Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 
Home Print this page Email this page
Users Online:729


 
 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 6  |  Issue : 3  |  Page : 75-80

Role of herpesviruses in coronary artery disease


1 Department of Medicine, AIIMS, Bhopal, Madhya Pradesh, India
2 Microbiology, AIIMS, Bhopal, Madhya Pradesh, India

Date of Web Publication12-Sep-2018

Correspondence Address:
Dr. Debasis Biswas
Head of Department, Department of Microbiology, AIIMS, Bhopal, Madhya Pradesh
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/heartindia.heartindia_18_18

Rights and Permissions
  Abstract 


Coronary artery disease (CAD) is a huge global burden and is a leading cause of morbidity and mortality across the world. We have done this review to elucidate the pathogenesis of herpesviruses in causing CAD and to study an association between herpesviruses (cytomegalovirus [CMV] and herpes simplex virus [HSV-1 and -2]) and CAD. CMV can cause atherosclerosis directly through the activity of its gene products on endothelial cells, monocytes/macrophages, and smooth muscle cells and indirectly through production of pro-inflammatory cytokines at far off place. HSV infection causes atherosclerosis mainly by causing increased prothrombotic activity on endothelial cells, accumulation of cholesterol esters and triacylglycerols in vascular smooth muscle cells, and upregulating expression of Lectin like oxidized Low density lipoprotein receptor-1 (LOX-1) receptor on macrophages. The association between CMV and CAD is related to its seroprevalence with a positive association in developing countries (higher seroprevalence) and no significant association in developed countries (lower seroprevalence). However, the association between HSV infection and atherosclerosis is not related to its seroprevalence.

Keywords: Atherosclerosis, coronary artery disease, cytomegalovirus, herpes simplex virus, herpesviruses


How to cite this article:
Bansal A, Biswas D. Role of herpesviruses in coronary artery disease. Heart India 2018;6:75-80

How to cite this URL:
Bansal A, Biswas D. Role of herpesviruses in coronary artery disease. Heart India [serial online] 2018 [cited 2018 Nov 21];6:75-80. Available from: http://www.heartindia.net/text.asp?2018/6/3/75/241067




  Introduction Top


Approximately 17.5 million people die each year from cardiovascular diseases (CVDs) worldwide.[1] Accounting for 31% of total deaths, coronary artery disease (CAD) is the leading cause of mortality and morbidity. It has been estimated that >75% of cardiovascular deaths occur in low- and medium-income countries.[1] CVDs act as a large financial burden on the economy of nation not only due to the direct cost involved in the treatment of disease but also due to lack of productivity associated with the disease. The combined direct and indirect cost of CVDs in the United States was estimated to be $444 billion in 2010. This staggeringly high number corresponds to $1 out of every $6 spent on health care.[2] Given the high global burden of CAD, prevention through identifying and mitigating risk factors is a priority. Although it is well known that hypertension, hypercholesterolemia, decreased high-density lipoprotein cholesterol, smoking, family history, and diabetes were regarded as absolute risk factors, they cannot explain all the cases of atherosclerosis.

Given the influx of inflammatory cells such as T-cells, B-cells, macrophages, and polymorphonuclear neutrophils in atherosclerotic plaques,[3] inflammation has been proposed to be one of the driving forces in the pathogenesis of CAD. The role of infective agents in triggering the inflammatory process is underscored by the relatively high prevalence of CAD in low- and middle-income countries, which often suffer from high rates of infection and poor sanitary and hygienic conditions. Apart from expediting the inflammatory process, infective agents can also lead to final complication of these plaques such as plaque rupture and thrombosis.

Zhu et al.[4] introduced the concept of pathogen burden and demonstrated that the number of infectious pathogens to which an individual has been exposed is related to the presence of CAD. Several studies have shown an association between previous infections with Chlamydia pneumonia,[5] herpes simplex virus (HSV), cytomegalovirus (CMV), Helicobacter pylori,[6] and hepatitis virus[7] or respiratory tract infection and the presence of CAD, whereas other studies have not shown such an association. We have done this review to elucidate the pathogenesis of herpesviruses in causing CAD. Furthermore, we have presented various studies and their association with CAD. By understanding the pathogenesis, we can target at molecular level to prevent the progression of atherosclerosis and thus the development of CAD.

Cytomegalovirus

CMV, a double-stranded DNA virus, is a member of the herpesvirus family. It is considered to have the highest infection rate among the infectious agents affecting humans. CMV infection is usually subclinical or latent. However, once acquired, the infection persists lifelong and may undergo periodic reactivation. Endothelial cells and smooth muscle cells can act as sites of latency for CMV. There have been various studies regarding the association between CMV and atherosclerosis. However, some document the presence of CMV in human plaques whereas others do not.

CMV can cause atherosclerosis both through direct and indirect mechanisms. Direct mechanisms involve the pathogenesis of atherosclerosis because of the gene products of CMV. CMV infection of endothelial cells generates gene products IE72 and IE84[8] that activate the COX-2 promoter. This increases the activity of nuclear factor-κB (NF-κB) transcription factor through increased reactive oxygen species production.[9] Increased NF-κB further mediates the expression of adhesion molecules such as ICAM-1, VCAM-1, VAP-1, and E-selectin on the endothelial cells. The increased expression of adhesion molecules favors the adhesion of monocytes/macrophages to the endothelial cells and contributes to atherosclerosis. Furthermore, increased levels of NF-κB also make the atherosclerotic plaque unstable by releasing matrix metalloproteinase-9. Smooth muscle migration and proliferation is an important step in the formation and progression of atherosclerotic plaque.[10] Infection with CMV expresses the US28 chemokine receptor.[11] This chemokine receptor promotes the migration of smooth muscle cells to tunica intima. In addition, the CMV IE84 gene product generated in endothelial cells inhibits the transcriptional activity of p53.[12] The downregulation of p53 increases the proliferation of smooth muscle cells by inhibiting apoptosis and thus contributes to the propagation of atherosclerosis.

Indirect mechanisms are due to the production of cytokines at far off place that mediates atherosclerosis through effects other than direct involvement of CMV gene products. Studies have shown that infection with CMV raises the level of pro-inflammatory cytokines, namely interferon-gamma and tumor necrosis factor-alpha (TNF-α).[13] Increased titer of pro-inflammatory cytokines increases the risk of rupture of plaque and makes the patient prone to CAD and its complications. TNF-α further transactivates NF-κB and thus predisposes to atherosclerosis by the mechanisms as described above.

CMV infection also predisposes to CAD by worsening the already established risk factors in affected individuals. CMV raises the levels of angiotensin II and renin in infected individuals and independently worsens blood pressure.[14] In diabetic patients with poor glycemic control, there is increased risk of CMV infection in the arterial wall. In addition, CMV can also act as a pro-thrombotic agent and enhances the production of thrombin and thus activates the coagulation cascade.[15] Increased thrombin generation worsens the risk of atherosclerosis and CAD.

[Table 1] illustrates the studies showing an association between CMV and CAD. Studies in developing countries such as India,[34] Iran,[35] Saudi Arabia, and Turkey[36] reported a positive association between CMV and development of CAD. However, studies in developed countries such as the USA,[37] the Netherlands, Canada, Belgium, and Ireland reported no association between CMV infection and CAD. This is consistent with higher seroprevalence of CMV in developing countries and lower seroprevalence in developed countries. Countries such as India, Iran, Saudi Arabia, and Turkey have reported >80% seropositivity of CMV, while European and North American countries have seropositivity ranging from 30% to 55%. However, in Russia, which is a developed country, Nikitskaya et al. have shown positive association between CMV and CAD. This could be because of the high CMV seropositivity ranging from 80% to 90% in Russia. Despite the lower prevalence of CMV in Germany,[38] Georges et al.[27] have reported a significant association between CMV and CAD. These results are contradicting to a study by Hoffmeister et al.,[31] which reported no association. A possible explanation for this could be arrived from a study by Voigt et al.[39] that showed a seroprevalence of 30% in individuals of German descent and 68% in individuals of non-German descent.
Table 1: Association between cytomegalovirus and coronary artery disease

Click here to view


Herpes simplex virus 1 and 2

HSV-1 and 2 members of herpesvirus family are double-stranded DNA viruses that can cause a wide range of presentation from benign cutaneous oral or genital lesions to severe HSV encephalitis. There are multiple studies that link an association between HSV-1/2 infection and atherosclerosis. HSV promotes atherosclerosis by acting on endothelial cells, vascular smooth muscle cells (VSMCs), and macrophages.

Endothelial cells can act as a site of latency for the virus, which may undergo periodic reactivation and cause enhanced atherosclerosis. HSV infection on the vascular endothelium causes an increase in pro-thrombotic activity and thereby atherosclerosis by various mechanisms. First, HSV infection decreases the synthesis of heparan sulfate proteoglycan that impairs the action of antithrombin 3 necessary for inactivating the activated coagulation factors, thus increasing the pro-thrombotic activity. Second, the infection by HSV causes impaired thrombomodulin surface expression on the endothelium that reduces the levels of protein C, further contributing to increased thrombotic activity and thus atherosclerosis. Third, HSV infection can increase the thrombin generation and decrease the levels of prostacyclins, thus increasing platelet adhesion. In addition, HSV infection of endothelial cells induces the cell surface expression of P-selectin (GMP 140) and von Willebrand factor that promote the adhesion of monocytes and platelets to the endothelium, favoring thrombosis and atherosclerotic plaque formation.[40]

HSV-1 infection of VSMCs causes the accumulation of saturated cholesterol esters (CEs) and triacylglycerols (TAGs) that predispose to atherosclerosis. There are various mechanisms responsible for the accumulation of CEs and TAGs including increased low-density lipoprotein (LDL) binding and uptake, increased LDL receptor gene transcription, increased 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity, and decreased CE hydrolase activity.[41],[42],[43] In addition, infection with HSV induces the expression of HSV glycoprotein that stimulates platelet-derived growth factor production and promotes smooth muscle cells proliferation, thereby enhancing atherosclerotic plaque formation.

Furthermore, HSV-1 infection also upregulates the expression of LOX-1 receptor on the macrophages, and thus, there is enhanced uptake of oxidized LDL promoting foam cell formation and thereby promoting atherosclerosis.[44]

[Table 2] illustrates the studies showing an association between HSV-1 and CAD. Guan et al.[46] reported a significant correlation between HSV-1 infection and CAD. Jafarzadeh et al.[47] and Vahdat et al.[48] reported contradicting results on association between HSV-1 and CAD. Mundkur et al.[45] from India have not reported any association between HSV-1 and CAD. Studies in Germany, Hungary, and the USA[4],[49],[50],[51] have not shown any association between HSV-1 and CAD.
Table 2: Association between herpesvirus 1 and coronary artery disease

Click here to view


Compared to HSV-1, seroprevalence of HSV-2 is low. Only a study by Georges et al.[27] has reported association between HSV-2 and CAD, whereas other studies do not show any association between HSV-2 infection and CAD. [Table 3] illustrates the studies showing an association between HSV-2 and CAD. In contrast to CMV infection, the association between HSV infection and CAD is not related to seroprevalence.
Table 3: Association between herpes simplex virus-2 and coronary artery disease

Click here to view


Clinical implication

Several trials have illustrated or are in process to evaluate the efficacy of anti-inflammatory therapy in the treatment of cardiovascular events. A recent randomized control CANTOS trial[51] showed that canakinumab, a therapeutic monoclonal antibody targeting the interleukin 1-beta, led to significantly lower recurrent cardiovascular events compared to placebo, independent of the lipid-lowering therapy. Micha et al.[52] reported that patients with rheumatoid arthritis or psoriatic arthritis taking low-dose methotrexate have a 21% lower risk of future cardiovascular events. A P-selectin antagonist inclacumab significantly reduces myocardial damage after percutaneous coronary intervention in patients with non-ST-segment elevation myocardial infarction.[53] Secretory phospholipase inhibitors, darapladib or varespladib, have not shown significant reduction in cardiovascular events in STABILITY[54] and SOLID-TIMI 52 trial.[55]

The ongoing Phase 1/2 CLEVER-ACS trial is studying the effect of mTOR inhibition through everolimus on infarct size, myocardial function, and inflammation in patients with ST-elevation myocardial infarction. A Phase 3 CIRT trial[56] is investigating whether taking lower dose methotrexate reduces heart attack, stroke, or death in patients with Type 2 diabetes mellitus or metabolic syndrome that have had a heart attack or multiple coronary blockages.


  Conclusion Top


The association between CMV and CAD is related to its seroprevalence with a positive association in developing countries (higher seroprevalence) and no significant association in developed countries (lower seroprevalence). However, the association between HSV infection and atherosclerosis is not related to its seroprevalence. The pathogenesis of atherosclerosis has major inflammatory influences and understanding those has helped evaluate the efficacy of anti-inflammatory therapies in CAD.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
WHO | Cardiovascular Diseases (CVDs). WHO. Available from: http://www.who.int/mediacentre/factsheets/fs317/en/. [Last accessed on 2018 Feb 25].  Back to cited text no. 1
    
2.
Heart Disease and Stroke | At A Glance Reports | Publications | Chronic Disease Prevention and Health Promotion | CDC. 2018 Available from: https://www.cdc.gov/chronicdisease/resources/publications/aag/heart-disease-stroke.htm. [Last accessed on 2018 Feb 25].  Back to cited text no. 2
    
3.
Tousoulis D, Charakida M, Stefanadis C. Endothelial function and inflammation in coronary artery disease. Postgrad Med J 2008;84:368-71.  Back to cited text no. 3
    
4.
Zhu J, Quyyumi AA, Norman JE, Csako G, Waclawiw MA, Shearer GM, et al. Effects of total pathogen burden on coronary artery disease risk and C-reactive protein levels. Am J Cardiol 2000;85:140-6.  Back to cited text no. 4
    
5.
Joshi R, Khandelwal B, Joshi D, Gupta OP. Chlamydophila pneumoniae infection and cardiovascular disease. N Am J Med Sci 2013;5:169-81.  Back to cited text no. 5
    
6.
Yu XJ, Yang X, Feng L, Wang LL, Dong QJ. Association between Helicobacter pylori infection and angiographically demonstrated coronary artery disease: A meta-analysis. Exp Ther Med 2017;13:787-93.  Back to cited text no. 6
    
7.
Vassalle C, Masini S, Bianchi F, Zucchelli GC. Evidence for association between hepatitis C virus seropositivity and coronary artery disease. Heart 2004;90:565-6.  Back to cited text no. 7
    
8.
Castillo JP, Yurochko AD, Kowalik TF. Role of human cytomegalovirus immediate-early proteins in cell growth control. J Virol 2000;74:8028-37.  Back to cited text no. 8
    
9.
Speir E, Shibutani T, Yu ZX, Ferrans V, Epstein SE. Role of reactive oxygen intermediates in cytomegalovirus gene expression and in the response of human smooth muscle cells to viral infection. Circ Res 1996;79:1143-52.  Back to cited text no. 9
    
10.
Zhou YF, Yu ZX, Wanishsawad C, Shou M, Epstein SE. The immediate early gene products of human cytomegalovirus increase vascular smooth muscle cell migration, proliferation, and expression of PDGF beta-receptor. Biochem Biophys Res Commun 1999;256:608-13.  Back to cited text no. 10
    
11.
Vomaske J, Nelson JA, Streblow DN. Human cytomegalovirus US28: A functionally selective chemokine binding receptor. Infect Disord Drug Targets 2009;9:548-56.  Back to cited text no. 11
    
12.
Tanaka K, Zou JP, Takeda K, Ferrans VJ, Sandford GR, Johnson TM, et al. Effects of human cytomegalovirus immediate-early proteins on p53-mediated apoptosis in coronary artery smooth muscle cells. Circulation 1999;99:1656-9.  Back to cited text no. 12
    
13.
Compton T, Kurt-Jones EA, Boehme KW, Belko J, Latz E, Golenbock DT, et al. Human cytomegalovirus activates inflammatory cytokine responses via CD14 and toll-like receptor 2. J Virol 2003;77:4588-96.  Back to cited text no. 13
    
14.
Cheng J, Ke Q, Jin Z, Wang H, Kocher O, Morgan JP, et al. Cytomegalovirus infection causes an increase of arterial blood pressure. PLoS Pathog 2009;5:e1000427.  Back to cited text no. 14
    
15.
Sherman S, Eytan O, Justo D. Thrombosis associated with acute cytomegalovirus infection: A narrative review. Arch Med Sci 2014;10:1186-90.  Back to cited text no. 15
    
16.
Nikitskaya EA, Grivel JC, Maryukhnich EV, Lebedeva AM, Ivanova OI, Savvinova PP, et al. Cytomegalovirus in plasma of acute coronary syndrome patients. Acta Naturae 2016;8:102-7.  Back to cited text no. 16
    
17.
Mundkur LA, Shivanandan H, Hebbagudi S, Endrész V, Varma M, Rao V, et al. Human cytomegalovirus neutralising antibodies and increased risk of coronary artery disease in Indian population. Heart 2012;98:982-7.  Back to cited text no. 17
    
18.
Al-Ghamdi A, Jiman-Fatani AA, El-Banna H. Role of Chlamydia pneumoniae, Helicobacter pylori and cytomegalovirus in coronary artery disease. Pak J Pharm Sci 2011;24:95-101.  Back to cited text no. 18
    
19.
Tewari R, Nijhawan V, Mishra M, Dudeja P, Salopal T. Prevalence of Helicobacter pylori, cytomegalovirus, and Chlamydia pneumoniae immunoglobulin seropositivity in coronary artery disease patients and normal individuals in North Indian population. Med J Armed Forces India 2012;68:53-7.  Back to cited text no. 19
    
20.
Alavi SM, Adel SM, Rajabzadeh AR. An evidence against the effect of chronic cytomegalovirus infection in unstable angina pectoris. Acta Med Iran 2011;49:78-80.  Back to cited text no. 20
    
21.
Safaie N, Ghotaslou R, Montazer Ghaem H. Seroprevalence of cytomegalovirus in patients with and without coronary artery diseases at Madani Heart Center, Iran. Acta Med Iran 2010;48:403-6.  Back to cited text no. 21
    
22.
Jha HC, Prasad J, Mittal A. High immunoglobulin A seropositivity for combined Chlamydia pneumoniae, Helicobacter pylori infection, and high-sensitivity C-reactive protein in coronary artery disease patients in India can serve as atherosclerotic marker. Heart Vessels 2008;23:390-6.  Back to cited text no. 22
    
23.
Gredmark S, Jonasson L, Van Gosliga D, Ernerudh J, Söderberg-Nauclér C. Active cytomegalovirus replication in patients with coronary disease. Scand Cardiovasc J 2007;41:230-4.  Back to cited text no. 23
    
24.
Eryol NK, Kiliç H, Gül A, Ozdogru I, Inanç T, Dogan A, et al. Are the high levels of cytomegalovirus antibodies a determinant in the development of coronary artery disease? Int Heart J 2005;46:205-9.  Back to cited text no. 24
    
25.
Sheehan J, Kearney PM, Sullivan SO, Mongan C, Kelly E, Perry IJ, et al. Acute coronary syndrome and chronic infection in the Cork coronary care case-control study. Heart 2005;91:19-22.  Back to cited text no. 25
    
26.
Arcari CM, Gaydos CA, Nieto FJ, Krauss M, Nelson KE. Association between Chlamydia pneumoniae and acute myocardial infarction in young men in the United States military: The importance of timing of exposure measurement. Clin Infect Dis 2005;40:1123-30.  Back to cited text no. 26
    
27.
Georges JL, Rupprecht HJ, Blankenberg S, Poirier O, Bickel C, Hafner G, et al. Impact of pathogen burden in patients with coronary artery disease in relation to systemic inflammation and variation in genes encoding cytokines. Am J Cardiol 2003;92:515-21.  Back to cited text no. 27
    
28.
Witherell HL, Smith KL, Friedman GD, Ley C, Thom DH, Orentreich N, et al. C-reactive protein, Helicobacter pylori, Chlamydia pneumoniae, cytomegalovirus and risk for myocardial infarction. Ann Epidemiol 2003;13:170-7.  Back to cited text no. 28
    
29.
Bloemenkamp DG, Mali WP, Tanis BC, Rosendaal FR, van den Bosch MA, Kemmeren JM, et al. Chlamydia pneumoniae, Helicobacter pylori and cytomegalovirus infections and the risk of peripheral arterial disease in young women. Atherosclerosis 2002;163:149-56.  Back to cited text no. 29
    
30.
De Backer J, Mak R, De Bacquer D, Van Renterghem L, Verbraekel E, Kornitzer M, et al. Parameters of inflammation and infection in a community based case-control study of coronary heart disease. Atherosclerosis 2002;160:457-63.  Back to cited text no. 30
    
31.
Hoffmeister A, Rothenbacher D, Bode G, Persson K, März W, Nauck MA, et al. Current infection with Helicobacter pylori, but not seropositivity to Chlamydia pneumoniae or cytomegalovirus, is associated with an atherogenic, modified lipid profile. Arterioscler Thromb Vasc Biol 2001;21:427-32.  Back to cited text no. 31
    
32.
Smieja M, Cronin L, Levine M, Goldsmith CH, Yusuf S, Mahony JB, et al. Previous exposure to Chlamydia pneumoniae, Helicobacter pylori and other infections in Canadian patients with ischemic heart disease. Can J Cardiol 2001;17:270-6.  Back to cited text no. 32
    
33.
Siscovick DS, Schwartz SM, Corey L, Grayston JT, Ashley R, Wang SP, et al. Chlamydia pneumoniae, herpes simplex virus type 1, and cytomegalovirus and incident myocardial infarction and coronary heart disease death in older adults: The cardiovascular health study. Circulation 2000;102:2335-40.  Back to cited text no. 33
    
34.
Kothari A, Ramachandran VG, Gupta P, Singh B, Talwar V. Seroprevalence of cytomegalovirus among voluntary blood donors in Delhi, India. J Health Popul Nutr 2002;20:348-51.  Back to cited text no. 34
    
35.
Shaiegan M, Rasouli M, Zadsar M, Zolfaghari S. Meta-analysis of cytomegalovirus seroprevalence in volunteer blood donors and healthy subjects in Iran from 1992 to 2013. Iran J Basic Med Sci 2015;18:627-34.  Back to cited text no. 35
    
36.
Ocak S, Zeteroglu S, Ozer C, Dolapcioglu K, Gungoren A. Seroprevalence of Toxoplasma gondii, rubella and cytomegalovirus among pregnant women in Southern Turkey. Scand J Infect Dis 2007;39:231-4.  Back to cited text no. 36
    
37.
Bate SL, Dollard SC, Cannon MJ. Cytomegalovirus seroprevalence in the United States: The national health and nutrition examination surveys, 1988-2004. Clin Infect Dis 2010;50:1439-47.  Back to cited text no. 37
    
38.
Enders G, Daiminger A, Lindemann L, Knotek F, Bäder U, Exler S, et al. Cytomegalovirus (CMV) seroprevalence in pregnant women, bone marrow donors and adolescents in Germany, 1996-2010. Med Microbiol Immunol 2012;201:303-9.  Back to cited text no. 38
    
39.
Voigt S, Schaffrath Rosario A, Mankertz A. Cytomegalovirus seroprevalence among children and adolescents in Germany: Data from the German health interview and examination survey for children and adolescents (KiGGS), 2003-2006. Open Forum Infect Dis 2016;3:ofv193.  Back to cited text no. 39
    
40.
Etingin OR, Silverstein RL, Hajjar DP. Identification of a monocyte receptor on herpesvirus-infected endothelial cells. Proc Natl Acad Sci U S A 1991;88:7200-3.  Back to cited text no. 40
    
41.
Etingin OR, Hajjar DP. Evidence for cytokine regulation of cholesterol metabolism in herpesvirus-infected arterial cells by the lipoxygenase pathway. J Lipid Res 1990;31:299-305.  Back to cited text no. 41
    
42.
Key NS, Vercellotti GM, Winkelmann JC, Moldow CF, Goodman JL, Esmon NL, et al. Infection of vascular endothelial cells with herpes simplex virus enhances tissue factor activity and reduces thrombomodulin expression. Proc Natl Acad Sci U S A 1990;87:7095-9.  Back to cited text no. 42
    
43.
Span AH, van Dam-Mieras MC, Mullers W, Endert J, Muller AD, Bruggeman CA, et al. The effect of virus infection on the adherence of leukocytes or platelets to endothelial cells. Eur J Clin Invest 1991;21:331-8.  Back to cited text no. 43
    
44.
Chirathaworn C, Pongpanich A, Poovorawan Y. Herpes simplex virus 1 induced LOX-1 expression in an endothelial cell line, ECV 304. Viral Immunol 2004;17:308-14.  Back to cited text no. 44
    
45.
Mundkur LA, Rao VS, Hebbagudi S, Shanker J, Shivanandan H, Nagaraj RK, et al. Pathogen burden, cytomegalovirus infection and inflammatory markers in the risk of premature coronary artery disease in individuals of Indian origin. Exp Clin Cardiol 2012;17:63-8.  Back to cited text no. 45
    
46.
Guan X, Yang W, Sun X, Wang L, Ma B, Li H, et al. Association of influenza virus infection and inflammatory cytokines with acute myocardial infarction. Inflamm Res 2012;61:591-8.  Back to cited text no. 46
    
47.
Jafarzadeh A, Nemati M, Tahmasbi M, Ahmadi P, Rezayati MT, Sayadi AR, et al. The association between infection burden in Iranian patients with acute myocardial infarction and unstable angina. Acta Med Indones 2011;43:105-11.  Back to cited text no. 47
    
48.
Vahdat K, Jafari SM, Pazoki R, Nabipour I. Concurrent increased high sensitivity C-reactive protein and chronic infections are associated with coronary artery disease: A population-based study. Indian J Med Sci 2007;61:135-43.  Back to cited text no. 48
[PUBMED]  [Full text]  
49.
Heltai K, Kis Z, Burian K, Endresz V, Veres A, Ludwig E, et al. Elevated antibody levels against Chlamydia pneumoniae, human HSP60 and mycobacterial HSP65 are independent risk factors in myocardial infarction and ischaemic heart disease. Atherosclerosis 2004;173:339-46.  Back to cited text no. 49
    
50.
Prasad A, Zhu J, Halcox JP, Waclawiw MA, Epstein SE, Quyyumi AA, et al. Predisposition to atherosclerosis by infections: Role of endothelial dysfunction. Circulation 2002;106:184-90.  Back to cited text no. 50
    
51.
Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119-31.  Back to cited text no. 51
    
52.
Micha R, Imamura F, Wyler von Ballmoos M, Solomon DH, Hernán MA, Ridker PM, et al. Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease. Am J Cardiol 2011;108:1362-70.  Back to cited text no. 52
    
53.
Tardif JC, Tanguay JF, Wright SR, Duchatelle V, Petroni T, Grégoire JC, et al. Effects of the P-selectin antagonist inclacumab on myocardial damage after percutaneous coronary intervention for non-ST-segment elevation myocardial infarction: Results of the SELECT-ACS trial. J Am Coll Cardiol 2013;61:2048-55.  Back to cited text no. 53
    
54.
White H, Held C, Stewart R, Watson D, Harrington R, Budaj A, et al. Study design and rationale for the clinical outcomes of the STABILITY trial (STabilization of atherosclerotic plaque by initiation of darapLadIb therapY) comparing darapladib versus placebo in patients with coronary heart disease. Am Heart J 2010;160:655-61.  Back to cited text no. 54
    
55.
O'Donoghue ML, Braunwald E, White HD, Serruys P, Steg PG, Hochman J, et al. Study design and rationale for the stabilization of pLaques usIng darapladib-thrombolysis in myocardial infarction (SOLID-TIMI 52) trial in patients after an acute coronary syndrome. Am Heart J 2011;162:613-90.  Back to cited text no. 55
    
56.
Everett BM, Pradhan AD, Solomon DH, Paynter N, Macfadyen J, Zaharris E, et al. Rationale and design of the cardiovascular inflammation reduction trial: A test of the inflammatory hypothesis of atherothrombosis. Am Heart J 2013;166:199-207.e15.  Back to cited text no. 56
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Conclusion
References
Article Tables

 Article Access Statistics
    Viewed360    
    Printed41    
    Emailed0    
    PDF Downloaded70    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]