Anti-varicella Zoster Virus IgG and hsCRP Levels Correlate with Progression of Coronary Artery Atherosclerosis
The relationship between high levels of anti-Varicella Zoster Virus (VZV) IgG in cerebrospinal fluid (CSF) and cerebrovascular atherosclerosis commends a possible similar association in other vessels. We aimed to investigate the association of VZV-seropositivity with coronary artery atherosclerosis. We recruited 88 newly diagnosed patients with more than 50% stenosis in at least one of the main coronary arteries. As the control group, 99 age-matched individuals with normal/insignificant coronary artery findings were included. Clinical, paraclinical, and demographical data were gathered at the time of sampling. High‐sensitivity C‐reactive protein (hsCRP) levels were measured by nephelometry. VZV-seropositivity was determined by measuring of anti-VZV IgG level in plasma. Multivariable logistic regression was used to evaluate the correlation of data with coronary vascular atherosclerosis. The frequency of VZV-seropositivity was significantly higher in the atherosclerosis group compared to the controls (OR=1.88; 95%CI=1.03-3.44). The plasma levels of anti-VZV IgG were significantly higher in patients with atherosclerosis (Median=2.70, IQR=1.53-4.30 AU/mL) than in the controls (Median=2.10, IQR=1.70-3.10 AU/mL, p=0.034). The hsCRP levels in patients and controls were 5.19±2.00 and 1.51±1.07 mg/L, respectively. The correlation between hsCRP and anti-VZV IgG level in plasma was observed (r=0.40, p<0.001). The levels of hsCRP and anti-VZV IgG increased based on the number of diseased vessels but only the difference in hsCRP levels reached a significant level (p<0.001 and p=0.168, respectively). Our data suggest that VZV-seropositivity and hsCRP elevation jointly increase the risk of atherosclerosis. The multifactorial nature of atherosclerosis; however, leaves more options for the inflammatory milieu to be generated.
2. Gershon AA, Breuer J, Cohen JI, Cohrs RJ, Gershon MD, Gilden D, et al. Varicella zoster virus infection. Nat Rev Dis Primers 2015; 1:15016.
3. Yawn BP, Wollan PC, Nagel MA, Gilden D, editors. Risk of stroke and myocardial infarction after herpes zoster in older adults in a US community population. Mayo Clin Proc; 2016: Elsevier.
4. Sundström K, Weibull CE, Söderberg-Löfdal K, Bergström T, Sparén P, Arnheim-Dahlström L. Incidence of herpes zoster and associated events including stroke—a population-based cohort study. BMC Infect Dis 2015; 15(1):488.
5. Breuer J, Pacou M, Gautier A, Brown MM. Herpes zoster as a risk factor for stroke and TIA: a retrospective cohort study in the UK. Neurology 2014; 83(2):e27-e33.
6. Zhu Y, Xian X, Wang Z, Bi Y, Chen Q, Han X, et al. Research Progress on the Relationship between Atherosclerosis and Inflammation. Biomolecules 2018; 8(3).
7. Shapiro MD, Fazio S. From lipids to inflammation: new approaches to reducing atherosclerotic risk. Circ Res 2016; 118(4):732-49.
8. Ridker PM. How common is residual inflammatory risk? Circ Res 2017; 120(4):617-9.
9. Minassian C, Thomas SL, Smeeth L, Douglas I, Brauer R, Langan SM. Acute cardiovascular events after herpes zoster: a self-controlled case series analysis in vaccinated and unvaccinated older residents of the United States. PLoS Med 2015; 12(12):e1001919.
10. Nagel M, Traktinskiy I, Azarkh Y, Kleinschmidt-DeMasters B, Hedley-Whyte T, Russman A, et al. Varicella zoster virus vasculopathy: analysis of virus-infected arteries. Neurology 2011; 77(4):364-70.
11. Elkind MS. The varicella zoster virus vasculopathies: Clinical, CSF, imaging, and virologic features. Neurology 2009; 72(11):1028-30.
12. Nagel M, Forghani B, Mahalingam R, Wellish M, Cohrs R, Russman A, et al. The value of detecting anti-VZV IgG antibody in CSF to diagnose VZV vasculopathy. Neurology 2007; 68(13):1069-73.
13. Wang CC, Lin CL, Chang YJ, Wang GJ, Sung FC, Kao CH. Herpes zoster infection associated with acute coronary syndrome: a population‐based retrospective cohort study. Br J Dermatol 2014; 170(5):1122-9.
14. Pesonen E, Andsberg E, Öhlin H, Puolakkainen M, Rautelin H, Sarna S, et al. Dual role of infections as risk factors for coronary heart disease. Atherosclerosis 2007; 192(2):370-5.
15. Erskine N, Tran H, Levin L, Ulbricht C, Fingeroth J, Kiefe C, et al. A systematic review and meta-analysis on herpes zoster and the risk of cardiac and cerebrovascular events. PLoS One 2017; 12(7):e0181565.
16. Sproston NR, Ashworth JJ. Role of C-reactive protein at sites of inflammation and infection. Front Immunol 2018; 9:754.
17. Hage FG, Szalai AJ. C-reactive protein gene polymorphisms, C-reactive protein blood levels, and cardiovascular disease risk. J Am Coll Cardiol 2007; 50(12):1115-22.
18. Ramamoorthy RD, Nallasamy V, Raghavendra Reddy NE, Maruthappan Y. A review of C-reactive protein: A diagnostic indicator in periodontal medicine. J Pharm Bioallied Sci 2012; 4(Suppl 2):S422.
19. Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein (a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA 2001; 285(19):2481-5.
20. Lowe GD, Yarnell JW, Rumley A, Bainton D, Sweetnam PM. C-reactive protein, fibrin D-dimer, and incident ischemic heart disease in the Speedwell study: are inflammation and fibrin turnover linked in pathogenesis? Arterioscler Thromb Vasc Biol 2001; 21(4):603-10.
21. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002; 347(20):1557-65.
22. Danesh J, Whincup P, Walker M, Lennon L, Thomson A, Appleby P, et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ 2000; 321(7255):199-204.
23. Roivainen M, Viik-Kajander M, Palosuo T, Toivanen P, Leinonen M, Saikku P, et al. Infections, inflammation, and the risk of coronary heart disease. Circulation 2000; 101(3):252-7.
24. Kim JY, Park G-H, Kim MJ, Sim HB, Lee WJ, Lee S-J, et al. Usefulness of Inflammatory Markers for the Prediction of Postherpetic Neuralgia in Patients with Acute Herpes Zoster. Ann Dermatol 2018; 30(2):158-63.
25. Skripuletz T, Pars K, Schulte A, Schwenkenbecher P, Yildiz Ö, Ganzenmueller T, et al. Varicella zoster virus infections in neurological patients: a clinical study. BMC Infect Dis 2018; 18(1):238.
26. Maleki A, Ghanavati R, Montazeri M, Forughi S, Nabatchi B. Prevalence of Coronary Artery Disease and the Associated Risk Factors in the Adult Population of Borujerd City, Iran. J Tehran Heart Cent 2019; 14(1):1.
27. Esteban-Hernandez J, San JRM, Gil R, Anegón M, Gil A. Association between herpetic burden and chronic ischemic heart disease: matched case-control study. Med Clin (Barc) 2011; 137(4):157-60.
28. Tezcan ME, Teksut TK, Oenal AB, Oeztuerk MA. Reactivated varicella zoster virus may cause peripheral arterial thrombosis. J Rheumatol 2010; 37(8):1785-6.
29. Nagel MA, Gilden D. Developments in varicella zoster virus vasculopathy. Curr Neurol Neurosci Rep 2016; 16(2):12.
30. Blumenthal D, Shacham-Shmueli E, Bokstein F, Schmid D, Cohrs R, Nagel M, et al. Zoster sine herpete: virologic verification by detection of anti-VZV IgG antibody in CSF. Neurology 2011; 76(5):484-5.
31. Smith-Norowitz TA, Saadia TA, Norowitz KB, Joks R, Durkin HG, Kohlhoff S. Negative IgG varicella zoster virus antibody status: immune responses pre and post re-immunization. Infect Dis Ther 2018; 7(1):175-81.
32. Ihara H, Miyachi M, Imafuku S. Relationship between serum anti‐varicella zoster virus antibody titer and time from onset of herpes zoster. J Dermatol 2018; 45(2):189-93.
33. Uthman I, Taher A, Khalil I. Hughes syndrome associated with varicella infection. Rheumatol Int 2001; 20(4):167-8.
34. Massano J, Ferreira D, Toledo T, Mansilha A, Azevedo E, Carvalho M. Stroke and multiple peripheral thrombotic events in an adult with varicella. Eur J Neurol 2008; 15(10):e90-e1.
35. Blum A, Peleg A, Weinberg M. Anti-cytomegalovirus (CMV) IgG antibody titer in patients with risk factors to atherosclerosis. Clin Exp Med 2003; 3(3):157-60.
36. Nagel MA, Traktinskiy I, Stenmark KR, Frid MG, Choe A, Gilden D. Varicella-zoster virus vasculopathy: immune characteristics of virus-infected arteries. Neurology 2013; 80(1):62-8.
37. Rosenfeld ME, Campbell LA. Pathogens and atherosclerosis: update on the potential contribution of multiple infectious organisms to the pathogenesis of atherosclerosis. Thromb Haemost 2011; 106(11):858-67.
38. Auer J, Berent R, Lassnig E, Eber B. C-reactive protein and coronary artery disease. Jpn Heart J 2002; 43(6):607-19.
39. Guilford T, Morris D, Gray D, Venketaraman V. Atherosclerosis: pathogenesis and increased occurrence in individuals with HIV and Mycobacterium tuberculosis infection. HIV AIDS (Auckl) 2010; 2:211.
40. Okamoto S, Hata A, Sadaoka K, Yamanishi K, Mori Y. Comparison of varicella-zoster virus-specific immunity of patients with diabetes mellitus and healthy individuals. J Infect Dis 2009; 200(10):1606-10.
41. Brisson M, Edmunds W, Law B, Gay N, Walld R, Brownell M, et al. Epidemiology of varicella zoster virus infection in Canada and the United Kingdom–corrigendum. Epidemiol Infect 2015; 143(6):1332-.
42. Spence JD, Pilote L. Importance of sex and gender in atherosclerosis and cardiovascular disease. atherosclerosis 2015; 241(1):208-10.
43. Thomas SL, Hall AJ. What does epidemiology tell us about risk factors for herpes zoster? Lancet Infect Dis 2004; 4(1):26-33.
44. Gialloreti LE, Merito M, Pezzotti P, Naldi L, Gatti A, Beillat M, et al. Epidemiology and economic burden of herpes zoster and post-herpetic neuralgia in Italy: a retrospective, population-based study. BMC Infect Dis 2010; 10(1):230.