Diminished impact of cytomegalovirus infection on graft vasculopathy development in the antiviral prophylaxis era – a retrospective study

Evidence concerning an association between cytomegalovirus (CMV) infection and accelerated cardiac allograft vasculopathy (CAV) is inconclusive. Data were analyzed retrospectively from 297 consecutive heart transplants between 1.1.2002 and 31.12.2012. Patients ≤18 years of age, survival, and follow‐up ≤1‐year post‐transplant and patients with early CAV were excluded. CMV‐infection was diagnosed and monitored closely in the first year. CAV was diagnosed by coronary angiography via left heart catheterization, and results were categorized according to the International Society of Heart and Lung Transplantation (ISHLT) scoring system. Risk factors for CAV were tested in a multivariable model. Median follow‐up was 7.5 years (IQR: 5.6–10.3). CMV infection in the first year after transplantation occurred in 26% of patients (n = 78), CMV disease in 5% (n = 15). CAV ≥1 ISHLT was detected in 36% (n = 108). Incidence of CAV >1 ISHLT and severity of CAV increased over time. No statistically significant association between CMV infection and disease within the first year and risk of CAV after 1‐year post‐HTx was detected in the univariate (P = 0.16) and multivariable [hazard ratio (HR), 1.36; confidence interval (CI), 0.89–2.07; P = 0.16] Cox regression. In the multivariable Cox regression, donor age (HR, 1.04; 95% CI, 1.02–1.06; P < 0.01) and acute cellular rejection (ACR) ≥2R in the first year after HTx (HR, 1.77; 95% CI, 1.06–2.95; P = 0.03) were independent risk factors for CAV development. In our cohort, CMV infection and disease in the first year after transplantation did not significantly influence the risk of CAV in the long‐term follow‐up.     

Clinical outcome and quality of life of patients surviving 20 years or longer after heart transplantation

To evaluate outcome and quality of life (QoL) in ≥20 years survivors after heart transplantation. Patients surviving ≥20 years with a single graft were retrospectively reviewed. Heterotopic, multiorgan and retransplantations were excluded. QoL was evaluated using the SF‐36 survey. Eight hundred and twenty‐seven heart transplants were performed from 1981 to 1993, and among these, 131 (16%) patients survived ≥20 years; 98 (75%) were male and mean age at transplant was 43 ± 13 years. Conditional survival in these 20 years survivors was 74.1 ± 4.3% at 23 years and 60.9 ± 5.3% at 25 years (45 deaths, 34%). Forty‐four (34%) patients suffered rejection ≥2R. Conditional survival free from rejection ≥2R was 68 ± 4.1% at 5 years and 66.4 ± 4.2% at 10 years. Thirty‐five (27%) patients had cardiac allograft vasculopathy (CAV) grade 2–3. Conditional CAV‐free survival was 76 ± 3.8% at 20 years and 72.1 ± 4% at 25. Sixty‐nine (53%) patients developed malignancy, mostly skin cancers. Conditional malignancy‐free survival was 53.5 ± 4.4% at 20 years and 45.2 ± 4.6% at 25 years. At latest follow‐up, 24.0 ± 3.0 years after transplantation, mean left ventricular ejection fraction was 62 ± 11% and mean physical and mental scores were 57 ± 23 and 58 ± 21, respectively. Sixteen per cent of heart recipients survived ≥20 years with good ventricular performance and QoL. CAV and malignancies account for late morbidity and mortality.     

Human leukocyte antigen matching in heart transplantation: systematic review and meta‐analysis

Allocation of donors with regard to human leukocyte antigen (HLA) is controversial in heart transplantation. This paper is a systematic review and meta‐analysis of the available evidence. PubMed, Embase, and the Cochrane Library were searched systematically for studies that addressed the effects of HLA matching on outcome after heart transplantation. Fifty‐seven studies met the eligibility criteria. 34 studies had graft rejection as outcome, with 26 of the studies reporting a significant reduction in graft rejection with increasing degree of HLA matching. Thirteen of 18 articles that reported on graft failure found that it decreased significantly with increasing HLA match. Two multicenter studies and nine single‐center studies provided sufficient data to provide summary estimates at 12 months. Pooled comparisons showed that graft survival increased with fewer HLA‐DR mismatches [0–1 vs. 2 mismatches: risk ratio (RR) = 1.09 (95% confidence interval (CI): 1.01–1.19; P = 0.04)]. Having fewer HLA‐DR mismatches (0–1 vs. 2) reduced the incidence of acute rejection [(RR = 0.81 (0.66–0.99; P = 0.04)]. Despite the considerable heterogeneity between studies, the short observation time, and older data, HLA matching improves graft survival in heart transplantation. Prospective HLA‐DR matching is clinically feasible and should be considered as a major selection criterion.     

Coronary artery disease in heart transplantation: new concepts for an old disease

Cardiac allograft vasculopathy (CAV) remains one of the main long‐term complications after heart transplantation. We performed a systematic review focused on articles published in the previous 6 years to reappraise the novel evidences supporting risk factors, pathology, prevention, and treatment of CAV. We identified a search string for a literature search on PubMed. We excluded articles specifically focused on diagnosis/biomarkers/imaging only or complications of other diseases. We included 98 studies out of our search. Forty‐eight articles describe risk factors for CAV, 13 pathology, 24 prevention, and 13 treatment for CAV. While confirming known concepts, we found supportive evidence that CAV pathophysiology may vary according to the time post‐transplant and the prevalence of metabolic versus immune‐mediated risk factors. Selective revascularization of focal lesions in patients with CAV may result in some clinical benefit, but CAV prevention, rather than treatment, by controlling risk factors and by using targeted immunosuppressive therapies is the most evidence‐based approach to reduce disease progression.     

Delayed occurrence of cardiac allograft vasculopathy in Chinese heart transplant recipients compared with their western counterparts

Cardiac allograft vasculopathy (CAV) is a leading limiting factor to long-term survival after cardiac transplantation. We investigated the prevalence of CAV and its associated factors in Chinese heart transplant recipients. From July 1987 to July 2000, we performed 140 consecutive heart transplantations at the National Taiwan University Hospital. Of the 140 patients, 98 who were > or = 17-yr old at the time of transplantation, had survived for more than 1 yr after transplantation, and who had normal findings at the 1-month coronary angiogram study, were included in this study. Group I consisted of 25 patients who eventually developed CAV in the follow-up, and group II consisted of 73 patients who were free from CAV in the follow-up. CAV was defined by coronary angiogram study.The donor and recipient characteristics were not statistically different between the two groups except the older donor age (p = 0.02), higher first-year mean rejection score (p = 0.03) and more prevalent cytomegalovirus infection rate (p = 0.03) in group I. Multivariate Cox regression analysis revealed that only higher first-year mean rejection score (p = 0.01), and older donor age (p = 0.04) were important risk factors for developing CAV. The 1-5 yr of actuarial freedom from the presence of CAV were 97, 93, 86, 80 and 69% in our study patients. In summary, these data show that CAV occurred later in Chinese heart transplant recipients in comparison with their western counterparts, but the risk factors for developing CAV were not different.     

Blood glutathione as a marker of cardiac allograft vasculopathy in heart transplant recipients

BACKGROUND: Cardiac allograft vasculopathy (CAV) limits survival after heart transplantation (HTx). Between immunologic and non-immunologic factors, reactive oxygen species generation has been proposed as pathogenetic mechanism. This study was aimed at evaluating redox status in HTx recipients and verifying whether it could be independently associated with CAV. METHODS: Fifty-five consecutive male HTx recipients, median [interquartile range] age 60 yr [50, 64], underwent angiography 67 months [21, 97] after HTx to assess CAV, defined as significant stenosis in >or=1 epicardial vessel or any distal vessel attenuation. All patients underwent blood sampling 89 months [67, 119] after HTx for biochemical (glucose, creatinine, total and LDL cholesterol, and cyclosporin levels) and redox evaluation [plasma reduced and total homocysteine, cysteine, cysteinylglycine, glutathione, blood reduced glutathione (GSH(bl)) and vitamin E]. Univariate Odds Ratios (OR) with 95% confidence interval (95% CI, highest vs. lowest quartile) were estimated on the basis of a logistic regression analysis between clinical, conventional biochemical and redox data. Only the significant variables at univariate entered into multivariate analysis. RESULTS: CAV was documented in 15 (27%) patients. Univariate analysis showed that time from HTx to angiography (OR 3.97, 95% CI 1.15-14, p = 0.03) and GSH(bl) (OR 0.31, 95% CI: 0.14-0.70, p = 0.005) were significantly associated with CAV. However, multivariate analysis revealed GSH(bl) as the only independent predictor of CAV (OR 0.31, 95% CI: 0.13-0.74, p = 0.008). CONCLUSIONS: In HTx recipients reduced levels of GSH(bl) are independently associated with CAV. Given its potent intracellular scavenger properties, GSH(bl) may serve as a marker of antioxidant defence consumption, favouring CAV development.     

Cardiogenic shock and coronary endothelial dysfunction predict cardiac allograft vasculopathy after heart transplantation

Cardiac allograft vasculopathy remains one of the major causes of death post‐heart transplantation. Its etiology is multifactorial and prevention is challenging. The aim of this study was to prospectively determine factors related to cardiac allograft vasculopathy after heart transplantation. This research was planned on 179 patients submitted to heart transplant. Performance of an early coronary angiography with endothelial function evaluation was scheduled at three‐month post‐transplant. Patients underwent a second coronary angiography after five‐yr follow‐up. At the 5‐ ± 2‐yr follow‐up, 43% of the patients had developed cardiac allograft vasculopathy (severe in 26% of them). Three independent predictors of cardiac allograft vasculopathy were identified: cardiogenic shock at the time of the transplant operation (OR: 6.49; 95% CI: 1.86–22.7, p = 0.003); early coronary endothelial dysfunction (OR: 3.9; 95% CI: 1.49–10.2, p = 0.006), and older donor age (OR: 1.05; 95% CI: 1.00–1.10, p = 0.044). Besides early endothelial coronary dysfunction and older donor age, a new predictor for development of cardiac allograft vasculopathy was identified: cardiogenic shock at the time of transplantation. In these high‐risk patient subgroups, preventive measures (treatment of cardiovascular risk factors, use of novel immunosuppressive agents such as mTOR inhibitors) should be earlier and much more aggressive.     

Long-term outcomes after 1000 heart transplantations in six different eras of innovation in a single center

The objective of this study was to evaluate long-term outcomes of cardiac transplantation (HTx) in different eras of innovation at a single center during a period of 27 years. We performed a retrospective analysis of 960 cardiac allograft recipients (40 re-HTx) between 1981 and 2008. The results of six different eras based on milestones in HTx were analysed: Era 1: the early years ( n  = 222, 1981–1992); era 2: introduction of inhalative nitric oxide, prostanoids, University of Wisconsin solution (UW) replacing Bretschneider's solution (HTK, n  = 118, 1992–1994); era 3: statins ( n  = 102, 1994–1995); era 4: tacrolimus ( n  = 115, 1995–1996); era 5: mycophenolate mofetil (MMF, n  = 143, 1997–2000) and era 6: sirolimus ( n  = 300, 2000–2008). Outcome variables were survival, freedom from cardiac allograft vasculopathy (CAV) and from acute rejection episodes (AREs). Differences in survival was found comparing era 1 and era 2 with era 4 and era 6 ( P  < 0.001). Organ preservation through UW demonstrated a significantly better survival as compared with HTK ( P  < 0.001). Less AREs occurred in patients receiving tacrolimus-sirolimus or tacrolimus-MMF ( P  < 0.001). Patients receiving tacrolimus-MMF showed less CAV than when treated with cyclosporine-MMF ( P  < 0.005). There were more ventricular assist device implantations and more re-HTx in era 6 ( P  < 0.0001) than when compared with other eras. Although the causes for improvement in survival over time are multifactorial, we believe that changes in immunosuppressive therapy have had a major impact on survival.     

Correlation between circulating endothelial progenitor cell function and allograft rejection in heart transplant patients

Endothelial progenitor cells (EPCs) may contribute to rejection and cardiac allograft vasculopathy (CAV) by being intrinsically involved in the rejection process and causing neointimal hyperplasia. The mammalian target of rapamycin inhibitors (mTORi), sirolimus and everolimus, have been demonstrated to attenuate the progression of CAV and are cytotoxic to EPC. Thus, one mechanism by which mTORi may protect against CAV is by altering EPC function. Our study measured circulating EPC function and correlated this assessment with rejection episodes in heart transplant (HT) recipients. In addition, we examined the effect of mTORi on EPCs. Patients who received HT at our institution between 1995 and 2007 were included and stratified by International Society for Heart and Lung Transplantation (ISHLT) rejection grade. Group A (n = 13) consisted of patients with at least one moderate/severe rejection episode (grade ≥ 2). Group B (n = 28) patients had no moderate/severe episodes (grade < 2). Patients were also independently stratified based on exposure as mTORi (n = 21) vs. non mTORi (n = 20). To assess EPC functional capacity, we counted the number of colony‐forming units (CFU) of EPCs in peripheral blood samples from HT recipients. There were no significant differences in baseline characteristics between groups. The mean EPC‐CFU counts/plate for group A (rejecting) were 30 ± 6 vs.16 ± 3 for group B (nonrejecting) (P = 0.03). The EPC‐CFU counts/plate in the mTORi group (15 ± 3) were lower compared to the non mTORi (27 ± 5) group (P = 0.04). We found that EPC colony‐forming capacity was higher in HT patients who experienced moderate/severe rejection episodes. Patients on mTORi showed a reduced EPC colony count consistent with our previous findings of EPC cytotoxicity. Detection of circulating EPC function post‐transplant may reliably identify patient risk level for subsequent allograft rejection and allow for appropriate adjustments to immunosuppression. Converting to mTORi therapy may reduce EPC function and provide a novel mechanism to prevent rejection and possibly attenuate the development of CAV.