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.     

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.     

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.     

Cardiac allograft vasculopathy: current knowledge and future direction

Cardiac allograft vasculopathy (CAV) is a unique form of coronary artery disease affecting heart transplant recipients. Although prognosis of heart transplant recipients has improved over time, CAV remains a significant cause of mortality beyond the first year of cardiac transplantation. Many traditional and non-traditional risk factors for the development of CAV have been described. Traditional risk factors include dyslipidemia, diabetes and hypertension. Non-traditional risk factors include cytomegalovirus infection, HLA mismatch, antibody-mediated rejection, and mode of donor brain death. There is a complex interplay between immunological and non-immunological factors ultimately leading to endothelial injury and exaggerated repair response. Pathologically, CAV manifests as fibroelastic proliferation of intima and luminal stenosis. Early diagnosis is paramount as heart transplant recipients are frequently asymptomatic owing to cardiac denervation related to the transplant surgery. Intravascular ultrasound (IVUS) offers many advantages over conventional angiography and is an excellent predictor of prognosis in heart transplant recipients. Many non-invasive diagnostic tests including dobutamine stress echocardiography, CT angiography, and MRI are available; though, none has replaced angiography. This review discusses the risk factors, pathogenesis, and diagnosis of CAV and highlights some current concepts and recent developments in this field.     

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.     

The effect of antiplatelet therapy on survival and cardiac allograft vasculopathy following heart transplantation: A systematic review and meta‐analysis

Cardiac allograft vasculopathy (CAV) is mediated by endothelial inflammation, platelet activation and thrombosis. Antiplatelet therapy may prevent the development of CAV. This systematic review and meta‐analysis summarizes and appraises the evidence on the effect of antiplatelet therapy after heart transplantation (HT). CENTRAL(Ovid), MEDLINE(Ovid), Embase(Ovid) were searched from inception until April 30, 2020. Outcomes included CAV, all‐cause mortality, and CAV‐related mortality. Data were pooled using random‐effects models. Seven observational studies including 2023 patients, mean age 52 years, 22% female, 47% with ischemic cardiomyopathy followed over a mean 7.1 years proved eligible. All studies compared acetylsalicylic acid (ASA) to no treatment and were at serious risk of bias. Data from 1911 patients in 6 studies were pooled in the meta‐analyses. The evidence is very uncertain about the effect of ASA on all‐cause or CAV‐related mortality. ASA may reduce the development of CAV (RR 0.75, 95% CI: 0.44–1.29) based on very low certainty evidence. Two studies that conducted propensity‐weighted analyses showed further reduction in CAV with ASA (HR 0.31, 95% CI: 0.13–0.74). In conclusion, there is limited evidence that ASA may reduce the development of CAV. Definitive resolution of the impact of antiplatelet therapy on CAV and mortality will require randomized clinical trials.     

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.     

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.     

Cardiac allograft vasculopathy: Insights on pathogenesis and therapy

Cardiac allograft vasculopathy (CAV) is a unique accelerated form of coronary vascular disease affecting heart transplant recipients. This complication is a significant contributor to medium- to long-term post-transplant morbidity and mortality. There is a high prevalence of CAV with approximately one in three patients developing CAV by 5 years post-transplant. Morphologically, CAV is characterized by concentric coronary intimal hyperplasia in both the epicardial arteries and intramural microvasculature. Although several immune and non-immune factors have been identified, their precise pathogenic mechanisms, interactions, and relative importance in the development of CAV are not well defined. The advent of improved imaging surveillance modalities has resulted in earlier detection during the disease process. However, overall management of CAV remains challenging due to paucity of treatment. This review aims to discuss key concepts on the pathogenesis of CAV and current management strategies, focusing on the use of mammalian target of rapamycin inhibitors.     

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.