcome in sensitized patients post-Htx. It is not established whether PSIs affect development of DSA in sensitized patients after Htx. Between 2010 and 2014, we evaluated 78 Htx patients (pts) with circulating Abs after Htx. Several were switched from mycophenolate mofetil (MMF) to PSI including everolimus (n=19) or sirolimus (n=11) in combination with a calcineurin inhibitor (CNI). Pts with pre-existing DSA were excluded. Pts were divided into 2 groups: maintenance of MMF use ≥1-year (Group A), and PSI use ≥ 1-year (Group B). Maintenance MMF group was matched to the switch-to-PSI group for time from Htx. Assessment of circulating Abs, including development of de novo DSA at 12 months after initiation of PSI was performed. In addition, 1-year subsequent survival and freedom from subsequent DSA development, cellular rejection, antibody-mediated rejection (AMR) were recorded. Reduction of PRA over 1 year was recorded for both groups. The PSI group compared to the MMF group had significantly greater freedom from de novo DSA development over the course of 1 year (see table). There was no significant difference between study groups in 1-year subsequent survival and 1-year subsequent freedom from cellular rejection and AMR. There was no significant difference with treatment of PSIs for subsequent 12-month Class I Abs levels %PRA (38 ± 37 vs. 33 ± 34, P=0.58) or Class II Abs levels %PRA (19 ± 29 vs. 20 ± 28, p=0.81). The use of PSIs in sensitized Htx pts appears to lower de novo development of subsequent DSA compared to maintenance MMF. Further study is warranted with a larger population.Tabled 1EndpointsGroup A Mycophenolate ≥ 1-Year (N=48)Group B PSI ≥ 1-Year (N=30)P-Value1-Year Subsequent Survival after PSI or MMF Initiation100.0%100.0%1.0001-Year Subsequent Freedom from De Novo Antibody Development after PSI or MMF Initiation86.9%100.0%0.0421-Year Subsequent Freedom from Any Treated Rejection93.8%96.7%0.5721-Year Subsequent Freedom from Acute Cellular Rejection97.9%96.7%0.7431-Year Subsequent Freedom from Antibody-Mediated Rejection97.9%93.2%0.3061-Year Subsequent Freedom from Biopsy Negative Rejection97.9%100.0%0.429 Open table in a new tab

Emerging importance of chemokine receptor CXCR3 and its ligands in cardiovascular diseases.

The CXC chemokines, CXCL4, -9, -10, -11, CXCL4L1, and the CC chemokine CCL21, activate CXC chemokine receptor 3 (CXCR3), a cell-surface G protein-coupled receptor expressed mainly by Th1 cells, cytotoxic T (Tc) cells and NK cells that have a key role in immunity and inflammation. However, CXCR3 is also expressed by vascular smooth muscle and endothelial cells, and appears to be important in controlling physiological vascular function. In the last decade, evidence from pre-clinical and clinical studies has revealed the participation of CXCR3 and its ligands in multiple cardiovascular diseases (CVDs) of different aetiologies including atherosclerosis, hypertension, cardiac hypertrophy and heart failure, as well as in heart transplant rejection and transplant coronary artery disease (CAD). CXCR3 ligands have also proven to be valid biomarkers for the development of heart failure and left ventricular dysfunction, suggesting an underlining pathophysiological relation between levels of these chemokines and the development of adverse cardiac remodelling. The observation that several of the above-mentioned chemokines exert biological actions independent of CXCR3 provides both opportunities and challenges for developing effective drug strategies. In this review, we provide evidence to support our contention that CXCR3 and its ligands actively participate in the development and progression of CVDs, and may additionally have utility as diagnostic and prognostic biomarkers.

Use of Proliferation Signal Inhibitors in Cardiac Transplantation

Cardiac transplantation remains the definitive and most highly successful therapy for patients with advanced heart failure who have failed all other therapies. Long-term survival is limited by cardiac allograft vasculopathy, the transplant coronary artery disease, and malignancy. Standard, traditional immunosuppressive agents such as calcineurin inhibitors, anti-proliferative agents, and corticosteroids do little to attenuate cardiac allograft vasculopathy, which, because of its diffuse nature, is usually not amenable to percutaneous or surgical revascularization approaches, and may potentiate the developments of malignancies after cardiac transplantation. Proliferation signal inhibitors block the mammalian target of rapamycin, a critical protein involved in cell proliferation, and inhibit lymphocyte and smooth muscle cell proliferation. This results in inhibition of the alloimmune response and acute cellular rejection, even in the setting of low calcineurin levels. More significantly, they have been shown in several clinical trials to attenuate the progression of cardiac allograft vasculopathy when compared to mycophenolate or azathioprine regimens.