Screening for transplant vasculopathy

Pathophysiology

CAV is a condition characterized by panarterial derangement, including adventitial fibrosis, diffuse concentric intimal proliferation and hyperplasia of the epicardial coronary arteries, and medial thickening of the smaller intramyocardial coronary vessels, which results in diffuse vessel narrowing, focal epicardial coronary stenoses, and obstructive microvasculopathy. ^, This is in contrast to the more focal lesions of traditional atherosclerosis, which tend to be noncircumferential and commonly involve the proximal segments of the epicardial coronary arteries. Nevertheless, superimposed atherosclerotic coronary lesions can coexist with CAV and have some overlap in their angiographic appearance. Histopathologically, atherosclerotic plaques are usually heterogenous and contain a distinctive fibrous cap (composed of macrophages, cholesterol clefts, and calcium deposits), and the lumen is eccentric, whereas allograft lesions tend to be more homogenous and symmetrically located with a composition mainly of fibrous tissue, and the lumen is more centrally located.

The pathogenesis of CAV is multifactorial and appears to be triggered by both immune-related mechanisms and nonimmunologic vascular risk factors that ultimately result in inflammatory vascular injury and perivascular fibrosis. Some of the risk factors associated with the development of CAV include cellular and antibody-mediated rejection, donor-specific antihuman leukocyte antigen (HLA) antibodies, cytomegalovirus infection, dyslipidemia, hypertension, recipient pretransplant diagnosis of ischemic cardiomyopathy, and older age.

Definition, epidemiology, diagnosis, and prognosis

In 2010, the International Society for Heart and Lung Transplantation (ISHLT) established a nomenclature for the definition of CAV based on information derived from ICA, in combination with markers of cardiac allograft function ( Table 22.1 ). With this system, patients are divided into four groups:

• ISHLT CAV ₀ includes patients with angiographically normal coronary arteries;

• ISHLT CAV ₁ refers to patients with nonobstructive disease (<70% luminal narrowing);

• ISHLT CAV ₂ includes patients with single-vessel obstructive CAV (≥70%); and

• ISHLT CAV ₃ includes patients with multivessel obstructive CAV and those with ISHLT CAV ₁ or CAV ₂ who also have graft dysfunction as evidenced by either left ventricular systolic dysfunction or restrictive physiology on right heart catheterization or echocardiography.

Some centers may also perform an intravascular ultrasound (IVUS) if the angiographic findings are inconclusive or insufficient to explain the clinical presentation. The general consensus is that detection of maximal intimal thickness of at least 0.5 mm, particularly in the left ascending anterior coronary artery, is consistent with CAV.

A recent report from the ISHLT Thoracic Organ Transplant Registry, which included 146,975 OHT survivors of all ages, found an overall CAV prevalence of 7.7%, 29%, and 46.8% within 1, 5, and 10 years post-OHT, respectively. Similar findings were described in a single-center study that used the recommended ISHLT CAV nomenclature in 501 adult recipients, with a prevalence for any CAV _1-3 of 9.8% at 1 year, 22% at 4 years, 44% at 10 years, 56% at 15 years, and 59% at 20 years. Of note, CAV _2-3 was rare within the first year (0.6%) and relatively uncommon at 4 years (3.9%), but its occurrence increased significantly at 10 years (13.7%), 15 years (18.7%), and 20 years (23.6%).

The distinction between CAV groups is clinically relevant and has important therapeutic and prognostic implications. For example, compared with CAV ₀ , the relative risk for death or retransplantation was 1.22 (0.85 to 1.76; p = .28) for CAV ₁ , 1.86 (1.08 to 3.22; p = .03) for CAV ₂ , and 5.71 (3.64 to 8.94; p < .001) for CAV ₃ among 501 patients with a mean follow-up of 11.9 ± 6.4 years. In a different study, 169 OHT recipients were followed for 5.6 ± 2.8 years for a composite of major adverse cardiovascular events (MACEs) and compared with CAV ₀ ; the relative risk for MACE was 1.1 (0.3 to 4.1; p = NS) for CAV ₁ , 3.6 (0.8 to 16.0; p = .088) for CAV ₂ , and 9.2 (3.1 to 5.27; p <.01) for CAV ₃ . Similar results have been observed in the pediatric population. Overall, these data highlight the high prevalence of CAV and the enhanced prognostic value of the ISHLT CAV grading system.

Clinical manifestations and treatment

CAV can affect people of all ages, including children, and is characterized by a heterogeneous clinical expression and diverse clinical course. For example, angina pectoris, the classic symptom of coronary obstruction leading to myocardial ischemia, is uncommon in OHT recipients because of the surgical transection of the presynaptic sympathetic nerve terminals that occurs after transplantation. Although myocardial re-innervation does eventually occur, this process is almost invariably incomplete. Thus, most individuals remain asymptomatic or report nonspecific symptoms, such as weakness, shortness of breath, and/or palpitations, whereas some patients may have more ominous clinical presentations related to more advanced CAV, including acute coronary syndrome, heart failure, and sudden death. In fact, CAV is the most common cause of graft failure and sudden death beyond the first year post-OHT. ^{, ,}

Management of CAV is aimed at preventing and treating established disease. In the former case, there is evidence that statin therapy improves OHT survival and may reduce the incidence of CAV. Once CAV is established, however, the options for treatment are more limited; nevertheless, observational data suggest that sirolimus, an inhibitor of mammalian target of rapamycin (mTOR), may slow down the progression of CAV. ^, Percutaneous and surgical coronary revascularization remain palliative options but can be considered in suitable patients with focal or multifocal epicardial stenoses. There is no evidence, however, that such procedures improve long-term outcomes. ^, Retransplantation appears to be the only viable option for the group of CAV patients who develop graft failure, with some data suggesting acceptable outcomes that are superior to those undergoing retransplantation for other causes.