Inflammation, infection, and cardiovascular risk: how good is the clinical evidence?

Abstract

HomeCirculationVol. 97, No. 17Inflammation, Infection, and Cardiovascular Risk Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBInflammation, Infection, and Cardiovascular Risk How Good Is the Clinical Evidence? Paul M. Ridker Paul M. RidkerPaul M. Ridker From the Cardiovascular Division and the Division of Preventiv Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass. Search for more papers by this author Originally published5 May 1998https://doi.org/10.1161/01.CIR.97.17.1671Circulation. 1998;97:1671–1674Despite substantial gains in the prevention and treatment of acute myocardial infarction, many atherothrombotic events occur among individuals without readily apparent risk factors. Several lines of basic research indicate that inflammation and perhaps chronic infection may play important roles in the initiation and progression of atherosclerosis. For example, pathological studies demonstrate that atherosclerotic lesions are heavily infiltrated with cellular components associated with inflammation, influx of neutrophils into the walls of the epicardial vessels has been demonstrated in response to acute ischemia, and sites of acute plaque rupture are preferentially associated with inflammatory components.123456 Further, proinflammatory cytokines as well as cellular adhesion molecules involved in the attachment of monocytes to the endothelial wall appear to be critical in early atherogenesis.78 With regard to chronic infection, evidence of prior exposure to Chlamydia pneumoniae, cytomegalovirus, and Helicobacter pylori has been detected within human atherosclerotic tissues,91011121314 and it has been hypothesized that these organisms may activate vessel-associated leukocytes or lead to a transformation of vascular smooth muscles or endothelial cells.15 In addition, animal studies suggest that infection with cytomegalovirus and perhaps other agents can lead to endothelial lesions similar to that of human atherosclerosis.1617From an epidemiological perspective, however, the role of inflammation and infection as potential cardiovascular risk factors is far from certain. Although several studies have reported associations between exposure to various infectious agents and prevalent coronary disease,1819202122232425 these data derive almost exclusively from cross-sectional or retrospective studies that cannot establish a temporal relation between exposure and disease. Furthermore, it is difficult for cross-sectional and retrospective studies to exclude the possibility that observed associations are the result of inadvertent selection bias or residual confounding on the basis of age, smoking pattern, and socioeconomic status. For example, individuals with greater inflammatory and infectious burdens may be at increased coronary risk simply because they are older, have poorer health habits, and have less access to care. In addition, both inflammation and infection are more prevalent among smokers. Thus, whether relationships between inflammation, infection, and atherosclerosis are causal or largely due to confounding requires careful consideration.26Fortunately, prospective epidemiological studies that can control for many of these effects have recently become available, at least with respect to clinical evidence of inflammation. In particular, several prospective studies have been presented that indicate that mildly elevated levels of C-reactive protein, a nonspecific marker for systemic inflammation, are present among individuals with stable and unstable angina at risk for future myocardial infarction, elderly patients at risk for symptomatic coronary heart disease, those at high risk for infarction primarily because of smoking, and apparently healthy middle-aged men at risk for first-ever myocardial infarction or stroke.272829303132Data from the prospective Physicians Health Study (PHS) have been particularly informative because that study evaluated a group of low-risk men with no prior history of cardiovascular disease and low rates of cigarette consumption.27 Overall, data from the PHS indicate that initially healthy men with baseline levels of C-reactive protein in the highest quartile had a threefold increase in risk of developing future myocardial infarction (relative risk, 2.9; P<.001) and twice the risk of developing stroke (relative risk, 1.9; P=.02) compared with men with levels in the lower quartile. These risk estimates were stable over an 8- to 10-year follow-up period, were not modified by smoking status, and were independent of other cardiovascular risk factors, including total and HDL cholesterol, triglycerides, lipoprotein(a), and fibrinogen. Moreover, measurement of C-reactive protein adds to the predictive value of lipids in determining vascular risk.33 For example, a fivefold increase in risk of future myocardial infarction was observed among those with high baseline levels of both C-reactive protein and total cholesterol, a risk estimate greater than the product of the risks associated with isolated elevations of either C-reactive protein or total cholesterol alone.33 Elevated baseline levels of C-reactive protein are also associated with a fourfold increase in the risk of developing clinically severe peripheral arterial disease, again independent of usual risk factors.34Whether C-reactive protein has direct vascular effects or is simply a marker for systemic inflammation remains uncertain. However, there appears to be no association between levels of C-reactive protein and risks of venous thrombosis,27 suggesting that this acute-phase reactant does not induce a hypercoagulable state. Furthermore, other acute-phase reactants, including fibrinogen and serum amyloid A, appear to be associated with vascular risk.2935 Recent prospective data indicate that plasma concentrations of the soluble intercellular adhesion molecule (sICAM-1) are elevated many years in advance of a first-ever myocardial infarction and that levels of sICAM-1 correlate with C-reactive protein.36 Because cellular adhesion molecules, such as ICAM-1, are critical in the adhesion of circulating leukocytes to the endothelial cell and subsequent endothelial transmigration, these data provide further epidemiological evidence that cellular mediators of inflammation have a critical role in atherogenesis.7836By contrast, prospective epidemiological data relating evidence of infection to future vascular risk are sparse. Thus, investigations evaluating whether infection is a cause of chronic inflammation and whether infection is a risk factor for cardiovascular disease have relied primarily on cross-sectional and retrospective approaches. Despite epidemiological limitations, these study approaches provide opportunities to generate new hypotheses and gain substantial pathophysiological insight.Such is the case for an intriguing paper in this issue of Circulation in which Pasceri and colleagues37 present data describing an association between virulent Helicobacter pylori strains and prevalent ischemic heart disease. In a thoughtful retrospective case-control study design, the prevalence of infection with Helicobacter pylori among 88 case subjects with a history of ischemic heart disease was compared with the prevalence of infection among a group of 88 age- and sex-matched control subjects of similar social background who were free of coronary disease. On an a priori basis, Pasceri and colleagues also sought to determine whether Helicobacter pylori strains associated with increased inflammatory virulence caused by possession of the cytotoxin-associated gene-A (Cag-A) might confer a particularly high risk of ischemic heart disease.Three findings in this study are particularly noteworthy. First, overall prevalence of Helicobacter pylori infection was significantly higher among patients than control subjects (62% versus 40%, P=.004), data consistent with prior observational studies relating prevalence of Helicobacter pylori to coronary disease.213839 Second, much of this effect appeared to be mediated through Cag-A positivity, an intriguing finding because this genetically mediated virulence factor may be associated with a greater inflammatory burden.40 Specifically, patients with ischemic heart disease had a significantly higher prevalence of Cag-A positive strains of Helicobacter pylori (43% versus 17%, P<.001) compared with patients without ischemic heart disease. In contrast, prevalence of Cag-A–negative Helicobacter pylori strains was similar between patients and control subjects (19% versus 23%, P=.8). Third, despite an association between Helicobacter pylori positivity and ischemic heart disease, there was no association between seropositivity and severity of coronary disease defined at angiography.These data provide yet another potential link between inflammation, infection, and vascular disease. Prior work suggests that Cag-A positivity may be associated with an increased inflammatory response, at least in the setting of duodenal ulcer disease.4041 Thus, if the association between Helicobacter pylori and vascular disease proves valid and indeed relates to the virulence of this bacterium, then infection with Helicobacter pylori may influence atherosclerosis through the generation of a persistent low-grade inflammatory stimulus. The fact that C-reactive protein levels increase with increasing prevalence of exposure to Helicobacter pylori provides indirect support for this hypothesis.42Pasceri and colleagues37 note that their data must be interpreted cautiously. Despite attempts to draw case and control subjects from a similar social background, case subjects with Helicobacter pylori positivity were of lower socioeconomic status than were those without evidence of infection, once again raising the possibility that Helicobacter pylori seropositivity may be a surrogate for reduced access to care and poorer health outcomes. Pasceri and colleagues further note that their results require confirmation in prospective controlled populations. To date, at least three such studies have been presented. In the first of these, IgG antibodies directed against Helicobacter pylori were determined among residents of 24 British towns who were then prospectively followed for myocardial infarction and stroke.43 In that study, unadjusted analysis suggested a positive association. However, Helicobacter pylori infection was also associated with lower social class, increased cigarette consumption, and several traditional cardiovascular risk factors. When these confounding factors were adjusted for, no statistically significant association was found between Helicobacter pylori and risk (P=.4 for myocardial infarction, P=.9 for stroke).43 Similarly, in the large-scale British United Provident Association (BUPA)44 study as well as in the Atherosclerosis Risk in Communities (ARIC)45 study, no associations between Helicobacter pylori seropositivity and future ischemic heart disease or coronary mortality were observed. However, in each of these studies, prevalence of infection was again associated with lower socioeconomic status.4445 Although none of these three prospective studies specifically evaluated for Cag-A positivity, they do indicate that retrospective associations must be interpreted with caution.How good, then, is the clinical evidence relating inflammation, infection, and cardiovascular risk? With regard to inflammation, the available prospective data are highly consistent and provide strong evidence that inflammatory parameters are independent risk factors for coronary disease that may well add to our ability to predict risk, even among otherwise low-risk individuals.33 Moreover, clinical evidence relating inflammation to vascular risk complements a large body of basic laboratory and experimental work demonstrating a fundamental role for inflammatory mediators in the atherothrombotic process. The strength of these observations suggests that ongoing work evaluating therapies that interfere with the inflammatory component of atherosclerosis is a potentially important line of research.With regard to infection, provocative hypotheses such as that raised by Pasceri and colleagues37 concerning Cag-A positivity and vascular disease deserve careful consideration, as do hypotheses concerning Chlamydia pneumoniae and cytomegalovirus. At a minimum, large-scale prospective studies evaluating early life infection with these agents and subsequent vascular disease need completion, preferably in populations homogenous for socioeconomic status and with long-term follow-up.Until such studies are completed, the role of infectious pathogens in coronary disease will remain uncertain. However, in the wake of two small studies that suggest that macrolide antibiotics might reduce cardiovascular event rates,4647 it is increasingly difficult to ignore the possibility that infection may be a novel cardiovascular risk factor. Large scale clinical trials will provide direct evidence as to whether eradication of infection has a role in cardiovascular disease prevention. If appropriately designed, such trials will enable scientists to clearly discern whether associations between infection and ischemic heart disease are causal or due to residual confounding.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Dr Ridker is supported by an Established Investigator Grant from the American Heart Association.FootnotesCorrespondence to Dr Paul M Ridker, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115 E-mail [email protected] References 1 Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature.1993; 362:801–809.CrossrefMedlineGoogle Scholar2 Libby P. Molecular basis of the acute coronary syndromes. Circulation.1995; 91:2844–2850.CrossrefMedlineGoogle Scholar3 Entman ML, Ballantyne CM. Inflammation in acute coronary syndromes. Circulation.1993; 88:800–803.CrossrefMedlineGoogle Scholar4 van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation.1994; 89:36–44.CrossrefMedlineGoogle Scholar5 Kloner RA, Giacomelli F, Alker KJ, Hale SL, Matthews R, Bellows S. Influx of neutrophils into the walls of large epicardial coronary arteries in response to ischemia/reperfusion. Circulation.1991; 84:1758–1772.CrossrefMedlineGoogle Scholar6 Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V, Fallon JT. Macrophage infiltration in acute coronary syndromes: implications for plaque rupture. Circulation.1994; 90:775–778.CrossrefMedlineGoogle Scholar7 Poston RN, Haskard DO, Coucher JR, Gall NP, Johnson-Tidey RR. Expression of intercellular adhesion molecule-1 in atherosclerotic plaques. Am J Pathol.1992; 140:665–673.MedlineGoogle Scholar8 Cybulsky MI, Gimbrone MA. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science.1991; 251:788–791.CrossrefMedlineGoogle Scholar9 Grayston JT, Kuo CC, Coulson AS, Campbell LA, Lawrence RD, Lee MJ, Strandness ED, Wang SP. Chlamydia pneumoniae (TWAR) in atherosclerosis of the carotid artery. Circulation.1995; 92:3397–3400.CrossrefMedlineGoogle Scholar10 Kuo CC, Shor A, Campbell L, Fukushi H, Patton DL, Grayston JT. Demonstration of Chlamydia pneumoniae in atherosclerotic lesions of coronary arteries. J Infect Dis.1993; 167:841–849.CrossrefMedlineGoogle Scholar11 Muhlestein JB, Hammond EH, Carlquist JF, Radicke E, Thomson MJ, Karagounis LA, Woods ML, Anderson JL. Increased incidence of Chlamydia species within the coronary arteries of patients with symptomatic atherosclerotic versus other forms of cardiovascular disease. J Am Coll Cardiol.1996; 27:1555–1561.CrossrefMedlineGoogle Scholar12 Melnick JL, Hu C, Burek J, Adam E, DeBakey ME. Cytomegalovirus DNA in arterial walls of patients with atherosclerosis. J Med Virol.1994; 42:170–174.CrossrefMedlineGoogle Scholar13 Wu TC, Hruban RH, Ambinder RF, Pizzorno M, Cameron DE, Baumgartner WA, Reitz BA, Hayward GS, Hutchins GM. Demonstration of cytomegalovirus nucleic acids in the coronary arteries of transplanted hearts. Am J Pathol.1992; 140:739–747.MedlineGoogle Scholar14 Cook PJ, Lip GY. Infectious agents and atherosclerotic vascular disease. Q J Med.1996; 89:727–735.CrossrefGoogle Scholar15 Libby P, Egan D, Skarlatos S. Roles of infectious agents in athero- slcerosis and restenosis: an assessment of the evidence and need for future research. Circulation.1997; 96:4095–4103.CrossrefMedlineGoogle Scholar16 Benditt EP, Barrett T, McDougall JK. Viruses in the etiology of atherosclerosis. Proc Natl Acad Sci U S A.1983; 80:6386–6389.CrossrefMedlineGoogle Scholar17 Lemstrom K, Koskinen P, Krogerus L, Daemen M, Bruggerman C, Hayry P. Cytomegalovirus antigen expression, endothelial cell proliferation, and intimal thickening in rat cardiac allografts after cytomegalovirus infection. Circulation.1995; 92:2594–2604.CrossrefMedlineGoogle Scholar18 Saikku P, Mattila K, Nieminen MS, Huttunen JK, Leinonen M, Ekman M-R, Mäkelä PH, Valtonen V. Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet.1988; 2:983–986.CrossrefMedlineGoogle Scholar19 Thom DH, Grayston JT, Siscovick D, Way S-P, Weiss NS, Daling JR. Association of prior infection with Chlamydia pneumoniae and angiographically demonstrated coronary artery disease. JAMA.1992; 268:68–72.CrossrefMedlineGoogle Scholar20 Mendall MA, Carrington D, Strachan DP, Patel P, Molineaux N, Levy J, Toosey T, Camm AJ, Northfield TC. Chlamydia pneumoniae: risk factors for seropositivity and association with coronary heart disease. J Infect.1995; 30:121–128.CrossrefMedlineGoogle Scholar21 Mendall MA, Goggin PM, Molineaux N, Levy J, Toosy T, Strachan D, Camm AJ, Northfield TC. Relation of Helicobacter pylori infection and coronary heart disease. Br Heart J.1994; 71:437–439.CrossrefMedlineGoogle Scholar22 Melnick JL, Adam E, DeBakey ME. Possible role of cytomegalovirus in atherogenesis. JAMA.1990; 263:2204–2207.CrossrefMedlineGoogle Scholar23 Zhou YF, Leon MB, Waclawiw MA, Popma JJ, Yu ZX, Finkel T, Epstein SE. Association between prior cytomegalovirus infection and the risk of restenosis after coronary atherectomy. N Engl J Med.1996; 335:624–630.CrossrefMedlineGoogle Scholar24 Nieto FJ, Adam E, Sorlie P, Farzadegan H, Melnick JL, Comstock GW, Szklo M. Cohort study of cytomegalovirus infection as a risk factor for carotid intimal-medial thickening, a measure of subclinical atherosclerosis. Circulation.1996; 94:922–927.CrossrefMedlineGoogle Scholar25 Sorlie PD, Adam E, Melnick SL, Folsom A, Skelton T, Chambless LE, Barnes R, Melnick JL. Cytomegalovirus/herpesvirus and carotid atherosclerosis: the ARIC study. J Med Virol.1994; 42:33–37.CrossrefMedlineGoogle Scholar26 Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: is there a link? Lancet.1997; 350:430–436.CrossrefMedlineGoogle Scholar27 Ridker PM, Cushman M, Stampfer MJ, Tracy R, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med.1997; 336:973–979.CrossrefMedlineGoogle Scholar28 Liuzzo G, Biasucci LM, Gallimore JR, Grillo RL, Rebuzzi AG, Pepys MB, Maseri A. The prognostic value of C-reactive protein and serum amyloid A protein in severe unstable angina. N Engl J Med.1994; 331:417–424.CrossrefMedlineGoogle Scholar29 Thompson SG, Kienast J, Pyke SDM, Haverkate F, van de Loo JCW. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris: European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med.1995; 332:635–641.CrossrefMedlineGoogle Scholar30 Kuller LH, Tracy RP, Shaten J, Meilahn EN, for the MRFIT Research Group. Relationship of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Am J Epidmiol.1996; 144:537–547.CrossrefMedlineGoogle Scholar31 Haverkate F, Thompson SG, Pyke SDM, Gallimore JR, Pepys MB, for the European Concerted Action on Thrombosis, and Disabilities Angina Pectoris Study Group. Production of C-Reactive protein and risk of coronary events in stable and unstable angina. Lancet.1997; 349:462–466.CrossrefMedlineGoogle Scholar32 Tracy RP, Lemaitre RN, Psaty BM, Ives DG, Evans RW, Cushman M, Meilahn EN, Kuller LH. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly: results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol.1997; 17:1121–1127.CrossrefMedlineGoogle Scholar33 Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation. In press.Google Scholar34 Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Plasma concentration of C-reactive protein and risks of developing peripheral vascular disease. Circulation.1998; 97:425–428.CrossrefMedlineGoogle Scholar35 Fyfe AI, Rothenberg LS, DeBeer FC, Cantor RM, Rotter JI, Lusis AJ. Association between serum amyloid A proteins and coronary artery disease: evidence from two distinct arteriosclerotic processes. Circulation.1997; 96:2914–2919.CrossrefMedlineGoogle Scholar36 Ridker PM, Hennekens CH, Roitman-Johnson B, Stampfer MJ, Allen J. Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet.1998; 351:88–92.CrossrefMedlineGoogle Scholar37 Pasceri V, Cammarota G, Patti G, Cuoco L, Gasbarrini A, Grillo RL, Fedeli G, Gasbarrini G, Maseri A. Association of virulent Helicobacter pylori strains with ischemic heart disease. Circulation.1998; 97:1675–1679.CrossrefMedlineGoogle Scholar38 Patel P, Mendall MA, Carrington D, Strachan DP, Leathan E, Molineaux N, Levy J, Blakeston C, Seymour CA, Camm AJ, Northfield TC. Association of Helicobacter pylori and Chlamydia pneumoniae infections with coronary heart disease and cardiovascular risk factors. BMJ.1995; 311:711–714.CrossrefMedlineGoogle Scholar39 Murray LJ, Bamford KB, O’Reilly DPJ, McCrum EE, Evans AE. Helicobacter pylori infection: relation with cardiovascular risk factors, ischaemic heart disease, and social class. Br Heart J.1995; 74:497–501.CrossrefMedlineGoogle Scholar40 Peek RM, Miller GG, Tham KT, Perez GI, Zhao X, Atherton JC, Blaser MJ. Heightened inflammatory response and cytokine expression in vivo to cagA+ Helicobacter pylori strains. Lab Invest.1995; 73:760–770.MedlineGoogle Scholar41 Blaser MJ, Perez GI, Kleanthous H, Cover TL, Peek RM, Chyou PH, Stemmermann GN, Nomura A. Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res.1995; 55:2111–2115.MedlineGoogle Scholar42 Mendall MA, Patel P, Ballam L, Strachan D, Northfield TC. C reactive protein and its relation to cardiovascular risk factors: a population based cross sectional study. BMJ.1996; 27:312:1061–1065.Google Scholar43 Whincup PH, Mendall MA, Perry IJ, Strachan DP, Walker M. Prospective relations between Helicobacter pylori infection, coronary heart disease, and stroke in middle aged men. Heart.1996; 75:568–572.CrossrefMedlineGoogle Scholar44 Wald NJ, Law MR, Morris JK, Bagnall AM. Helicobacter pylori infection and mortality from ischemic heart disease: negative results from a large, prospective study. BMJ.1997; 315:1199–1201.CrossrefMedlineGoogle Scholar45 Folsom AR, Nieto FJ, Sorlie P, Chambless LE, Graham DY. No association of Helicobacter pylori seropositivity with coronary heart disease in a prospective study. Circulation. 1997;96(suppl I):I-100. Abstract.Google Scholar46 Gupta S, Leatham EW, Carrington D, Mendall MA, Kaski JC, Camm J. Elevated Chlamydia pneumoniae antibodies, cardiovascular events, and azithromycin in male survivors of myocardial infarction. Circulation.1997; 96:404–407.CrossrefMedlineGoogle Scholar47 Gurfinkel E, Bozovich G, Daroca A, Beck E, Mautner B, for the ROXIS Study Group. Randomized trial of roxithromycin in non-Q-wave coronary syndromes: ROXIS pilot study. Lancet.1997; 350:404–407.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Ma Y, Xu L, Yin B, Shang J, Chen F, Xu J, Song Z, Nan B, Song G and Zhang X (2021) Ratiometric Semiconducting Polymer Nanoparticle for Reliable Photoacoustic Imaging of Pneumonia-Induced Vulnerable Atherosclerotic Plaque in Vivo, Nano Letters, 10.1021/acs.nanolett.1c01359, 21:10, (4484-4493), Online publication date: 26-May-2021. Little M, Azizova T and Hamada N (2021) Low- and moderate-dose non-cancer effects of ionizing radiation in directly exposed individuals, especially circulatory and ocular diseases: a review of the epidemiology, International Journal of Radiation Biology, 10.1080/09553002.2021.1876955, 97:6, (782-803), Online publication date: 3-Jun-2021. Kim D, Her S, Ahn Y, Shin D, Han S, Kim D, Choi D, Kwon H, Gwon H, Jo S, Rha S and Baek S (2018) Clinical outcome according to spasm type of single coronary artery provoked by intracoronary ergonovine tests in patients without significant organic stenosis, International Journal of Cardiology, 10.1016/j.ijcard.2017.08.052, 252, (6-12), Online publication date: 1-Feb-2018. Hammadah M, Sullivan S, Pearce B, Al Mheid I, Wilmot K, Ramadan R, Tahhan A, O'Neal W, Obideen M, Alkhoder A, Abdelhadi N, Mohamed Kelli H, Ghafeer M, Pimple P, Sandesara P, Shah A, Hosny K, Ward L, Ko Y, Sun Y, Weng L, Kutner M, Bremner J, Sheps D, Esteves F, Raggi P, Vaccarino V and Quyyumi A (2018) Inflammatory response to mental stress and mental stress induced myocardial ischemia, Brain, Behavior, and Immunity, 10.1016/j.bbi.2017.10.004, 68, (90-97), Online publication date: 1-Feb-2018. Liang X, Yang L, Guo R, Shi Y, Hou X, Yang Z, Zhou X and Liu H (2017)(2017) Atorvastatin attenuates plaque vulnerability by downregulation of EMMPRIN expression via COX-2/PGE2 pathway, Experimental and Therapeutic Medicine, 10.3892/etm.2017.4062, 13:3, (835-844), Online publication date: 1-Mar-2017. Zafar M and Rahman M (2016) CORRELATION BETWEEN SERUM hs-CRP AND LDL CHOLESTEROL AS A PREDICTOR OF CARDIOVASCULAR DISEASES, Journal of Evolution of Medical and Dental Sciences, 10.14260/jemds/2016/407, 5:32, (1725-1728), Online publication date: 21-Apr-2016. Little M (2016) Radiation and circulatory disease, Mutation Research/Reviews in Mutation Research, 10.1016/j.mrrev.2016.07.008, 770, (299-318), Online publication date: 1-Oct-2016. Little M, Zablotska L, Brenner A and Lipshultz S (2015) Circulatory disease mortality in the Massachusetts tuberculosis fluoroscopy cohort study, European Journal of Epidemiology, 10.1007/s10654-015-0075-9, 31:3, (287-309), Online publication date: 1-Mar-2016. Little M and Lipshultz S (2015) Low dose radiation and circulatory diseases: a brief narrative review, Cardio-Oncology, 10.1186/s40959-015-0007-6, 1:1, Online publication date: 1-Dec-2015. Oktay B, Abdullah Ozgur Y, Metin K, Naim A, Zeliha A, Mehmet Y, Ayse K, Sebahat B, Bora A and Yasar N (2014) Serum hsCRP and procalcitonin levels in dyspeptic patients infected with CagA-positive Helicobacter pylori , Journal of Clinical Laboratory Analysis, 10.1002/jcla.21795, 29:6, (469-473), Online publication date: 1-Nov-2015. Sung B, Park S, Ha Y, Kim D, Park C, Jung K, Kim M, Kim Y, Kim M, Moon J, Yokozawa T, Kim N, Yu B and Chung H (2014) Salicylideneamino-2-thiophenol modulates nuclear factor-κB through redox regulation during the aging process, Geriatrics & Gerontology International, 10.1111/ggi.12255, 15:2, (211-219), Online publication date: 1-Feb-2015. Zablotska L, Little M and Cornett R (2013) Potential Increased Risk of Ischemic Heart Disease Mortality With Significant Dose Fractionation in the Canadian Fluoroscopy Cohort Study, American Journal of Epidemiology, 10.1093/aje/kwt244, 179:1, (120-131), Online publication date: 1-Jan-2014. Little M (2013) A review of non-cancer effects, especially circulatory and ocular diseases, Radiation and Environmental Biophysics, 10.1007/s00411-013-0484-7, 52:4, (435-449), Online publication date: 1-Nov-2013. Kadhim M, Salomaa S, Wright E, Hildebrandt G, Belyakov O, Prise K and Little M (2013) Non-targeted effects of ionising radiation—Implications for low dose risk, Mutation Research/Reviews in Mutation Research, 10.1016/j.mrrev.2012.12.001, 752:2, (84-98), Online publication date: 1-Apr-2013. Srinivasarao Bandaru V, Boddu D, Mridula K, Akhila B, Alladi S, Laxmi V, Pathapati R, Neeraja M and Kaul S (2012) Outcome of Chlamydia pneumoniae associated acute ischemic stroke in elderly patients: A case–control study, Clinical Neurology and Neurosurgery, 10.1016/j.clineuro.2011.09.016, 114:2, (120-123), Online publication date: 1-Feb-2012. Chuang Y, Chuang H, Lin T, Chang C, Lu C, Chang W, Chen S, Tan T, Huang C and Chan S (2011) Effects of long-term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis, Epilepsia, 10.1111/j.1528-1167.2011.03316.x, 53:1, (120-128), Online publication date: 1-Jan-2012. Orehek A (2012) The Micron Stroke Hypothesis of Alzheimer’s Disease and Dementia, Medical Hypotheses, 10.1016/j.mehy.2012.01.020, 78:5, (562-570), Online publication date: 1-May-2012. Little M, Azizova T, Bazyka D, Bouffler S, Cardis E, Chekin S, Chumak V, Cucinotta F, de Vathaire F, Hall P, Harrison J, Hildebrandt G, Ivanov V, Kashcheev V, Klymenko S, Kreuzer M, Laurent O, Ozasa K, Schneider T, Tapio S