Cardiac allograft vasculopathy pathophysiology
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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
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 [1].
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 [1] [2]. Calcified lesions and necrotic core begin to appear within 2 years of transplantation.
Immunologic and non-immunologic risk factors | |||||||||||||||||||||||||||||||
Persistent enthothelial injury and dysfunction | |||||||||||||||||||||||||||||||
Subendothelial accumulation of lymphocytes, 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 | |||||||||||||||||||||||||||||||
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 Risk 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 [3]. 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 [4].
MHC Class 1 antigens on donor enthelium recognized by CD8 T lymphocytes | |||||||||||||||||||||||||||||||
CD8 T lymphocytes secrete cytokines which activates endothelial cells | |||||||||||||||||||||||||||||||
Increased expression of MHC Class II antigens on endothelium | |||||||||||||||||||||||||||||||
CD4 T lymphocytes recognize MHC Class II antigens | |||||||||||||||||||||||||||||||
Recruitment of other inflammatory cells and increased expression of adhesion molecules on endothelium | |||||||||||||||||||||||||||||||
Accelerates the process of intimal proliferation | |||||||||||||||||||||||||||||||
A recent study by Labarrere et al. [5] 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 [6].
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 [7] [8].
Non-Immunologic Risk Factors
References
- ↑ 1.0 1.1 Pollack A, Nazif T, Mancini D, Weisz G (2013). "Detection and imaging of cardiac allograft vasculopathy". JACC Cardiovasc Imaging. 6 (5): 613–23. doi:10.1016/j.jcmg.2013.03.001. PMID 23680373.
- ↑ Billingham ME (1992). "Histopathology of graft coronary disease". J Heart Lung Transplant. 11 (3 Pt 2): S38–44. PMID 1622997.
- ↑ Tambur AR, Pamboukian SV, Costanzo MR, Herrera ND, Dunlap S, Montpetit M; et al. (2005). "The presence of HLA-directed antibodies after heart transplantation is associated with poor allograft outcome". Transplantation. 80 (8): 1019–25. PMID 16278580.
- ↑ Hruban RH, Beschorner WE, Baumgartner WA, Augustine SM, Ren H, Reitz BA; et al. (1990). "Accelerated arteriosclerosis in heart transplant recipients is associated with a T-lymphocyte-mediated endothelialitis". Am J Pathol. 137 (4): 871–82. PMC 1877542. PMID 1699422.
- ↑ Labarrere CA, Nelson DR, Miller SJ, Nieto JM, Conner JA, Pitts DE; et al. (2000). "Value of serum-soluble intercellular adhesion molecule-1 for the noninvasive risk assessment of transplant coronary artery disease, posttransplant ischemic events, and cardiac graft failure". Circulation. 102 (13): 1549–55. PMID 11004146.
- ↑ Labarrere CA, Nelson DR, Faulk WP (1997). "Endothelial activation and development of coronary artery disease in transplanted human hearts". JAMA. 278 (14): 1169–75. PMID 9326477.
- ↑ Nagano H, Libby P, Taylor MK, Hasegawa S, Stinn JL, Becker G; et al. (1998). "Coronary arteriosclerosis after T-cell-mediated injury in transplanted mouse hearts: role of interferon-gamma". Am J Pathol. 152 (5): 1187–97. PMC 1858591. PMID 9588888.
- ↑ Hosenpud JD, Everett JP, Morris TE, Wagner CR, Shipley GD (1995). "Cellular and humoral immunity to vascular endothelium and the development of cardiac allograft vasculopathy". J Heart Lung Transplant. 14 (6 Pt 2): S185–7. PMID 8719483.