The incidence of CAV increases temporally in a progressive manner. Per the latest registry report from the ISHLT [16], for adult heart transplant recipients, the prevalence of CAV is 7.8% at 1 year post-transplant, 30% at 5 years post-transplant, and 50% 10 years following heart transplant. CAV is the third leading cause of death for heart transplant recipients who are more than 3 years post-transplant. In one early study, mortality was over 50% at 2 years after diagnosis of CAV [17]. Graft failure, which may reflect undiagnosed CAV, is another main cause of mortality post-transplant. In the pediatric population, CAV rates are reduced compared to adult heart transplant recipients with the prevalence of CAV primarily dependent on recipient age at time of heart transplant. In infants and young children (ages 1–5), 31% of heart transplant recipients will have CAV within 11 years post-transplant. For children age 6–10, 43% of transplant recipients will have CAV within 11 years post-transplant. For children age 11–17, 45% of recipients will have CAV within 11 years post-transplant. In the pediatric population, survival was 42–48% in the 6 years after diagnosis of CAV [18].

Prevention and treatment options for CAV include medical therapies, modulation of the immune system, mechanical therapies including percutaneous intervention, and redo-heart transplant. The 3-hydroxy-3 methylglutaryl coenzyme A reductase inhibitor, pravastatin, was shown in a prospective clinical trial to reduce the incidence of CAV, reduce cholesterol levels, reduce cardiac rejection with hemodynamic compromise and increase survival at 1 year post-transplant [28]. This study was supported by another prospective trial of simvastatin, a similar drug, which demonstrated superior 8-year survival and freedom from CAV compared to a control group [29]. In another trial, use of vitamins C and E showed no progression of CAV (compared to placebo treated control patients) [30]. Given risk of development of CAV and likely contribution of traditional risk factors to development of CAV, low dose aspirin is generally advised post-transplant. The use of induction agents at time of heart transplant, including T cell depleting agents and interleukin (IL)-2 receptor antagonists, may lead to reduced rates of CAV. Anti-thymocyte globulin (ATG), a commonly used T cell depleting agent, has shown delayed onset of CAV [31] and decreased CAV progression by IVUS parameters between baseline and 1-year post-transplant [32]. Different approaches to maintenance immunosuppression have shown differences in the development of CAV. The purine inhibitor mycophenolate mofetil (MMF) in combination with the calcineurin inhibitor (CNI) cyclosporine showed decreased incidence of CAV [33]. Clinical trials using the proliferation signal inhibitors (PSI) sirolimus or everolimus in conjunction with CNIs have shown reduced rates of CAV compared to maintenance immunosuppressive regimens with CNI in combination with purine antagonist. Everolimus in combination with cyclosporine showed lower rates of CAV compared to cyclosporine with azathioprine [34]. Sirolimus in combination with cyclosporine showed lower rates of CAV compared to cyclosporine in combination with azathioprine [35]. High-dose everolimus in combination with cyclosporine showed harm in one trial, but low-dose everolimus with cyclosporine showed similar mortality compared to cyclosporine with MMF [36]. Everolimus showed efficacy over MMF for CAV in subpopulations including women, diabetics, patients over age 60, and patients with higher cholesterol levels [37]. A more recent study examined low-dose everolimus with reduced-dose cyclosporine versus standard-dose cyclosporine with MMF. Low-dose CNI was withdrawn and PSI dose increased to target levels 7–11 weeks post-transplant. This study also demonstrated lower CAV burden in the PSI arm [38].

Immunomodulation with photopheresis may reduce rates of CAV due to reduction of rejection episodes. Photopheresis involves removal of approximately 5% of peripheral blood lymphocytes. These cells are treated with ultraviolet-A light and methoxsalen. Treated cells are reinfused into the patient [39]. This treatment is thought to cause apoptosis of T cells and creation of regulatory T cells that, in theory, reduce the inflammatory state. Benefit from photopheresis was demonstrated when used empirically post-transplant [40] and for treatment of post-heart transplant rejection with hemodynamic compromise or recurrent heart transplant rejection [41]. Patients treated empirically with photopheresis for the first 6 months post-transplant had reduced rates of acute rejection without increased risk of infection. Using photopheresis in the treatment of patients with rejection with hemodynamic compromise or recurrent rejection decreased the risk of subsequent significant rejection episodes. Reduction of rejection and the inflammatory state may lead to decreased rates of CAV, although this has not formally been studied in a clinical trial format.

CAV is generally a pan-arteritis, but it can present with focal stenosis. Percutaneous intervention and stent placement is generally a temporizing measure for CAV. One study showed equivalent outcomes following placement of sirolimus drug eluting stents (DES) compared to bare metal stents for significant CAV [42]. Data with newer everolimus DES suggest durability of stented segments with low rates of target lesion revascularization [43]. Prior attempts at revascularization by coronary artery bypass grafting (CABG) surgery resulted in high post-surgical mortality and low rates of survival 1 year after CABG [44, 45]. CAV is the main cause of need for redo-heart transplant. Annually, 2–4% of heart transplant recipients are redo heart transplant recipients. Unfortunately, survival after redo heart transplant is reduced compared to index heart transplant. For adult recipients, 1 year survival after redo heart transplant is approximately 70% and 10 year survival is 38% [16].

The main limitations to long-term survival after heart transplant are CAV, graft failure, and malignancy. The use of chronic immunosuppression after transplant to prevent allograft rejection increases the risk of malignancy in the long term. Recipients of heart transplant may have a pre-existing history of malignancy that, after transplant and on immunosuppression, predisposes them to recurrence of their primary malignancy. For patients with history of low-risk tumors, potential heart transplant recipients need not be delayed in evaluation for heart transplant. For patients with pre-existing cancer with a high risk of recurrence, heart transplant should be delayed for an adequate time as opined by oncology to ensure patients remain free from cancer recurrence. High-risk cancers include melanoma, breast, and colorectal cancer. Although data is limited, there is possible transmission of malignant oncogenic cells from donor to recipient. Caution should be considered in donors with history of renal cell carcinoma with vascular invasion, melanoma, choriocarcinoma, and central nervous system tumors [46]. Malignancy may be discovered in organ donors after the process of organ transplant or may be known at the time of organ transplant. The rate of de novo malignancy is approximately twofold higher in transplant recipients compared to the general population [47]. Proposed mechanisms for increased rates of de novo malignancy include direct effects of immunosuppression, reduced immune surveillance, and expansion of atypical cells. In addition, oncogenic viruses may proliferate in the setting of immunosuppression and contribute to the development of malignancy. Viruses including Epstein-Barr virus (EBV), human herpes virus 8 (HHV-8), human papillomavirus (HPV), human T-cell lymphotropic virus 1 (HTLV-1), and Merkel cell polyomavirus (MCV) have association with particular malignancies. Survival after diagnosis of malignancy depends on many factors including size of tumor, local or distant spread of the tumor, aggressiveness of the tumor, and ability of the patient to tolerate treatments directed against the tumor.

Cardiac transplant may require more intense immunosuppression because of the risk of death with graft loss. Animal studies suggest CNI may promote cancer through increased production of transforming growth factor (TGF) beta [48]. Common malignancies after heart transplant include post-transplant lymphoproliferative disease (PTLD), Kaposi’s sarcoma, skin cancer, lung cancer, and anogenital cancer. PTLD represents a heterogeneous group of lymphoproliferative disorders. EBV infection is associated with PTLD. EBV-seronegative recipients receiving transplants from EBV-seropositive donors are at elevated risk for development of PTLD. With EBV infection, B cells incorporate EBV DNA into the cellular genome, decreasing the rate of apoptosis and leading to cellular proliferation. EBV DNA load is suggestive in the right clinical context for PTLD. Imaging studies including fluorodeoxyglucose (FDG)-positron emission tomography can assess hyper metabolic tissue, but ultimately, diagnosis of PTLD is made on histopathology. Risk of PTLD is highest in the first year after transplant when immunosuppression is most intense. Common sites of PTLD in heart transplant recipients include lung, GI tract, liver, lymph nodes, and disseminated disease. In heart-lung transplant recipients, PTLD is primarily found in the lung. Symptoms are variable with PTLD. PTLD can present with fever, fatigue, malaise, recurrent infections that do not respond to antibiotic therapy, lymphadenopathy, or with significant organ dysfunction. PTLD is generally treated with significant reduction of immunosuppressive therapies. Reduction of EBV can be attempted with the antiviral agent acyclovir or gancyclovir. In high-risk patients, prophylaxis with anti-viral agents can be considered. For treatment of neoplastic B cells, a number of approaches are possible including use of chemotherapy, anti-B cell therapy with Rituximab, use of PSI (and withdrawal of one immunosuppressant agent), and tumor resection [49]. When reduction or withdrawal of immunosuppressant therapies is not effective, mortality from PTLD is high. Kaposi’s sarcoma is associated with HHV-8 and occurs in men at rates threefold higher than is seen in women. Lesions typically affect the legs and cause lymphedema. Skin cancers include squamous cell and basal cell carcinomas, melanoma, and Merkel cell carcinoma. Factors that mitigate risk of skin cancer development include ultraviolet radiation, fair skin, pre-transplant history of skin cancer or actinic keratosis, geographic location, and intensity, duration, and type of immunosuppressant therapy. Use of voriconazole for treatment of fungal infections has been associated with the development of aggressive squamous cell carcinomas [50]. Lung cancer, particularly in patients with prior significant tobacco exposure, is increased in heart transplant recipients. Anogenital cancer occurs in 2–3% of transplant recipients. Lesions may be multiple and extensive and may resemble genital warts. Screening for the presence of malignancy after heart transplant is critical. Dermatologic evaluation should be done to screen for skin cancer. There are no formal guidelines for cancer screening after heart transplant, but regular health maintenance screening would be appropriate.

As with CAV, use of PSIs instead of anti-metabolites may be favorable in the context of malignancy. Transition to PSIs may decrease the risk of development of subsequent malignancies after heart transplant [51]. Additional indications for use of PSIs in this context include history of heart transplant rejection and viral infection with CMV. Although PSIs can cause proteinuria kidney disease, it can be used instead of CNI in a renal sparing effort [52] (see Table 13.2 for a summary of indications). PSI use should be made on an individual basis. Potential risks of PSIs include increased risk of fungal infection, fluid retention, risk of venous thromboembolism, hypertriglyceridemia, oral ulcers, proteinuria renal disease, nausea, diarrhea, leukopenia, and pneumonitis.