Document Type : Review


1 Cardiovascular Research Center, Department of Cardiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

2 Student Research Committee, Department of Modern Sciences & Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran


Coronary artery disease (CAD) is a major global problem. In addition, it is higher risk of mortality for women more than men are when develop in female gender Atherosclerotic plaques consist of deposits of fatty material in the tunica intima. The role of inflammatory process in CAD has been known from 1980’s. Several studies investigated the innate immunity and adaptive immunity roles in atherosclerosis and they concluded that it plays a key role in atherosclerosis. Coronary artery bypass grafting (CABG) is a widely used method for the treatment of CAD. Based on the literature, CABG is the most common surgical operation done worldwide. In During the first 10 years after CABG, up to 50% of saphenous grafts will occlude. Graft restenosis is beginning with acute thrombosis, intima hyperplasia, and plaque formation. In this review, some molecular pathways of graft failure and restenosis such as apoptosis and nuclear factor kappa B (NF-ĸB) are described.



Atherosclerosis is a chronic inflammatory blood vessels condition affecting some important great arteries, which is the principal pathophysiological pathway of coronary artery disease (CAD) and Cerebrovascular events. Several studies confirmed the existence of T cells, B cells, monocytes and dendritic cells (DCs) inside the atherosclerotic plaques of mice and men (1).
Atherosclerotic plaques consist of deposits of fatty material in the tunica intima, smooth muscle cells that form an overlying cap, and elaborated extracellular matrix molecules that together lead to luminal narrowing. There are also a significant population of activated inflammatory cells, particularly macrophages that secrete metalloproteinases that can degrade the matrix molecules and lead to plaque instability and rupture(2). Atherosclerosis is also associated with innate and acquired immune responses, that start in the early years of life, but that becomes clinically apparent in later life (3-6).
The role of inflammation in CAD has been known from 1980’s. Several studies investigated the innate immunity and adaptive immunity roles in atherosclerosis and they concluded that it plays a key role in atherosclerosis (7,8). It was shocking to refer to atherosclerosis as an inflammatory disorder in the arterial linings almost about a century ago. Furthermore, after 1850, which was the date of confirming the involvement of inflammatory processes in atherosclerosis, so many studies have been done proving this fact by verifying cellular structure of atherosclerotic lesions which is possible by particular monoclonal antibodies for each cell (9-12).
Several studies confirmed the existence of T cells, B cells, monocytes, and dendritic cells (DCs) inside the atherosclerotic plaques of mice and men (13-15). Atherosclerotic plaques could released different biomarkers such as proinflammatory cytokines, amyloid A, adhesion molecules, and C-reactive protein in plasma (16).
The role of Interleukin-2 (IL-2) in the process of atherosclerosis is yet ambiguous; nevertheless, its immunomodulatory role in the activation of immune cells such as lymphocytes and monocytes has been proven. Martins et al. in their study in 2006, mentioned a significant elevation in IL-2 concentrations in their CAD study group(17).
Atherosclerosis is thought to be initiated by damage to the endothelium resulting in altered endothelial function. The risk factors of CAD are generally the cause of this damage through one or more of the following pathways including high levels of oxidized low-density lipoprotein (LDL), free radicals (reactive oxygen species (ROS)), genetic variations, elevated plasma homocysteine concentrations, infectious microorganisms (herpes virus or chlamydia pneumonia), shear stress in the areas of turbulent blood flow, or endogenous inflammatory signals such as cytokines (18).
It is reported that 12 million people in United States have atherosclerosis-associated conditions (19, 20). CADs causes about 30% of all global deaths. In 2008 approximately 17.3 million people died and about 23.3 million will die from CAD in 2030 (2).
In low- and middle-income countries, CAD leads to more than 80% of mortality; almost equally in men and women. It is estimated that by 2015, nearly 20 million people will die from CADs, main reasons are heart diseases and stroke. It is projected that these will remain the leading causes of death (21).
According to the Ebrahimi et al. review article, prevalence of CAD and coronary risk factors in Iran is higher than Western countries but similar to some Middle East countries (22).
The most prevalent clinical manifestations of CAD are myocardial infarction (MI), stable or unstable angina, and sudden death. Atherosclerosis, as a prominent predisposing factor, plays the major role in the pathogenic processes leading to CAD (23).
However, most cases of myocardial infarction occur due to thrombosis followed by plaque rupture (24).

Coronary arteries bypass grafting (CABG)
Coronary artery bypass grafting (CABG) is a widely used method for the treatment of CAD. Based on the literature, CABG is the most common surgical operation done worldwide (25,26).
There are criteria because of which a patient will be considered as a CABG candidate including:
A) Extensive coronary artery diseases (CAD) including narrowing, atherosclerosis, and stenosis (in general obstructive diseases) in the main left coronary artery or all three coronary arteries
B) Stable angina with persistent symptoms in patients who have taken adequate medication
C) Severe dysfunction of the left heart ventricle,
D) Having a high risk of future heart attack or any cardiac events diagnosed by exercise test or angiography
E) Unstable angina
F) Chronic or calcified arterial occlusions
G) Occlusive coronary disease in a patient with diabetes mellitus (27)
More than 300,000 CABG operations were performed in the North America annually (28) with about 467,000 CABG performed operations just in 2003 (29). Furthermore, it has been reported that over 10,000 patients requires CABG every year in Iran (30). Many percutaneous coronary interventions were done in the patients with the history of CABG. Therefore, restenosis occur more frequently in these patients, which may lead to new coronary events (31,32).
Artery bypass grafting failure is an unfavorable outcome of CABG operation (33) and lead to morbidity and mortality (34). Diabetes, plasma fibrinogen, creatinine, and high-density lipoprotein are as potential biomarkers of graft failure (33, 35). In the first 10 years after CABG, up to 50% of saphenous grafts will occlude (36,37).
Plasma anticardiolipin antibody is related to artery bypass grafting failure and it shows that an autoimmune pathway is activated in graft failure (38).
Endothelial injury is an important factor in atherosclerosis progression (18,19) which can influence the graft failure as well. Therefore, vein harvesting is one of the risk factors for graft failure (34). Endoscopic greater saphenous vein harvesting (EVH) is a minimally invasive technique for vein harvesting (39) and may reduce endothelial injury (40). Allen KB et al. in a five-year follow-up of a prospective RCT, displayed that use of EVH does not influence event-free survival (41). Some other scientists believe that EVH is independently associated with vein graft failure (42). Cellular proliferation and cell migration of smooth muscle cells are the main causes of graft failure after CABG in saphenous vein graft (43).
Graft restenosis is beginning by acute thrombosis, intima hyperplasia (IH), and plaque formation (34). Five years after grafting, the signs and symptoms of restenosis appear (44). Leukocyte endothelial interactions are increased by the adhesion molecule overexpression (45) due to abnormal blood flow in saphenous graft (46).
Apoptosis occurs in early-stage vein grafts. Mayr et al. also reported that IH is increased in the vein graft of P53 transgenic mice vein wall (47). Mitogen-activated protein kinase P38-MAPK is the main apoptosis signaling pathway that might be activated by mechanical stretch (stretch-induced injury) in high blood pressure aorta (48). These stresses of graft wall, change the blood flow, transmural pressure, shear stress, and radial stress and they can activate a lot of apoptosis and inflammation intercellular pathways (49).
Apoptosis could be a potential strategic target for inhibiting graft restenosis and graft failure (34). Another mechanism of graft failure is the activation of NF kappa B (NF-ĸB) signaling pathway, which involve in cytokines and adhesion molecule secretion pathways (50). On the other hand, ischemia of graft due to vasa vasorum occlusion in graft harvesting procedures could increase danger signals of apoptosis (51). Inhibition of P38 kinase could be another pharmacological target for decreasing graft failure after CABG (48). For example 4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole (SB 203580) can inhibit P38α and P38β in animal model, which it has been used for graft apoptosis and myocardial reperfusion apoptosis (51).

Graft atherosclerosis and risk factors
Triglyceride-rich lipoproteins such as very-low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) could be great risk factors and strong predictors of graft lesion (52).
Bourassa et al. in 1984, mentioned that post-CABG graft occlusion during 10-12 years, made them to limit CABG indication into patients with very severe 3 vessels disease (VD) or left main CAD (53).
Diabetes mellitus (DM) is one of CAD risk factors but Singh SK et al. in 2008, showed that DM was very important in graft occlusion at 1-year angiography follow-up (54).
Type of the graft for CAGB is another factor in graft occlusion. Most of the time, saphenous graft has been used but in one meta-analysis, in 2011, radial artery had less potency for early and midterm graft occlusion (55). Graft age is another most important factor in graft occlusion. Therefore, graft age can also predict graft obstruction risk following graft type (56).
Elevated serum lipid profile may lead to total graft occlusion (57) and lipid reducing agents especially gemfibrozil are recommended (52); Some researchers suggested LDL tight control (less than 90 mg/dL) (58). Lp(a) may influence graft obstruction in normolipidemic patients (59).
Serum level of homocysteine is a risk factor for graft occlusion especially in saphenous graft. In Iwama Y et al. study, a positive correlation was found between plasma level of homocysteine and graft occlusion (60).
Smoking is a risk factor for CAD and post-CABG graft occlusion (61). It seems that apopetosis and inflamation intercellular pathway are involved in smoking.
Hypertension has indirect correlation with graft occlusion. HTN can lead to intima hyperplasia in graft. So, hyperplasia is a trigger for graft obstruction (62,63).

Graft occlusion management
5-10% of percutaneous coronary intervention (PCI) are performed in USA due to graft occlusion annually (64). Some other suggested that managements of graft occlusion therapy are repeated CABG and medical control (62).
Asymptomatic ischemia testing after graft occlusion is the worst and dangerous method for a cardiologist. It could confuse patients and cardiologists, but in some cases recurrent angina could be detected (65).
Favorable conditions for PCI management of graft occlusion:
1.Single graft lesion
2.Focal graft lesion
3.Patent indicates left internal mammary artery (LIMA) graft
4.Patent LAD graft
Some other patients should undergo repeated CABG:
1.Multiple graft lesions
2.Diffuse graft lesions
3.Adequate pulmonary and renal function, life expectation>5 yr (62)

During first decay after CABG with saphenous grafting, 50% of patients have signs and symptoms of graft restenosis and graft failure. Therefore, inhibition of molecular pathway of apoptosis in graft tissue is very important. Apoptosis and NF-ĸB signaling pathway are the most involved pathways in graft failing. Therefore, minimally invasive graft harvesting, pharmacological anti-apoptosis medications, life style, diet, smoking cessation, and any modern molecular inhibitors are considerable.

We would like to thank Clinical Research Development Center of Ghaem Hospital for their assistant in this manuscript. This study was supported by a grant from the Vice Chancellor for Research of the Mashhad University of Medical Sciences for the research project as a medical student thesis with approval number of 910404.

 Conflict of Interest
The authors declare no conflict of interest.

  1. Ross R, Glomset J, Harker L. Response to injury and atherogenesis. Am J Pathol. 1977;86:675-684.
  2. Mendis S, Puska P, Norrving B. Global atlas on cardiovascular disease prevention and control: World Health Organization; 2011.
  3. Liao D-F, Jin Z-G, Baas AS, et al. Purification and Identification of Secreted Oxidative Stress-induced Factors from Vascular Smooth Muscle Cells. J Biol Chem. 2000;275:189-196.
  4. Chung S-W, Lee J-H, Choi K-H, et al. Extracellular heat shock protein 90 induces interleukin-8 in vascular smooth muscle cells. Biochem Biophys Res Commun. 2009;378:444-449.
  5. Xu Q. Role of Heat Shock Proteins in Atherosclerosis. Arterioscler Thromb Vasc Biol. 2002;22:1547-1559.
  6. Luikart SD, Panoskaltsis-Mortari A, Hinkel T, et al. Mactinin, a fragment of cytoskeletal alpha-actinin, is a novel inducer of heat shock protein (Hsp)-90 mediated monocyte activation. BMC Cell Biol. 2009;10:60.
  7. Elkind MS. Impact of innate inflammation in population studies. Ann N Y Acad Sci. 2010;1207:97-106.
  8. Wick G, Knoflach M, Xu Q. Autoimmune and inflammatory mechanisms in atherosclerosis. Annu Rev Immunol. 2004;22:361-403.
  9. Spence JD, Norris J. Infection, inflammation, and atherosclerosis. Stroke. 2003;34:333-334.
  10. Virchow R. Der Ateromatose Prozess der Arterien. Wien Med Wochenschr. 1856;6:825-827.
  11. Satoh M, Shimoda Y, Akatsu T, et al. Elevated circulating levels of heat shock protein 70 are related to systemic inflammatory reaction through monocyte Toll signal in patients with heart failure after acute myocardial infarction. Eur J Heart Fail. 2006;8:810-815.
  12. Libby P, Hansson GK. Involvement of the immune system in human atherogenesis: current knowledge and unanswered questions. Lab Invest. 1991;64:5-15.
  13. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:1685-1695.
  14. Steffens S, Mach F. Inflammation and atherosclerosis. Herz.2004;29:741-748.
  15. Kazemi-Bajestani SM, Ghayour-Mobarhan M, Ebrahimi M, et al. C-reactive protein associated with coronary artery disease in Iranian patients with angiographically defined coronary artery disease. Clin Lab. 2007;53:49-56.
  16. Rajappa M, Sen S, Sharma A. Role of pro-/anti-inflammatory cytokines and their correlation with established risk factors in South Indians with coronary artery disease. Angiology. 2009;60:419-426.
  17. Martins TB, Anderson JL, Muhlestein JB, et al. Risk factor analysis of plasma cytokines in patients with coronary artery disease by a multiplexed fluorescent immunoassay. Am J Clin Pathol. 2006;125:906-913.
  18. Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999;340:115-126.
  19. Kleindienst R, Schett G, Amberger A, et al. Atherosclerosis as an autoimmune condition. Isr J Med Sci. 1995;31:596-599.
  20. Sun J, Liao JK. Induction of angiogenesis by heat shock protein 90 mediated by protein kinase Akt and endothelial nitric oxide synthase. Arterioscler Thromb Vasc Biol. 2004;24:2238-2244.
  21. Statistical Fact-Sheet Populations. International Cardiovascular Disease Statistics. 2009.
  22. Ebrahimi M, Kazemi-Bajestani SM, Ghayour-Mobarhan M, et al. Coronary Artery Disease and Its Risk Factors Status in Iran: A Review. Iran Red Crescent Med J. 2011;13:610-623.
  23. Lewis SL, Dirksen SR, Heitkemper MM, et al. Medical-Surgical Nursing: Assessment and Management of Clinical Problems, Single Volume: Elsevier Health Sciences; 2013.
  24. George SJ, Johnson J. Atherosclerosis: molecular and cellular mechanisms: John Wiley & Sons; 2010.
  25. Rihal CS, Raco DL, Gersh BJ, et al. Indications for coronary artery bypass surgery and percutaneous coronary intervention in chronic stable angina: review of the evidence and methodological considerations. Circulation. 2003;108:2439-2445.
  26. Serruys PW, Morice MC, Kappetein AP, et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med. 2009;360:961-972.
  27. Eagle KA, Guyton RA, Davidoff R, et al. ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery). Circulation. 2004;110:e340-437.
  28. Taheri MS, Haghighatkhah H, Tash MH, et al. The prevalence of carotid artery disease in candidates of coronary artery bypass graft. Iran J Radiol. 2006;3:221-224.
  29. Magee MJ, Alexander JH, Hafley G, et al. Coronary artery bypass graft failure after on-pump and off-pump coronary artery bypass: findings from PREVENT IV. Ann Thorac Surg. 2008;85:494-499.
  30. Anvari MS, Boroumand MA, Emami B, et al. ABO blood group and coronary artery diseases in Iranian patients awaiting coronary artery bypass graft surgery: a review of 10,641 cases. Lab Medicine. 2009;40:528-530.
  31. Frimerman A, Rechavia E, Eigler N, et al. Long-term follow-up of a high risk cohort after stent implantation in saphenous vein grafts. J Am Coll Cardiol. 1997;30:1277-1283.
  32. Labinaz M, Kilaru R, Pieper K, et al. Outcomes of patients with acute coronary syndromes and prior coronary artery bypass grafting: results from the platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression using integrilin therapy (PURSUIT) trial. Circulation. 2002;105:322-327.
  33. Yanagawa B, Algarni KD, Singh SK, et al. Clinical, biochemical, and genetic predictors of coronary artery bypass graft failure.J Thorac Cardiovasc Surg. 2014;148:515-520.
  34. Zheng H, Xue S, Lian F, et al. A novel promising therapy for vein graft restenosis: overexpressed Nogo-B induces vascular smooth muscle cell apoptosis by activation of the JNK/p38 MAPK signaling pathway. Med Hypotheses. 2011;77:278-281.
  35. Influence of diabetes on 5-year mortality and morbidity in a randomized trial comparing CABG and PTCA in patients with multivessel disease: the Bypass Angioplasty Revascularization Investigation (BARI). Circulation. 1997;96:1761-1769.
  36. Bhardwaj S, Roy H, Yla-Herttuala S. Gene therapy to prevent occlusion of venous bypass grafts. Expert Rev Cardiovasc Ther. 2008;6:641-652.
  37. Motwani JG, Topol EJ. Aortocoronary saphenous vein graft disease: pathogenesis, predisposition, and prevention. Circulation. 1998;97:916-931.
  38. Morton KE, Gavaghan TP, Krilis SA, et al. Coronary artery bypass graft failure--an autoimmune phenomenon? Lancet. 1986;2:1353-1357.
  39. Nezafati MH, Nezafati P. Descriptive Analysis of Endoscopic versus Traditional Open Vein Harvest Technique for Coronary Artery Bypass Graft Surgery: Report of 1974 Cases. Iran Heart J. 2014;14:17-22.
  40. Hussaini BE, Lu XG, Wolfe JA, et al. Evaluation of endoscopic vein extraction on structural and functional viability of saphenous vein endothelium. J Cardiothorac Surg. 2011;6:82.
  41. Allen KB, Heimansohn DA, Robison RJ, et al. Influence of endoscopic versus traditional saphenectomy on event-free survival: five-year follow-up of a prospective randomized trial. Heart Surg Forum. 2003;6:E143-145.
  42. Lopes RD, Hafley GE, Allen KB, et al. Endoscopic versus open vein-graft harvesting in coronary-artery bypass surgery. N Engl J Med. 2009;361:235-244.
  43. Porter KE, Turner NA. Statins for the prevention of vein graft stenosis: a role for inhibition of matrix metalloproteinase-9. Biochem Soc Trans. 2002;30:120-126.
  44. Mitra AK, Gangahar DM, Agrawal DK. Cellular, molecular and immunological mechanisms in the pathophysiology of vein graft intimal hyperplasia. Immunol Cell Biol. 2006;84:115-124.
  45. Farzadnia M, Ayatollahi H, Hasan-Zade M, et al. A Comparative Study of Serum Level of Vascular Cell Adhesion Molecule-1 (sVCAM-1), Intercellular Adhesion Molecule-1(ICAM-1) and High Sensitive C-reactive protein (hs-CRP) in Normal and Pre-eclamptic Pregnancies. Iran J Basic Med Sci. 2013;16:689-693.
  46. Poston RS, Gu J, Brown JM, et al. Endothelial injury and acquired aspirin resistance as promoters of regional thrombin formation and early vein graft failure after coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2006;131:122-130.
  47. Mayr M, Li C, Zou Y, et al. Biomechanical stress-induced apoptosis in vein grafts involves p38 mitogen-activated protein kinases. FASEB J. 2000;14:261-270.
  48. Cornelissen J, Armstrong J, Holt CM. Mechanical stretch induces phosphorylation of p38-MAPK and apoptosis in human saphenous vein. Arterioscler Thromb Vasc Biol. 2004;24:451-456.
  49. Dobrin PB, Littooy FN, Endean ED. Mechanical factors predisposing to intimal hyperplasia and medial thickening in autogenous vein grafts. Surgery. 1989;105:393-400.
  50. Miyake T, Aoki M, Shiraya S, et al. Inhibitory effects of NFkappaB decoy oligodeoxynucleotides on neointimal hyperplasia in a rabbit vein graft model. J Mol Cell Cardiol. 2006;41:431-440.
  51. Ma XL, Kumar S, Gao F, et al. Inhibition of p38 mitogen-activated protein kinase decreases cardiomyocyte apoptosis and improves cardiac function after myocardial ischemia and reperfusion. Circulation. 1999;99:1685-1691.
  52. Syvanne M, Nieminen MS, Frick MH, et al. Associations between lipoproteins and the progression of coronary and vein-graft atherosclerosis in a controlled trial with gemfibrozil in men with low baseline levels of HDL cholesterol. Circulation. 1998;98:1993-1999.
  53. Bourassa MG, Enjalbert M, Campeau L, et al. Progression of atherosclerosis in coronary arteries and bypass grafts: ten years later. Am J Cardiol. 1984;53:102C-107C.
  54. Singh SK, Desai ND, Petroff SD, et al. The impact of diabetic status on coronary artery bypass graft patency: insights from the radial artery patency study. Circulation. 2008;118:S222-225.
  55. Hu X, Zhao Q. Systematic comparison of the effectiveness of radial artery and saphenous vein or right internal thoracic artery coronary bypass grafts in non-left anterior descending coronary arteries. J Zhejiang Univ Sci B. 2011;12:273-279.
  56. Domanski MJ, Borkowf CB, Campeau L, et al. Prognostic factors for atherosclerosis progression in saphenous vein graftsThe postcoronary artery bypass graft (post-CABG) trial. J Am Coll Cardiol. 2000;36:1877-1883.
  57. Palac RT, Meadows WR, Hwang MH, et al. Risk factors related to progressive narrowing in aortocoronary vein grafts studied 1 and 5 years after surgery. Circulation. 1982;66:I40-44.
  58. Rodes-Cabau J, Facta A, Larose E, et al. Predictors of aorto-saphenous vein bypass narrowing late after coronary artery bypass grafting. Am J Cardiol. 2007;100:640-645.
  59. Dangas G, Mehran R, Harpel PC, et al. Lipoprotein (a) and inflammation in human coronary atheroma: association with the severity of clinical presentation. J Am Coll Cardiol. 1998;32:2035-2042.
  60. Iwama Y, Mokuno H, Watanabe Y, et al. Relationship between plasma homocysteine levels and saphenous vein graft disease after coronary artery bypass grafts. Jpn Heart J. 2001;42:553-562.
  61. Campeau L, Enjalbert M, Lesperance J, et al. The relation of risk factors to the development of atherosclerosis in saphenous-vein bypass grafts and the progression of disease in the native circulation. A study 10 years after aortocoronary bypass surgery. N Engl J Med. 1984;311:1329-1332.
  62. Harskamp R, Lopes R, Baisden C, et al. Saphenous vein graft failure after coronary artery bypass surgery: pathophysiology, management, and future directions. Ann Surg. 2013;257:824-833.
  63. Cox JL, Chiasson DA, Gotlieb AI. Stranger in a strange land: the pathogenesis of saphenous vein graft stenosis with emphasis on structural and functional differences between veins and arteries. Prog Cardiovasc Dis. 1991;34:45-68.
  64. Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery: Executive summary: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Thorac Cardiovasc Surg. 2012;143:4-34.
  65. Lopes RD, Mehta RH, Hafley GE, et al. Relationship between vein graft failure and subsequent clinical outcomes after coronary artery bypass surgery. Circulation. 2012;125:749-756.