Honoring 50 Years of Clinical Heart Transplantation in Circulation: In-Depth State-of-the-Art Review

Josef Stehlik, MD, MPH; Jon Kobashigawa, MD; Sharon A. Hunt, MD; Hermann Reichenspurner, MD, PhD; James K. Kirklin, MD


Circulation. 2018;137(1):71-87. 

In This Article

Posttransplantation Surveillance and Complications

Long-term posttransplantation care is directed at preserving optimal graft function and minimizing the risk of complications that result from the immune response of the recipient against the graft (rejection, CAV) and the effects of long-term immunosuppressive therapy (infection, hypertension, diabetes mellitus, renal dysfunction, malignancy).

Cardiac Allograft Vasculopathy

CAV is a frequent long-term complication of heart transplantation and a leading cause of late mortality. Despite improvements in immunosuppressive drugs, the incidence of CAV has decreased only marginally, affecting up to 50% of recipients within 10 years of transplantation.[36] In contrast to atherosclerotic plaques of native coronary artery disease, CAV manifests as a diffuse, pan-arterial thickening of vessel intima. CAV can affect the entire length of the epicardial vessel and typically extends to the microvasculature. On histology, epicardial and intramyocardial vessels show concentric intimal thickening, migrated smooth muscle cells, foamy macrophages, and lymphocytic infiltrates. Unlike in atherosclerotic coronary disease, thrombotic occlusion of the vessel lumen in CAV is rare.

The pathogenesis of CAV is complex, with immunological and nonimmunological factors contributing. The donor arrest, organ procurement, and allograft ischemia and reperfusion can all trigger inflammation and endothelial injury. Both innate immunity and adaptive immunity contribute to the development of CAV. During implantation, the donor heart sheds HLA antigens and heat-shock proteins, which can be processed by recipient antigen-presenting cells, leading to activation of T cells. Endothelial cells lining allograft vessels are the primary source of antigens activating the host immune system. Donor-specific antibodies can form against HLA or non-HLA antigens (vimentin, anticardiac myosin) in the allograft. Immune system activation leads to the release of proinflammatory cytokines, further vascular inflammation, and endothelial damage, all of which contribute to the pathogenesis of CAV in the form of myxoid changes in the intima in early lesions and fibrotic and hyalinized changes in advanced lesions.

CAV also shares many of the risk factors associated with native coronary artery disease, including hypertension, hypercholesterolemia, and diabetes mellitus.[60] Other risk factors unique to CAV include cytomegalovirus infection, older donor age, and explosive brain death in the donor.[60,61]

The denervated transplanted heart prevents recipients from experiencing ischemic pain. Patients with CAV can be asymptomatic for some time or have nonspecific symptoms of fatigue, nausea, or abdominal discomfort. By the time the patient presents with reduced left ventricular ejection fraction and heart failure symptoms, the prognosis is typically poor. Therefore, close monitoring of the allograft for early signs of CAV is essential. The mainstay of CAV surveillance is serial coronary angiography, which will typically demonstrate diffuse stenoses in large epicardial vessels and reduction of smaller coronary branches (peripheral "pruning"; Figure 6). Because CAV often occurs along the entire length of the vessel, CAV may be missed or underestimated by angiography alone. Intravascular ultrasound is a more sensitive method that can reliably detect intimal changes (Figure 6). An increase in maximal intimal thickness of ≥0.5 mm on intravascular ultrasound from baseline to 1 year after transplantation is prognostic for poor outcomes and the development of angiographic CAV within 5 years.[62] Negative vessel remodeling is another important feature of CAV that can be assessed on intravascular ultrasound. This is a paradoxical decrease in vessel volume despite intimal thickening. Negative remodeling of the left anterior descending artery on intravascular ultrasound at 1 year after transplantation is an independent risk factor for death or retransplantation.[63]

Figure 6.

Cardiac allograft vasculopathy (CAV).
A, Angiographic appearance of severe diffuse CAV. B, Histological examination of an epicardial coronary artery showing diffuse intimal proliferation. C, Severe intimal proliferation (arrows) seen on intravascular ultrasound.

Noninvasive alternatives to screening angiography include dobutamine stress echocardiography, positron emission tomography, and computed tomographic angiography.[64,65] Proposed biomarkers for increased risk of CAV include C-reactive protein, serum brain natriuretic peptide, troponin I,[61] and possibly serum microRNA 628–5p.[66]

Once CAV develops, current treatments are often ineffective, so prevention is important. The statins pravastatin and simvastatin started early after transplantation decrease the incidence of CAV.[67,68] Pravastatin may provide additional protection by inhibiting natural killer cells.[67] Vitamins C and E may also slow the progression of CAV.[69] Aspirin is typically prescribed daily because of its established benefits in native coronary artery disease. Once CAV is detected, the introduction of a proliferation signal inhibitor such as sirolimus or everolimus can slow disease progression.[44] Clinically significant CAV can be palliated with percutaneous coronary interventions for focal disease, but restenosis rates are high.[70] Retransplantation is often the only viable option but raises questions about equitable organ allocation.


Because immunosuppression will place the transplant recipient at higher risk of infection, specific interventions aimed at mitigating this risk take place even before transplantation. It is recommended that transplantation candidates have all age-appropriate vaccinations administered.[71] This includes immunizations against pneumococcal pneumonia, tetanus, hepatitis A and B, influenza, and varicella/Herpes zoster. This is to ensure an appropriate immune response to vaccinations before posttransplantation immunosuppression blunts the immune response and makes the vaccinations less effective. Use of live vaccines will typically be contraindicated after transplantation because even the attenuated viruses used for vaccination can cause disease in the immunosuppressed host. Screening for and treatment of latent tuberculosis is also recommended before transplantation.

Perioperatively, antibacterial antibiotic prophylaxis is typically used with drugs active against the usual skin flora, especially Staphylococcus species.[72] The combination of piperacillin/tazobactam and vancomycin is commonly used and continued for 2 to 4 days after transplantation. Protocol-based antimicrobial treatments are also started shortly after heart transplantation with the goal of preventing opportunistic infections at the time of the highest level of immunosuppression. Various approaches are currently in place for the prevention of cytomegalovirus reactivation, including the use of intravenous gancyclovir and oral valgancyclovir, typically for 3 months after transplantation and longer in the highest-risk patient group (cytomegalovirus-positive donor/cytomegalovirus-negative recipient). Prophylaxis against Pneumocystis jiroveci pneumonia is also routine and includes sulfamethoxazole/trimethoprim therapy, with dapsone or inhaled pentamidine as alternatives. Antifungal prophylaxis against mucocutaneous candidiasis may include topical nystatin liquid (swish and swallow), clotrimazole lozenges, or prophylactic-dose fluconazole. Additional specific antifungal prophylaxis may be useful in endemic areas.[73–75]

Antimicrobial prophylaxis protocols have evolved over the years, and their meticulous implementation has greatly reduced the incidence of opportunistic infections that used to result in significant morbidity and mortality in the early posttransplantation period. Although the use of selective antimicrobial prophylaxis and advances in immunosuppression have reduced the risk of infectious complications after heart transplantation,[76] infections remain an important cause of posttransplantation mortality. Approximately 3% of transplant recipients die of infection in the first postoperative year, which represents one third of the deaths in this time period. Approximately 8% of heart transplant recipients succumb to infection within 20 years of transplantation.[18] The leading infections resulting in mortality are bacterial pneumonia, fungal infections (aspergillus, coccidiomycosis, nocardia), and cytomegalovirus.

Hypertension, Diabetes Mellitus, and Renal Dysfunction

Hypertension, diabetes mellitus, and renal dysfunction are frequent posttransplantation comorbidities, and their aggressive treatment reduces the morbidity and mortality associated with these conditions. The incidence of severe renal dysfunction after heart transplant has decreased over the past 20 years, likely a result of strategies aimed at renal function preservation as described in Immunosuppression.


The increased risk of malignancy after transplantation relates to long-term exposure to immunosuppressive therapies and increases with time since transplantation. Careful age-appropriate screening for malignancy is done at the time of transplantation evaluation and is continued after transplantation. The leading posttransplantation malignancy is skin cancer, seen in >20% of patients within 10 years of transplantation. There is higher incidence of cervical, hepatobiliary, and renal cell carcinoma and lymphoma. Posttransplantation lymphoproliferative disorder is a specific type of lymphoma seen in organ transplant recipients. Posttransplantation lymphoproliferative disorder diagnosed early after transplantation is typically associated with Epstein-Barr virus infection, whereas posttransplantation lymphoproliferative disorder late after transplantation is considered a complication of long-term immunosuppression.