ABSTRACT
Infections have long been recognized as a potential, if uncommon, cause of cerebrovascular disease. In recent years, with the growing recognition of the importance of inflammation in atherosclerosis, there has been renewed interest in the possibility that common infections may participate in the atherosclerotic process or lead to stroke through other mechanisms. Specific organisms that have been implicated include Chlamydia pneumoniae, herpes viruses, human immunodeficiency virus, Helicobacter pylori, and organisms associated with periodontal infections. This article outlines the epidemiological, pathological, and laboratory evidence that these infections may be associated with atherosclerosis and stroke. Although definitive proof of an association between a specific infection and stroke is generally lacking, the accumulating evidence does indicate that several types of infections may be among the modifiable risk factors that contribute to the risk of stroke.
KEYWORDS
Infection - stroke - risk factors -
Chlamydia pneumoniae
- human immunodeficiency virus
REFERENCES
-
1
Sacco R L.
Risk factors, outcomes, and stroke subtypes for ischemic stroke.
Neurology.
1997;
49(suppl 4)
S39-S44
-
2
Zhu J, Nieto F J, Horne B D, Anderson J L, Muhlestein J B, Epstein S E.
Prospective study of pathogen burden and risk of myocardial infarction or death.
Circulation.
2001;
103
45-51
-
3
Espinola-Klein C, Rupprecht H J, Blankenberg S et al..
Impact of infectious burden on extent and long-term prognosis of atherosclerosis.
Circulation.
2002;
105
15-21
-
4
Bova I Y, Bornstein N M, Korczyn A D.
Acute infection as a risk factor for ischemic stroke.
Stroke.
1996;
27
2204-2206
-
5
Grau A J, Buggle F, Becher H et al..
Recent bacterial and viral infection is a risk factor for cerebrovascular ischemia.
Neurology.
1998;
50
196-203
-
6
Grau A J, Buggle F, Ziegler C et al..
Association between acute cerebrovascular ischemia and chronic or recurrent infection.
Stroke.
1997;
28
1724-1729
-
7
Grau A J, Brandt T, Buggle F et al..
Association of cervical artery dissection with recent infection.
Arch Neurol.
1999;
56
851-856
-
8
Meier C R, Derby L E, Jick S S, Vasilakis C, Jick H.
Antibiotics and risk of subsequent first-time acute myocardial infarction.
JAMA.
1999;
281
427-431
-
9
Luchsinger J A, Pablos-Mendez A, Knirsch C, Rabinowitz D, Shea S.
Antibiotic use and risk of ischemic stroke in the elderly.
Am J Med.
2001;
111
361-366
-
10
Grayston J T, Kuo C C, Wang S P, Altman J.
A new Chlamydia psittaci strain, TWAR, isolated in acute respiratory tract infections.
N Engl J Med.
1986;
315
161-168
-
11
Kuo C C, Jackson L A, Campbell L A, Grayston J T.
Chlamydia pneumoniae (TWAR).
Clin Microbiol Rev.
1995;
8
451-461
-
12
Chaim W, Sarov B, Sarov I, Piura B, Cohen A, Insler V.
Serum IgG and IgA antibodies to chlamydia in ectopic pregnancies.
Contraception.
1989;
40
59-71
-
13
Kuo C C, Shor A, Campbell L A, Fukushi H, Patton D L, Grayston J T.
Demonstration of Chlamydia pneumoniae in atherosclerotic lesions of coronary arteries.
J Infect Dis.
1993;
167
841-849
-
14
Ramirez J A.
Isolation of Chlamydia pneumoniae from the coronary artery of a patient with coronary atherosclerosis.
Ann Intern Med.
1996;
125
979-982
-
15
Grayston J T, Kuo C C, Coulson A S et al..
Chlamydia pneumoniae (TWAR) in atherosclerosis of the carotid artery.
Circulation.
1995;
92
3397-3400
-
16
Maass M, Bartels C, Engel P M, Mamat U, Sievers H H.
Endovascular presence of viable Chlamydia pneumoniae is a common phenomenon in coronary artery disease.
J Am Coll Cardiol.
1998;
31
827-832
-
17
Jackson L A, Campbell L A, Kuo C C, Rodriguez D I, Lee A, Grayston J T.
Isolation of Chlamydia pneumoniae from a carotid artery specimen.
J Infect Dis.
1997;
176
292-295
-
18
Virok D, Kis Z, Karai L et al..
Chlamydia pneumoniae in atherosclerotic middle cerebral artery.
Stroke.
2001;
32
1973-1976
-
19
Vink A, Poppen M, Schoneveld A H et al..
Distribution of Chlamydia pneumoniae in the human arterial system and its relation to the local amount of atherosclerosis within the individual.
Circulation.
2001;
103
1613-1617
-
20
Danesh J, Collins R, Peto R.
Chronic infections and coronary heart disease: is there a link?.
Lancet.
1997;
350
430-436
-
21
Gaydos C A, Summersgill J T, Sahney N N, Ramirez J A, Quinn T C.
Replication of Chlamydia pneumoniae in vitro in human macrophages, endothelial cells, and aortic artery smooth muscle cells.
Infect Immun.
1996;
64
1614-1620
-
22
Kaukoranta-Tolvanen SSE, Teppo A M, Laitinen K, Saikku P, Linnavuori K, Leinonen M.
Growth of Chlamydia pneumoniae in cultured human peripheral blood mononuclear cells and induction of a cytokine response.
Microb Pathog.
1996;
21
215-221
-
23
Nadareishvili Z G, Koziol D E, Szekely B et al..
Increased CD8+ T cells associated with Chlamydia pneumoniae in symptomatic carotid plaque.
Stroke.
2001;
32
1966-1972
-
24
Linnanmäki E, Leinonen M, Ekman M R et al..
Chlamydiae pneumoniae specific circulating immune complexes in chronic coronary heart disease.
Circulation.
1993;
87
1130-1134
-
25
Wimmer MLJ, Sandmann-Strupp R, Saikku P, Haberl R L.
Association of chlamydial infection with cerebrovascular disease.
Stroke.
1996;
27
2207-2210
-
26
Kalayoglu M V, Byrne B I.
Induction of macrophage foam cell formation by Chlamydia pneumoniae
.
J Infect Dis.
1998;
177
725-729
-
27
Morrison R P, Belland R J, Lyng K, Caldwell H D.
Chlamydial disease pathogenesis: the 57-kD chlamydial hypersensitivity antigen is a stress response protein.
J Exp Med.
1989;
170
1271-1283
-
28
Dahlén G H, Boman J, Birgander L S, Lindblom B.
Lp(a) lipoprotein, IgG, IgA and IgM antibodies to Chlamydia pneumoniae and HLA class II genotype in early coronary artery disease.
Atherosclerosis.
1995;
114
165-174
-
29
Kalayoglu M V, Libby P, Byrne G I.
Chlamydia pneumoniae as an emerging risk factor in cardiovascular disease.
JAMA.
2002;
288
2724-2731
-
30
Madre J G, Garcia J L, Gonzalez R C et al..
Association between seropositivity to Chlamydia pneumoniae and acute ischaemic stroke.
Eur J Neurol.
2002;
9
303-306
-
31
Cook P J, Honeybourne D, Lip GYH, Beevers D G, Wise R, Davies P.
Chlamydia pneumoniae antibody titers are significantly associated with acute stroke and transient cerebral ischemia: the West Birmingham Stroke Project.
Stroke.
1998;
29
404-410
-
32
Fagerberg B, Gnarpe J, Gnarpe H, Agewall S, Wikstrand J.
Chlamydia pneumoniae but not cytomegalovirus antibodies are associated with future risk of stroke and cardiovascular disease.
Stroke.
1999;
30
299-305
-
33
Glader C A, Stegmayr B, Boman J et al..
Chlamydia pneumoniae antibodies and high lipoprotein(a) levels do not predict ischemic cerebral infarctions.
Stroke.
1999;
30
2013-2018
-
34
Tanne D, Haim M, Boyko V et al..
Prospective study of Chlamydia pneumoniae IgG and IgA seropositivity and risk of incident ischemic stroke.
Cerebrovasc Dis.
2003;
16
166-170
-
35
Heuschmann P U, Neureiter D, Gesslein M et al..
Association between infection with Helicobacter pylori and Chlamydia pneumoniae and risk of ischemic stroke subtypes: results from a population-based case-control study.
Stroke.
2001;
32
2253-2258
-
36
Elkind M S, Lin I F, Grayston T J, Sacco R L.
Chlamydia pneumoniae and the risk of first ischemic stroke: the Northern Manhattan Stroke Study.
Stroke.
2000;
31
1521-1525
-
37
Elkind M S, Sciacca R, Tondella MLC, Feikin D, Fields B, DiTullio M R.
Antibodies to Chlamydia pneumoniae are associated with risk of ischemic stroke.
Neurology.
2003;
60(suppl 1)
A256-A257
-
38
Von Hertzen L, Alakarppa H, Koskinen R et al..
Chlamydia pneumoniae infection in patients with chronic obstructive pulmonary disease.
Epidemiol Infect.
1997;
118
155-164
-
39
Chaim W, Sarov B, Sarov I, Piura B, Cohen A, Insler V.
Serum IgG and IgA antibodies to chlamydia in ectopic pregnancies.
Contraception.
1989;
40
59-71
-
40
Minick C R, Fabricant C G, Fabricant J, Litrenta M M.
Atheroarteriosclerosis induced by infection with a herpesvirus.
Am J Pathol.
1979;
96
673-706
-
41
Fabricant C G, Fabricant J, Minick C R, Litrenta M M.
Herpesvirus-induced atherosclerosis in chickens.
Fed Proc.
1983;
42
2476-2479
-
42
Benditt E P, Barrett T, McDougall J K.
Viruses in the etiology of atherosclerosis.
Proc Natl Acad Sci USA.
1983;
80
6386-6389
-
43
Ventura H O, Mehra M R, Smart F W, Stapleton D D.
Cardiac allograft vasculopathy: current concepts.
Am Heart J.
1995;
129
791-798
-
44
Melnick J L, Adam E, Debakey M E.
Possible role of cytomegalovirus in atherogenesis.
JAMA.
1990;
263
2204-2207
-
45
Espinola-Klein C, Rupprecht H-J, Blankenberg S et al..
Are morphological or functional changes in the carotid artery wall associated with Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, or herpes simplex virus infection?.
Stroke.
2000;
31
2127-2133
-
46
Sorlie P D, Nieto F J, Adam E, Folsom A R, Shahar E, Massing M.
A prospective study of cytomegalovirus, herpes simplex virus 1, and coronary heart disease: the atherosclerosis risk in communities (ARIC) study.
Arch Intern Med.
2000;
160
2027-2032
-
47
Muhlestein J B, Horne B D, Carlquist J F et al..
Cytomegalovirus seropositivity and C-reactive protein have independent and combined predictive value for mortality in patients with angiographically demonstrated coronary artery disease.
Circulation.
2000;
102
1917-1923
-
48
Speir E, Modali R, Huang E S et al..
Potential role of human cytomegalovirus and p53 interaction in coronary restenosis.
Science.
1994;
265
391-394
-
49
Hendrix M G, Salimans M M, van Boven C P, Bruggeman C A.
High prevalence of latently present cytomegalovirus in arterial walls of patients suffering from grade III atherosclerosis.
Am J Pathol.
1990;
136
23-28
-
50
Ridker P M, Hennekens C H, Stampfer M J et al..
Prospective study of herpes simplex virus, cytomegalovirus, and the risk of future myocardial infarction and stroke.
Circulation.
1998;
98
2796-2799
-
51
Lemstrom K B, Aho P T, Bruggeman C A, Hayry P J.
Cytomegalovirus infection enhances mRNA expression of platelet-derived growth factor-BB and transforming growth factor-beta 1 in rat aortic allografts: possible mechanism for cytomegalovirus-enhanced graft arteriosclerosis.
Arterioscler Thromb.
1994;
14
2043-2052
-
52
Geist L J, Monick M M, Stinski M F, Hunninghake G W.
The immediate early genes of human cytomegalovirus upregulate expression of the interleukin 2 and interleukin 2 receptor genes.
Am J Respir Cell Mol Biol.
1991;
5
292-296
-
53
Geist L J, Monick M M, Stinski M F, Hunninghake G W.
The immediate early genes of human cytomegalovirus upregulate tumor necrosis factor-alpha gene expression.
J Clin Invest.
1994;
93
474-478
-
54
Kowalik T F, Wing B, Haskill J S, Azizkhan J C, Baldwin A S, Huang E S.
Multiple mechanisms are implicated in the regulation of NF-B activity during human cytomegalovirus infection.
Proc Natl Acad Sci USA.
1993;
90
1107-1111
-
55
Yonemitsu Y, Kaneda Y, Komori K, Hirai K, Sugimachi K, Sueishi K.
The immediate early gene of human cytomegalovirus stimulates vascular smooth muscle cell proliferation in vitro and in vivo.
Biochem Biophys Res Commun.
1997;
231
447-451
-
56
Pinto A N.
AIDS and cerebrovascular disease.
Stroke.
1996;
27
538-545
-
57
Cole J W, Pinto A N, Hebel J R et al..
Acquired immunodeficiency syndrome and the risk of stroke.
Stroke.
2004;
35
51-56
-
58
Evers S, Nabavi D, Rahmann A, Heese C, Reichelt D, Husstedt I W.
Ischemic cerebrovascular events in HIV infection.
Cerebrovasc Dis.
2003;
15
199-205
-
59
Shen Y M, Frenkel E P.
Thrombosis and a hypercoagulable state in HIV-infected patients.
Clin Appl Thromb Hemost.
2004;
10
277-280
-
60
Johnson R M, Barbarini G, Barbaro G.
Kawasaki-like syndromes and other vasculitic syndromes in HIV-infected patients.
AIDS.
2003;
17(suppl 1)
S77-S82
-
61
Connor M D, Lammie G A, Bell J E et al..
Cerebral infarction in adult AIDS patients: observation from the Edinburgh HIV Autopsy Cohort.
Stroke.
2000;
31
2117-2126
-
62
Trotti R, Rondanelli M, Anesi A, Gabanti E, Brustia R, Minoli L.
Increased erythrocyte glutathione peroxidase activity and serum tumor necrosis factor-α in HIV-infected patients: relationship to on-going prothrombotic state.
J Hematother Stem Cell Res.
2002;
11
369-375
-
63
Schecter A D, Berman A B, Yi L et al..
HIV envelope gp120 activates human arterial smooth muscle cells.
Proc Natl Acad Sci USA.
2001;
98
10142-10147
-
64
Saif M W, Greenberg B.
HIV and thrombosis: a review.
AIDS Patient Care STDS.
2001;
15
15-24
-
65
Hoffmann M, Berger J R, Nath A, Rayens M.
Cerebrovascular disease in young, HIV-infected black Africans in the KwaZulu Natal Province of South Africa.
J Neurovirol.
2000;
6
229-236
-
66
Chetty R.
Vasculitides associated with HIV infection.
J Clin Pathol.
2001;
54
275-278
-
67
Noel B.
Vascular complications of cocaine use.
Stroke.
2002;
33
1747-1748
-
68
Wu D T, Woodman S E, Weiss J M et al..
Mechanisms of leukocyte trafficking into the CNS.
J Neurovirol.
2000;
6
S82-S85
-
69
Brilla R, Nabavi D G, Schulte-Atedorneburg G et al..
Cerebral vasculopathy in HIV infection revealed by transcranial doppler: a pilot study.
Stroke.
1999;
30
811-813
-
70
Lee G A, Seneviratne T, Noor M A et al..
The metabolic effects of lopinavir/ritonavir in HIV-negative men.
AIDS.
2004;
18
641-649
-
71
Copur A S, Smith P R, Gomez V, Bergman M, Homel P.
HIV infection is a risk factor for venous thromboembolism.
AIDS Patient Care STDS.
2002;
16
205-209
-
72
Wanke C A, Falutz J M, Shevitz A, Phair J P, Kotler D P.
Clinical evaluation and management of metabolic and morphologic abnormalities associated with human immunodeficiency virus.
Clin Infect Dis.
2002;
34
248-259
-
73
Dressman J, Kincer J, Matveev S V et al..
HIV protease inhibitors promote atherosclerotic lesion formation independent of dyslipidemia by increasing CD36-dependent cholesterol ester accumulation in macrophages.
J Clin Invest.
2003;
111
389-397
-
74
Hui D Y.
HIV protease inhibitors and atherosclerosis.
J Clin Invest.
2003;
111
317-318
-
75
Ninomiya J K, L’Italien G, Criqui M H et al..
Association of the metabolic syndrome with history of myocardial infarction and stroke in the Third National Health and Nutrition Examination Survey.
Circulation.
2004;
109
42-46
-
76
Williams R C.
Periodontal disease.
N Engl J Med.
1990;
322
373-382
-
77
Brown L J, Brunelle J A, Kingman A.
Periodontal status in the United States, 1988-1991: prevalence, extent, and demographic variation.
J Dent Res.
1996;
75
672-683
-
78
Silver J G, Martin A W, McBride B C.
Experimental transient bacteremias in human subjects with varying degrees of plaque accumulation and gingival inflammation.
J Clin Periodontol.
1977;
4
92-99
-
79
Engebretson S P, Lamster I B, Elkind MSV et al..
Radiographic measures of periodontal disease and carotid atherosclerosis.
Stroke.
2005;
36
561-566
-
80
Beck J, Garcia R, Heiss G, Vokonas P S, Offenbacher S.
Periodontal disease and cardiovascular disease.
J Periodontol.
1996;
67
1123-1137
-
81
Wu T, Trevisan M, Genco R J, Dorn J P, Falkner K L, Sempos C T.
Periodontal disease and risk of cerebrovascular disease: the first National Health and Nutrition Examination Survey and its follow-up study.
Arch Intern Med.
2000;
160
2749-2755
-
82
Hujoel P P, Drangsholt M, Spiekerman C, DeRouen T A.
Periodontal disease and coronary heart disease risk.
JAMA.
2000;
284
1406-1410
-
83
Veldhuyzen van Zanten S J, Sherman P M.
Helicobacter pylori infection as a cause of gastritis, duodenal ulcer, gastric cancer and nonulcer dyspepsia: a systematic overview.
CMAJ.
1994;
150
177-185
-
84
Koenig W, Rothenbacher D, Hoffmeister A et al..
Infection with Helicobacter pylori is not a major independent risk factor for stable coronary heart disease.
Circulation.
1999;
100
2326-2331
-
85
Pasceri V, Cammarota G, Patti G et al..
Association of virulent Helicobacter pylori strains with ischemic heart disease.
Circulation.
1998;
97
1675-1679
-
86
Ameriso S F, Fridman E A, Leiguarda R C, Sevlever G E.
Detection of Helicobacter pylori in human carotid atherosclerotic plaques.
Stroke.
2001;
32
385-391
-
87
Blasi F, Denti F, Erba M et al..
Detection of Chlamydia pneumoniae but not Helicobacter pylori in atherosclerotic plaques of aortic aneurysms.
J Clin Microbiol.
1996;
34
2766-2769
-
88
Moazed T C, Kuo C, Grayston J T, Campbell L A.
Murine models of Chlamydia pneumoniae infection and atherosclerosis.
J Infect Dis.
1997;
175
883-890
-
89
Laitinen K, Laurila A, Pyhala L, Leinonen M, Saikku P.
Chlamydia pneumoniae infection induces inflammatory changes in the aortas of rabbits.
Infect Immun.
1997;
65
4832-4835
-
90
Muhlestein J B, Anderson J L, Hammond E H et al..
Infection with Chlamydia pneumoniae accelerates the development of atherosclerosis and treatment with azithromycin prevents it in a rabbit model.
Circulation.
1998;
97
633-636
-
91
Gurfinkel E, Bozovich G, Beck E, Testa E, Livellara B, Mautner B.
Treatment with the antibiotic roxithromycin in patients with acute non-Q-wave coronary syndromes: the final report of the ROXIS Study.
Eur Heart J.
1999;
20
121-127
-
92
Sander D, Winbeck K, Klingelhöfer J, Etgen T, Conrad B.
Reduced progression of early carotid atherosclerosis after antibiotic treatment and C. pneumoniae seropositivity.
Circulation.
2002;
106
2428-2433
-
93
Sander D, Winbeck K, Klingelhöfer J et al..
Reduced progression of early carotid atherosclerosis after antibiotic treatment and C. pneumoniae seropositivity.
Circulation.
2002;
106
2428-2433
-
94
Sander D, Winbeck K, Klingelhöfer J et al..
Progression of early carotid atherosclerosis is only temporarily reduced after antibiotic treatment of Chlamydia pneumoniae seropositivity.
Circulation.
2004;
109
1010-1015
-
95
O'Connor C M, Dunne M W, Pfeffer M A et al..
Azithromycin for the secondary prevention of coronary heart disease events-the WIZARD study: a randomized controlled trial.
JAMA.
2003;
290
1459-1466
-
96
Grayston J T, Kronmal R A, Jackson L A et al..
Azithromycin for the secondary prevention of coronary events.
N Engl J Med.
2005;
352
1637-1645
-
97
Cannon C P, Braunwald E, McCabe C H et al..
Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome.
N Engl J Med.
2005;
352
1646-1654
-
98
Prospective Studies Collaboration .
Cholesterol, diastolic blood pressure and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts.
Lancet.
1995;
346
1647-1653
-
99
Espinola-Klein C, Rupprecht H J, Blankenberg S et al..
Impact of infectious burden on extent and long-term prognosis of atherosclerosis.
Circulation.
2002;
105
15-21
-
100
Espinola-Klein C, Rupprecht H J, Blankenberg S et al..
Impact of infectious burden on progression of carotid atherosclerosis.
Stroke.
2002;
33
2581-2586
-
101
Smieja M, Gnarpe J, Lonn E et al..
Multiple infections and subsequent cardiovascular events in the Heart Outcomes Prevention Evaluation (HOPE) Study.
Circulation.
2003;
107
251-257
-
102
Ezekowitz R A.
Genetic heterogeneity of mannose-binding proteins: the Jekyll and Hyde of innate immunity?.
Am J Hum Genet.
1998;
62
6-9
-
103
Hegele R A, Ban M R, Anderson C M, Spence J D.
Infection-susceptibility alleles of mannose-binding lectin are associated with increased carotid plaque area.
J Investig Med.
2000;
48
198-202
-
104
Momiyama Y, Hirano R, Taniguchi H, Nakamura H, Ohsuzu F.
Effects of interleukin-1 gene polymorphisms on the development of coronary artery disease associated with Chlamydia pneumoniae infection.
J Am Coll Cardiol.
2001;
38
712-717
Mitchell S.V ElkindM.D. M.S. F.A.A.N.
Assistant Professor of Neurology, Department of Neurology, Gertrude H. Sergievsky Center, Columbia University, New York-Presbyterian Hospital, 710 West 168th Street, Box 182, New York, NY 10032