Orthotopic heart transplantation (OHT) remains the treatment of choice for refractory end-stage heart failure.1–4 It is reserved for patients with severe hemodynamic compromise, intractable ventricular arrhythmias or uncontrollable angina.5

According to data from the 2016 International Society for Heart and Lung Transplantation (ISHLT) registry, one-year and 10-year survival post-OHT exceed 85% and 50%, respectively.6 At our center, the equivalent rates are 87% and 79%.7 Survival is hampered by several factors, one of which is cardiac allograft vasculopathy (CAV), a common form of chronic rejection and one of the most limiting long-term complications of OHT.8

The aims of this study are to investigate the incidence of CAV after OHT at our institution and to identify its predictors.

CAV is defined as an accelerated fibroproliferative disease that affects epicardial and intramural arteries in OHT patients.10 It results in progressive luminal narrowing and reduced myocardial blood flow.11 CAV appears to develop first in distal vessels and to progress centripetally to the large coronary vessels,10,12 in contrast to the focal, eccentric, proximal epicardial lesions in classical atherosclerotic coronary artery disease. However, the two conditions appear to share common pathogenic factors.10

CAV results from an interaction between numerous immunologic and non-immunologic donor and recipient features that are still not well understood.13–15 Among donor features, a history of hypertension, diabetes, smoking, higher BMI, older age and male gender are under study as likely predictors of CAV.4,15–17 On the side of the recipient, previous IHD, higher BMI, dyslipidemia, hypertension, diabetes and high urinary uric acid levels have been recognized as possible pre-OHT features predicting CAV.4,18 Also, recipient CMV infection is known to be associated with CAV, because it generates a proatherogenic environment and impairs nitric oxide production, leading to immune-mediated endothelial injury.10,15

Patients with CAV are usually asymptomatic because of allograft denervation, and so ICA is the standard diagnostic technique.10 However, its sensitivity is limited by the diffuse nature of CAV, especially during the first year post-OHT.10,11 Intracoronary imaging techniques such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT) are therefore of growing importance in the diagnosis of CAV.10,19–21

CAV therapy focuses on modification of underlying classical cardiovascular risk factors and optimization of immunosuppression.11

Statins are recommended early after OHT, regardless of cholesterol levels.22 They slow CAV progression and improve endothelial dysfunction, as shown by landmark trials in the mid-1990s.11,23

Once a patient is diagnosed with CAV, sirolimus or its derivative everolimus is included in the immunosuppressive regimen.24,25

PCI is an option for patients with focal disease who present symptoms or evidence of ischemia.26 Coronary artery bypass grafting is rarely indicated due to the distal and diffuse nature of CAV lesions.22 Retransplantation is the only definitive treatment capable of improving survival in highly selected candidates.14,22

In our large OHT cohort, the incidence of CAV was 2.91 cases per 100 person-years, and its prevalence was 3.3%, 9.7% and 17.6% at one, five, and eight years post-OHT, respectively. CAV was in most cases grade 1 (38%) or 2 (35%).

According to the 2015 ISHLT report, the five- and eight-year prevalence of CAV is 29% and 40%, respectively.27 A single-center retrospective study, based on a prospective cohort, enrolling 495 OHT patients and using ICA for CAV diagnosis, showed a CAV prevalence of 47% 12 years after OHT.28 Another study with a similar design but a smaller population (54) using both ICA and IVUS for CAV diagnosis presented a CAV prevalence of 46.2% within 10 years of OHT.29 At our center, the incidence and prevalence were lower than previously reported, possibly because of our larger sample and the high-quality follow-up program in our center. We identified abnormal carotid ultrasound at the time of OHT, prior history of IHD and donor age as being independently associated with CAV.

Using ICA for CAV diagnosis, two single-center retrospective studies enrolling 361 and 113 OHT patients also found previous recipient IHD to be a powerful independent predictor for CAV (6- to 10-fold higher risk).16,30 Neither of these studies included abnormal carotid ultrasound at the time of OHT in their analysis, probably due to differences in pre-OHT assessment protocols. However, considering that IHD and carotid disease share similar predictors and are highly correlated, it would also likely be a predictor in these two cohorts.

Neither immunologic nor non-immunologic donor and recipient factors underlying CAV have been established, however IHD risk factors are thought to play a part in the pathophysiology of CAV.31 In our population, none of the classical cardiovascular risk factors demonstrated an association with CAV, as predicted by previous articles from our center.32 However, both IHD and abnormal carotid Doppler at the time of OHT suggest that recipients who presented CAV after OHT had some cardiovascular risk factors at that time. Therefore, even though no single classical cardiovascular factor showed an association with CAV in our cohort, our findings support the existence of a common atherosclerotic basis between CAV and classical coronary artery disease in non-transplanted patients. Both IHD and carotid disease imply persistence of classical cardiovascular risk factors that might be associated with coronary plaque progression after OHT.33,34

Donor age was the other CAV predictor in our cohort. A previous retrospective analysis of 162 OHT patients conducted in our center looking at CAV prevalence also identified donor age as a strong positive predictor, concluding that the 50-year cut-off was significant.35 Other studies have also identified age as a CAV predictor.4,28 Importantly, older recipients usually receive the hearts of older donors, both (donor and recipient) with a higher burden of cardiovascular risk factors,35 and additionally, when CAV appears early after OHT, the hypothesis of pre-existing donor disease should be considered.36 Age limits are a controversial topic in OHT, and according to the international guidelines, carefully selected patients older than 70 years may be considered.3 In our study, 62 patients were older than 70 years and interestingly, recipient age was not statistically associated with CAV development.

In view of the immunological process behind CAV, a history of acute cellular rejection assessed by endomyocardial biopsy has been suggested in previous studies of single-center cohorts as a predictor of CAV development.29,37 We did not find such an association in our population during the first year post-OHT.

Using ICA for CAV diagnosis is in agreement with recent ISHLT recommendations, but it has limited ability to detect the early stages of CAV.22 Other imaging techniques, including IVUS and OCT,20,21 may have greater sensitivity for CAV diagnosis.38 The inclusion of these techniques in follow-up programs could lead to earlier detection of abnormalities after OHT and provide more accurate identification of CAV predictors, although this would significantly increase the program cost and the time taken for each invasive exam.

Revascularization procedures are associated with poor long-term results and are considered palliative due to the diffuse and progressive nature of vascular changes.15 In the setting of three-vessel disease, for example, PCI is associated with only 27% two-year freedom from cardiac death or graft loss.26 Small single-center experiences suggest higher (90-98%) initial procedural success but a restenosis prevalence of 35-100% for PCI alone and 20-56% for PCI with stenting during the first year.39,40 The higher restenosis rate in CAV compared to IHD is explained by the lymphoproliferative response that characterizes CAV.12 Nevertheless, in our population, PCI had very good results. DES were chosen for the majority of CAV lesions described in our series. As the treatment of established CAV is disappointing, the primary effort should be directed to early diagnosis and prevention. For this, identifying CAV predictors should be a priority.

Due to the higher incidence of CAV in these subgroups (previous vascular disease and donor age over 50), we are proposing changes to our protocol. Firstly, coronary angiography will be mandatory for donors over the age of 50 years in order to confirm eligibility for heart procurement. Secondly, recipients deemed at higher risk for CAV according to the clinician's judgment (including the above subgroups) will be further studied with OCT at the time of the first routine angiography, in order to improve our diagnostic performance and to adjust immunosuppressive therapy accordingly (including initiating everolimus/sirolimus therapy on top of standard lipid-lowering treatment).

In this retrospective analysis of a single-center OHT cohort, the incidence of CAV (2.91 cases per 100 patient-years) was lower than that reported in other series. CAV predictors were previous ischemic heart disease, carotid artery disease and donor age.

The authors have no conflicts of interest to declare. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.