Cardiac allograft vasculopathy in pediatric heart transplant recipients

Metabolic parameters for coronary allograft vasculopathy (CAV) have not been well defined in children. CAV (by angiography or autopsy) was studied in 337 heart recipients on a cyclosporine-based steroid-sparing regimen. Freedom from CAV for all was 79% at 10 years. Fifty-nine patients (18%) developed CAV at a mean of 6.5 +/- 3 years post-transplant. First year rejections were significantly higher in CAV, mean 2.3 vs. 1.4, P = 0.003, odds ratio (OR) 1.8. Rejection with hemodynamic compromise beyond 1 year post-transplant was associated with CAV, P < 0.001, OR 8.4. There was no significant correlation among human leukocyte antigen DR (HLA DR) mismatch, pacemaker use or homocysteine levels and the development of CAV. Maximum cholesterol and low density lipoprotein (LDL) levels were not significantly different. Neither diabetes nor hypertension was significant predictors of CAV on multivariate logistic regression analysis. In conclusion, frequent and severe rejection episodes may predict pediatric CAV. Neither glucose intolerance nor lipid abnormalities appeared to alter risk for CAV in this population.     

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.     

Recurrence of in-stent restenosis in cardiac allograft vasculopathy following implantation of a sirolimus-eluting stent

Coronary lesions in patients with advanced cardiac allograft vasculopathy (CAV) are frequently treated with percutaneous coronary intervention. Despite high primary success rates, long-term outcome is significantly impaired by a high incidence of restenosis. In nontransplanted patients, the use of drug-eluting stents (DES) significantly decreases the rate of coronary in-stent restenosis. We report a case treated for cardiac allograft coronary in-stent restenosis with a sirolimus-eluting stent presenting with recurrent in-stent restenosis at follow up. However, the pattern of in-stent restenosis changed from diffuse proliferative disease in the bare-metal stent to a focal pattern in the sirolimus-eluting stent concordant with observations in nontransplanted patients. This case highlights the need for further studies addressing the effect of DES for the prevention of restenosis both in de novo as well as in-stent restenotic lesions in patients with CAV.     

Clinical implementation of coronary computed tomography angiography for routine detection of cardiac allograft vasculopathy in heart transplant patients

Cardiac allograft vasculopathy (CAV) is an accelerated form of coronary artery disease that affects long-term outcomes in heart transplant (HTx) patients. We prospectively evaluated the feasibility of coronary computed tomography angiography (CCTA) for the detection of CAV during clinical implementation at our center. All consecutive HTx patients >4 years post-transplant were actively converted from myocardial perfusion imaging to CCTA for the annual assessment of CAV. Between February 2018 and May 2019, 129/172 (75%) HTx patients underwent a CCTA. Renal impairment (n = 21/43) was the most frequent reason for patients could not undergo CCTA. CCTA image quality was good–excellent in 118/129 (92%) patients, and the radiation dose was 2.1 (1.6–2.8) mSv. CCTA showed obstructive CAV in 19/129 (15%) patients. Thirteen (10%) patients underwent additional tests, of which 8 patients underwent coronary revascularization within 90 days of CCTA. After 1 year, 3 additional coronary angiograms were performed, resulting in one revascularization in a patient with known severe CAV who developed ventricular tachycardia. One myocardial infarction after coronary stenting and 2 non-cardiac deaths were observed. CCTA can be successfully implemented for routine detection of CAV with good image quality and low radiation dose. CCTA allows CAV evaluation with the limited need for additional invasive testing.     

Visfatin serum concentration is associated with cardiac allograft vasculopathy in heart transplant recipients

Cardiac allograft vasculopathy (CAV) still is one of the most important limiting factors of long‐term survival following heart transplant (HT). This study aimed to investigate the association between proinflammatory adipokine‐visfatin and the incidence of CAV in HT recipients. After HT, 182 patients who had a follow‐up visit at the Transplantation Clinic between 2016 and 2017 were analyzed. The median age was 60.5 years, and 76.4% were men. The incidence of CAV was 54.9%. According to the multivariable proportional hazard regression analysis, visfatin level (1.795 [1.539‐2.094]; P < .001) was significantly associated with CAV, and statin use was protective against CAV (0.504 [0.32‐0.793]; P = .003). The area under the receiver operating characteristic curve indicated an excellent discriminatory power of visfatin (0.9548 [0.9281‐0.9816]) for CAV detection. The cutoff value of 5.42 ng/mL for visfatin yielded a sensitivity of 89% and specificity of 91%. This is the first study to demonstrate that visfatin serum concentrations are independently associated with the incidence of CAV in HT recipients. Visfatin allows for simple and cheap detection of CAV given its excellent discriminatory ability and high sensitivity and specificity. In addition, we have found an independent association between the statin use and a lower risk of CAV.     

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.     

C4d immunostaining is an independent predictor of cardiac allograft vasculopathy and death in heart transplant recipients

Antibody‐mediated rejection (AMR) occurs in 10–20% of patients after heart transplantation. C4d immunostaining is one parameter used in its diagnosis. This study aimed to determine whether C4d staining has prognostic significance for mortality, coronary allograft vasculopathy (CAV), cell‐mediated rejection (CMR), and graft dysfunction in patients post‐transplantation. Consecutive patients receiving an endomyocardial biopsy between 2007 and 2008 were selected. Left ventricular function, angiography, episodes of AMR/CMR, and death were noted. C4d was graded from 0 to 3 (immunostaining). Cox proportional models (recurrent events analysis) were used to evaluate C4d staining with mortality, graft dysfunction, CAV (≥grade 2), and episodes of ≥2R‐CMR. We analyzed 2525 biopsy specimens (n = 217). During a follow‐up of 4.5 ± 2 years, 35 died, 49 had graft dysfunction, seven had ≥grade 2 CAV, and 95 episodes of CMR occurred. A one‐grade increase in C4d staining was associated with an increase in mortality (HR 1.57; 95% CI 1.0–2.5), a higher risk of CAV (HR 2.4, 95% CI 1.04–5.4), and a trend toward graft dysfunction (HR 1.42; 95% CI 1.0–2.09). C4d was not associated with CMR. C4d immunostaining was a significant predictor of CAV and death but not subsequent episodes of CMR. There was also a trend toward increased graft failure.     

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.     

Angiographic assessment of cardiac allograft vasculopathy: results of a Consensus Conference of the Task Force for Thoracic Organ Transplantation of the German Cardiac Society

Angiograms of cardiac transplant (HTx) recipients were to be evaluated in a ring experiment and a joint consensus on criteria of angiographic evaluation of coronary arteries of HTx patients was to be reached. Twenty‐four coronary angiograms from 11 hospitals were circulated. One hundred eighty‐eight blinded evaluations were returned. A joint evaluation by six experienced cardiologists was used as reference standard and a consensus evaluation form was developed. Significant lesions (stenosis 75%, 50% in the left main coronary artery) were diagnosed in 10/23 abnormal coronary angiograms (41.7%). Interventional revascularization was recommended in 8/10 (80%). In 21 coronary angiograms distal pruning was found and in 11/21 (52.4%) cases with distal pruning occlusion of at least one peripheral vessel was detected. The best kappa value (0.7) was found for the presence of at least one clinically significant stenosis. Agreement on the site and grade of local stenosis was much less. Some agreement on remodeling was found in assessing diffuse narrowing in the LCA (kappa = 0.371, P < 0.001). The kappa value for peripheral obliteration was 0.331 (P = 0.001). Angiographic evaluation of cardiac allograft vasculopathy, particularly of diffuse and peripheral disease and remodeling, needs standardization. This should be performed in a downward compatible improvement process.