Cardiac allograft vasculopathy pathophysiology

# Overview
Cardiac allograft vasculopathy (CAV) is a fibro-proliferative disorder of graft coronary arteries in heart transplant recipients. 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, native atherosclerotic process is non-circumferential, focal and localized to epicardial coronary vessels.

# Pathophysiology

## Pathology
The pathogenesis of CAV is believed to be an interplay between immunological and non-immunological factors. Histologically, 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 .
Early-CAV is associated with thickening of the intima with or without expansion of external elastic lamina (positive remodeling) and is not accompanied by decrease in the intraluminal diameter. This is followed by concentric remodeling and luminal compromise (negative remodeling). 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 accelerated progression of CAV. Serial intravascular ultrasound imaging has demonstrated that majority of the intraluminal narrowing occurs in the first year after transplant.
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.

## 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.

### Immunologic Factors
- HLA mismatch and antibody production:
Studies have reported a higher incidence of CAV in recipients with HLA mismatch. HLA-DR and HLA-A mismatches have been more strongly associated with occurrence of CAV . Moreover presence of HLA class I and class II antibodies by solid phase, flow cytometry, panel reactive antibody (PRA) assay post heart transplant co-relate with worse graft outcomes. Tambur et al. showed that class II HLA specific antibodies were associated with IVUS evidence of severe vasculopathy.
- Interplay between T-cell lymphocytes and endothelium:
Proposed mechanism is outlined in the following algorithm .
A recent study by Labarrere et al.  found elevated levels of soluble intercellular adhesion molecule - 1 in the graft arterial endothelial surface during the first three months post transplant, further increasing the risk of CAV development and graft failure. ICAM-1 has been recently proven to have prognostic importance for those at risk for developing CAV, acute myocardial infarction and subsequent allograft failure .
- Cytokines:
Numerous cytokines such as IL-1, IL-6, TNF alpha, fibroblastic growth factor, vascular endothelial growth factor, insulin-like growth factor-1, transforming growth factor, and platelet-derived growth factor have proliferative effects on the vascular smooth muscle cells. Interferon-gamma is also thought to play a role by enhancing the expression of adhesion molecules and recruitment of cells, thereby accelerating the process of vascular damage  .

### Non-Immunologic Factors
- Donor age:
Gao et al.  demonstrated that older donors and donors with pre-existing angiographic evidence of coronary artery disease were more likely to develop CAV in 3 years following transplant, however no significant difference in long term survival was noted in patients who received heart transplants from donors belonging to an older age group. This finding was further validated in retrospective studies by Patavov et al.  and Blanche et al .
- Donor- recipient sex mismatch:
Multiple single centered studies showed significant associations between donor- recipient gender mismatch but the results are conflicting. A study by Al-Khaldi et al.  and Erinc K et al.  showed worse graft related outcomes in those with female allografts, especially in males above 45 years of age.
Recently, a prospective analysis of the data from United Network for Organ Sharing was studied to look for donor- recipient sex mismatch. It demonstrated significantly improved short and long- term mortality in men receiving organ from same sex donor. However, no survival advantage was noted in females with same sex donors .
- Insulin resistance syndrome:
Studies performed in animal models have demonstrated that insulin resistance (hyperinsulinemia) can accelerate the process of development of CAV in post-transplant subjects . Further research by the same group demonstrated some degree of insulin resistance, hyperinsulinemia, LDL, triglycerides, total cholesterol and higher plasma glucose in non-diabetic post-transplant patients.  In addition to insulin resistance, typical pattern of dyslipidemia observed in patients with CAV was hypertriglyceridemia and reduced HDL levels. The mechanisms underlying the development of insulin resistance and dyslipidemia post-transplant is unclear, but is thought to be an interplay between genetic predisposition and adverse effects from immunosuppressants.
- Hyperlipidemia:
- Hyperlipidemia:
Recent studies using intravascular ultrasound have shown continuing increase in intimal hyperplasia, especially within first year post transplant and is strongly associated with LDL levels . The elevations in LDL, triglycerides and total cholesterol occur within the first year post-transplant and is probably secondary to immunosuppressive drugs as mentioned above. In another prospective study by Kapadia SR et al.  using intravascular ultrasound, severe CAV was related to greater changes in serum LDL cholesterol levels rather than absolute levels during the first year status post cardiac transplant.
LDL and oxidized LDL enhance vascular inflammation by causing endothelial dysfunction, activating coagulation pathways and recruitment of inflammatory cells. They are also known to upregulate the HLA-DR and CD86 in immature dendritic cells in the allograft coronary arteries, thereby activating them and accelerate the process of vasculopathy . Use of statins have been proven to have long term survival benefits in heart transplant recipients . A study that compared impact on 1 year survival with use of simvastatin versus pravastatin found similar beneficial effects with a higher drop in LDL levels with simvastatin compared to pravastatin .
- Hypertension:
- Hypertension:
Analysis of the data from The Registry of the International Society of Heart and Lung Transplant , reported incidence of hypertension one year after heart transplant is 76% compared to 94% at the end of 5 years. Development of hypertension post transplant leads to indothelial injury and has been significantly associated with CAV.
In a study by Mehra MR et al. using IVUS , intimal thickness at the end of 1 year was significantly greater in those left untreated compared to patients treated with ACE inhibitors and/or calcium channel blockers or both. There is evidence to suggest that both immunosuppressive therapy (especially calcineurin antigonists) and de-nervation of cardiac volume and chemo-receptors .
- Hyperglycemia:
- Hyperglycemia:
In a prospective study, 66 patients without overt diabetes underwent IVUS 2 to 3 years after transplant surgery. Intimal thickness was significant higher in patients with higher glucose and serum insulin levels (P < 0.05 and P < 0.01). Also, use of immunosuppressants like cyclosporine and corticosteroids may cause increase in baseline glucose and insulin levels which further increases the risk of CAV.
- Cytomegalovirus infection:
CMV infection is particularly known to predict progression and accelerate the development of CAV resulting in discrete stenosis in major epicardial vessels .  In a study by Koshiken et al. , the number of vessels affected was significantly higher in CMV patients compared to CMV-free patients particularly after 2nd postoperative year. Moreover, the arteriolar endothelial proliferation and intimal thickening in endomyocardial biopsy specimens preceded the angiographically detected vascular changes. The author also quoted that the endothelial injury was more pronounced during the first two years post-transplant and remained stable thereafter. Studies using combination prophylaxis consisting of CMV hyperimmune globulin (CMV IVIG) and ganciclovir have shown decreased intimal thickening, reduced incidence of coronary artery disease and thereby improved survival .
- History of coronary artery disease:
Presence of atherosclerotic coronary artery disease in the either recipient or donor is a well established risk factor in predicting poor long-term graft survival. In a prospective analysis, CAV was more frequent in patients with angiographically significant donor coronary artery disease.
Other factors that affect the pathogenesis and development of CAV include:
- Smoking 
- Obesity 
- Endothelial dysfunction  
- Etiology of brain death in donor, accidental or cerebrovascular cause  
- Pre-transplant diagnosis of ischemic cardiomyopathy vs. non-ischemic cardiomyopathy
- Long graft ischemia time