|Year : 2018 | Volume
| Issue : 3 | Page : 75-80
Role of herpesviruses in coronary artery disease
Agam Bansal1, Debasis Biswas2
1 Department of Medicine, AIIMS, Bhopal, Madhya Pradesh, India
2 Microbiology, AIIMS, Bhopal, Madhya Pradesh, India
|Date of Web Publication||12-Sep-2018|
Dr. Debasis Biswas
Head of Department, Department of Microbiology, AIIMS, Bhopal, Madhya Pradesh
Source of Support: None, Conflict of Interest: None
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
| Introduction|| |
Approximately 17.5 million people die each year from cardiovascular diseases (CVDs) worldwide. 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. 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. 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, 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. 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, herpes simplex virus (HSV), cytomegalovirus (CMV), Helicobacter pylori, and hepatitis virus 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.
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 that activate the COX-2 promoter. This increases the activity of nuclear factor-κB (NF-κB) transcription factor through increased reactive oxygen species production. 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. Infection with CMV expresses the US28 chemokine receptor. 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. 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). 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. 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. 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, Iran, Saudi Arabia, and Turkey reported a positive association between CMV and development of CAD. However, studies in developed countries such as the USA, 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, Georges et al. have reported a significant association between CMV and CAD. These results are contradicting to a study by Hoffmeister et al., which reported no association. A possible explanation for this could be arrived from a study by Voigt et al. 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|
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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.
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.,, 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.
[Table 2] illustrates the studies showing an association between HSV-1 and CAD. Guan et al. reported a significant correlation between HSV-1 infection and CAD. Jafarzadeh et al. and Vahdat et al. reported contradicting results on association between HSV-1 and CAD. Mundkur et al. from India have not reported any association between HSV-1 and CAD. Studies in Germany, Hungary, and the USA,,, have not shown any association between HSV-1 and CAD.
Compared to HSV-1, seroprevalence of HSV-2 is low. Only a study by Georges et al. 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|
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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 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. 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. Secretory phospholipase inhibitors, darapladib or varespladib, have not shown significant reduction in cardiovascular events in STABILITY and SOLID-TIMI 52 trial.
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 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|| |
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.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]
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