Cardiac allograft vasculopathy pathophysiology

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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 Factors Non-immunologic Factors

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 [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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 Factors

  • Donor age:

Gao et al. [9] 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. [10] and Blanche et al [11].

  • 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. [12] and Erinc K et al. [13] 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 [14].

Studies performed in animal models have demonstrated that insulin resistance (hyperinsulinemia) can accelerate the process of development of CAV in post-transplant subjects [15]. 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.

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 [16]. 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. [17] 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 [18]. Use of statins have been proven to have long term survival benefits in heart transplant recipients [19]. 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 [20].

Analysis of the data from The Registry of the International Society of Heart and Lung Transplant [21], 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 [22], 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 [23].

In a prospective study[24], 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.

CMV infection is particularly known to predict progression and accelerate the development of CAV resulting in discrete stenosis in major epicardial vessels [25]. In a study by Koshiken et al. [26], 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 [27].

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[28], CAV was more frequent in patients with angiographically significant donor coronary artery disease.

Other factors that affect the pathogenesis and development of CAV include:

References

  1. ↑ 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.
  2. ↑ Billingham ME (1992). "Histopathology of graft coronary disease". J Heart Lung Transplant. 11 (3 Pt 2): S38–44. PMID 1622997.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ Gao HZ, Hunt SA, Alderman EL, Liang D, Yeung AC, Schroeder JS (1997). "Relation of donor age and preexisting coronary artery disease on angiography and intracoronary ultrasound to later development of accelerated allograft coronary artery disease". J Am Coll Cardiol. 29 (3): 623–9. PMID 9060902.
  10. ↑ Potapov EV, Loebe M, Hübler M, Musci M, Hummel M, Weng Y; et al. (1999). "Medium-term results of heart transplantation using donors over 63 years of age". Transplantation. 68 (12): 1834–8. PMID 10628759.
  11. ↑ Blanche C, Kamlot A, Blanche DA, Kearney B, Magliato KE, Czer LS; et al. (2002). "Heart transplantation with donors fifty years of age and older". J Thorac Cardiovasc Surg. 123 (4): 810–5. PMID 11986611.
  12. ↑ Al-Khaldi A, Oyer PE, Robbins RC (2006). "Outcome analysis of donor gender in heart transplantation". J Heart Lung Transplant. 25 (4): 461–8. doi:10.1016/j.healun.2005.11.456. PMID 16563978.
  13. ↑ Erinc K, Yamani MH, Starling RC, Young JB, Crowe T, Ratliff NB; et al. (2004). "The influence of donor gender on allograft vasculopathy: evidence from intravascular ultrasound". Transplant Proc. 36 (10): 3129–31. doi:10.1016/j.transproceed.2004.10.072. PMID 15686711.
  14. ↑ Weiss ES, Allen JG, Patel ND, Russell SD, Baumgartner WA, Shah AS; et al. (2009). "The impact of donor-recipient sex matching on survival after orthotopic heart transplantation: analysis of 18 000 transplants in the modern era". Circ Heart Fail. 2 (5): 401–8. doi:10.1161/CIRCHEARTFAILURE.108.844183. PMID 19808369.
  15. ↑ Cantin B, Zhu D, Wen P, Panchal SN, Dai X, Gwathmey JK; et al. (2002). "Reversal of diabetes-induced rat graft transplant coronary artery disease by metformin". J Heart Lung Transplant. 21 (6): 637–43. PMID 12057696.
  16. ↑ Pethig K, Klauss V, Heublein B, Mudra H, Westphal A, Weber C; et al. (2000). "Progression of cardiac allograft vascular disease as assessed by serial intravascular ultrasound: correlation to immunological and non-immunological risk factors". Heart. 84 (5): 494–8. PMC 1729477. PMID 11040007.
  17. ↑ Kapadia SR, Nissen SE, Ziada KM, Rincon G, Crowe TD, Boparai N; et al. (2001). "Impact of lipid abnormalities in development and progression of transplant coronary disease: a serial intravascular ultrasound study". J Am Coll Cardiol. 38 (1): 206–13. PMID 11451276.
  18. ↑ 18.0 18.1 Valantine H (2004). "Cardiac allograft vasculopathy after heart transplantation: risk factors and management". J Heart Lung Transplant. 23 (5 Suppl): S187–93. doi:10.1016/j.healun.2004.03.009. PMID 15093804.
  19. ↑ Kobashigawa JA, Moriguchi JD, Laks H, Wener L, Hage A, Hamilton MA; et al. (2005). "Ten-year follow-up of a randomized trial of pravastatin in heart transplant patients". J Heart Lung Transplant. 24 (11): 1736–40. doi:10.1016/j.healun.2005.02.009. PMID 16297773.
  20. ↑ Mehra MR, Uber PA, Vivekananthan K, Solis S, Scott RL, Park MH; et al. (2002). "Comparative beneficial effects of simvastatin and pravastatin on cardiac allograft rejection and survival". J Am Coll Cardiol. 40 (9): 1609–14. PMID 12427413.
  21. ↑ Taylor DO, Edwards LB, Boucek MM, Trulock EP, Waltz DA, Keck BM; et al. (2006). "Registry of the International Society for Heart and Lung Transplantation: twenty-third official adult heart transplantation report--2006". J Heart Lung Transplant. 25 (8): 869–79. doi:10.1016/j.healun.2006.05.002. PMID 16890107.
  22. ↑ Mehra MR, Ventura HO, Smart FW, Collins TJ, Ramee SR, Stapleton DD (1995). "An intravascular ultrasound study of the influence of angiotensin-converting enzyme inhibitors and calcium entry blockers on the development of cardiac allograft vasculopathy". Am J Cardiol. 75 (12): 853–4. PMID 7717300.
  23. ↑ Ciarka A, Najem B, Cuylits N, Leeman M, Xhaet O, Narkiewicz K; et al. (2005). "Effects of peripheral chemoreceptors deactivation on sympathetic activity in heart transplant recipients". Hypertension. 45 (5): 894–900. doi:10.1161/01.HYP.0000161875.32767.ac. PMID 15795365.
  24. ↑ Valantine H, Rickenbacker P, Kemna M, Hunt S, Chen YD, Reaven G; et al. (2001). "Metabolic abnormalities characteristic of dysmetabolic syndrome predict the development of transplant coronary artery disease: a prospective study". Circulation. 103 (17): 2144–52. PMID 11331254.
  25. ↑ Fateh-Moghadam S, Bocksch W, Wessely R, Jäger G, Hetzer R, Gawaz M (2003). "Cytomegalovirus infection status predicts progression of heart-transplant vasculopathy". Transplantation. 76 (10): 1470–4. doi:10.1097/01.TP.0000090163.48433.48. PMID 14657688.
  26. ↑ Koskinen PK, Nieminen MS, Krogerus LA, Lemström KB, Mattila SP, Häyry PJ; et al. (1993). "Cytomegalovirus infection accelerates cardiac allograft vasculopathy: correlation between angiographic and endomyocardial biopsy findings in heart transplant patients". Transpl Int. 6 (6): 341–7. PMID 8297464.
  27. ↑ Weill D (2001). "Role of cytomegalovirus in cardiac allograft vasculopathy". Transpl Infect Dis. 3 Suppl 2: 44–8. PMID 11926750.
  28. ↑ 28.0 28.1 Radovancevic B, Poindexter S, Birovljev S, Velebit V, McAllister HA, Duncan JM; et al. (1990). "Risk factors for development of accelerated coronary artery disease in cardiac transplant recipients". Eur J Cardiothorac Surg. 4 (6): 309–12, discussion 313. PMID 2361019.
  29. ↑ Hollenberg SM, Klein LW, Parrillo JE, Scherer M, Burns D, Tamburro P; et al. (2001). "Coronary endothelial dysfunction after heart transplantation predicts allograft vasculopathy and cardiac death". Circulation. 104 (25): 3091–6. PMID 11748106.
  30. ↑ Hollenberg SM, Klein LW, Parrillo JE, Scherer M, Burns D, Tamburro P; et al. (2004). "Changes in coronary endothelial function predict progression of allograft vasculopathy after heart transplantation". J Heart Lung Transplant. 23 (3): 265–71. doi:10.1016/S1053-2498(03)00150-5. PMID 15019634.
  31. ↑ Mehra MR, Uber PA, Ventura HO, Scott RL, Park MH (2004). "The impact of mode of donor brain death on cardiac allograft vasculopathy: an intravascular ultrasound study". J Am Coll Cardiol. 43 (5): 806–10. doi:10.1016/j.jacc.2003.08.059. PMID 14998621.
  32. ↑ Yamani MH, Starling RC, Cook DJ, Tuzcu EM, Abdo A, Paul P; et al. (2003). "Donor spontaneous intracerebral hemorrhage is associated with systemic activation of matrix metalloproteinase-2 and matrix metalloproteinase-9 and subsequent development of coronary vasculopathy in the heart transplant recipient". Circulation. 108 (14): 1724–8. doi:10.1161/01.CIR.0000087604.27270.5B. PMID 12975253.
  33. ↑ Mastrobuoni S, Dell'Aquila AM, Azcarate PM, Rabago G, Herreros J (2012). "Long-term survival (>20 years) following heart transplantation". J Cardiovasc Surg (Torino). 53 (5): 677–84. PMID 22955557.

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