Cardiac allograft vasculopathy pathophysiology

Cardiac allograft vasculopathy Microchapters
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]

Overview

CAV is a fibro-proliferative disorder of the coronary arteries of cardiac allografts. It is characterized by longitudinal concentric intraluminal narrowing secondary to intimal proliferation in epicardial coronary arteries. There is also concentric medial hyperplasia in the myocardial microvasculature. In contrast, atherosclerotic process is non-circumferential, focal and localized to epicardial vessels.

Pathophysiology

Pathology

Serial intravascular ultrasounds have demonstrated that majority of the intraluminal narrowing occurs in the first year after transplant. In the initial stages, there is expansion of the external elastic lamina and subsequently constriction of this layer leads to intra-luminal narrowing. There may also be associated mural thrombi which may lead to acute myocardial infarction. Early clots are platelet rich which may later be replaced by organized thrombus rich in fibrin. Increased platelet activation with expression of surface membrane glycoproteins has been linked to acclerated progression of CAV.

Histologically, the immunological and non-immunological factors cause sub-endothelial inflammation resulting in migration of lymphocytes (T cells especially), proliferation of smooth muscle cells, formation of lipid laden foam cells and fibrosis. This further accelerates the process of endothelial dysfunction. The end result is progressive luminal compromise, reduced coronary blood flow and vasodilatory capacity leading to ischemia and chronic ventricular dysfunction .

Immunologic and non-immunologic risk factors
Persistent enthothelial injury and dysfunction
Subendothelial accumulation of lymtphocytes, myointimal proliferation, formation of foam cells and fibrosis
Concentric intimal hyperplasia and luminal narrowing
Decreased coronary blood flow and reduced vasodilatory capacity
Myocardial ischemia and ventricular dysfunction

CAV on VH-IVUS

VH-IVUS detects coronary artery lesions of CAV earlier than coronary angiography. It classifies plaques according to its composition and has played a crucial role in understanding the natural history and morphology of CAV lesions. Half of heart transplant recipients with angiographically normal coronary arteries have moderate to severe intimal thickening in the left anterior descending artery (LAD) on IVUS studies later than one year post transplantation.

In the initial stages of CAV, there is thickening of the intima with or without expansion of external elastic lamina. These changes are not accompanied by changes in the intra-luminal diameter. This is followed by concentric remodeling and luminal compromise. In the early post-transplant period, lesions tend to be non-circumferential, focal, composed of fibrous and fibro-fatty material. This fibro-fatty tissue may represent either CAV or traditional atherosclerosis, and represents the most common lesions found on IVUS studies. However, presence of necrotic core may be in this period may be associated with graft atherosclerotic coronary artery disease, donor age, male gender, and other traditional risk factors . Calcified lesions and necrotic core begin to appear within 2 years of transplantation.

However, findings of intimal proliferation or fibro-fatty plaque on IVUS does not necessarily co-relate with presence of small vessel disease by immunohistochemistry or histopathological analysis. The size of the IVUS catheter makes visualization of smaller peripheral vessels technically difficult. Moreover, multivessel analysis should be performed to increase the sensitivity of IVUS. It has therefore not been adopted as a routine screening procedure for diagnosis of CAV .

Pathogenesis

The pathogenesis of CAV appears to multifactorial with immunological and non-immunological factors both contributing to the process. Predominant factors include donor specific HLA antibodies, cellular mediated injury, cytomegalovirus infection and hypercholesterolemia. Immunological insult is the most accepted theory owing to the fact that CAV develops in donor arteries only.

Acute phase reactants may be elevated and is thought to be a marker of progression of CAV.

1) HLA mismatch: Studies have reported a higher incidence of CAV in recipients with HLA mismatching. HLA-DR and HLA-A mismatches have been more strongly associated with occurrence of CAV.