Several studies have suggested that inflammation and infection may be important for accelerated progression of atherosclerosis, but few data are available on subjects with early stages of atherosclerosis.
Methods and Results
We included, in a prospective 5-year follow-up study, 150 patients with subclinical carotid atherosclerosis, evaluating at baseline all established traditional cardiovascular risk factors (eg, older age, male sex, obesity, hypertension, diabetes, smoking, family history of coronary artery disease, and dyslipidemia); 2 markers of inflammation, fibrinogen, and high-sensitivity C-reactive protein (CRP); and the seropositivity to Helicobacter pylori, Chlamydia pneumoniae, and cytomegalovirus. After follow-up, cardiovascular and cerebrovascular events were registered in the 19% of patients, and the increment in CRP levels (in quintiles) was significantly associated with ischemic stroke (P = 0.0253), acute myocardial infarction (P = 0.0055), cardiovascular or cerebrovascular death (P = 0.0145), and the presence of any event (P = 0.0064). Most traditional cardiovascular risk factors (eg, older age, hypertension, diabetes, and dyslipidemia) were significantly associated with the events but only in the unadjusted analysis; in fact, at logistic regression analysis, among all baseline variables, only elevated CRP levels showed a predictive role (odds ratio, 7.0; 95% confidence interval, 2.2-18.4; P = 0.0247).
Conclusions
Our findings suggest that elevated CRP concentrations may significantly influence the occurrence of cerebrovascular and cardiovascular events in patients with baseline subclinical carotid atherosclerosis. Notably, null findings were obtained by viral and bacteria titers, suggesting a greater role of inflammation (and not of infection) in the progression of atherosclerosis in our cohort. However, further studies are needed to evaluate the therapeutic implications in this category of patients.
CravenTE, RyuJE, EspelandMA, . Evaluation of the associations between carotid artery atherosclerosis and coronary artery stenosis. A case-control study. Circulation1990;82:1230–1242.
2.
WoffordJL, KahlFR, HowardGR, . Relation of extent of extracranial carotid artery atherosclerosis as measured by B-mode ultrasound to the extent of coronary atherosclerosis. Arterioscler Thromb1991;11:1786–1794.
3.
SalonenJT, SalonenR. Ultrasound B-mode imaging in observational studies of atherosclerotic progression. Circulation1993;87:II56-II65.
4.
BurkeGL, EvansGW, RileyWA, . Arterial wall thickness is associated with prevalent cardiovascular disease in middle-aged adults. The Atherosclerosis Risk in Communities (ARIC) Study. Stroke1995;26:386–391.
5.
BotsML, MoonsKG, HollanderM, . Is carotid intima-media thickness useful in cardiovascular disease risk assessment? The Rotterdam Study. Circulation1997;96:1432–1437.
6.
O'LearyDH, PolakJF, KronmalRA, . Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med1999;340:14–22.
7.
CorradoE, RizzoM, TantilloR, . Markers of inflammation and infection influence the outcome of patients with baseline asymptomatic carotid lesions: a 5-year follow-up study. Stroke2006;37:482–486.
8.
CorradoE, NovoS. Role of inflammation and infection in vascular disease. Acta Chir Belg2005;105:567–579.
9.
AcevedoM, FoodyJM, PearceGL, . Fibrinogen: associations with cardiovascular events in an outpatient clinic. Am Heart J2002;143:277–282.
10.
FolsomAR, AleksicN, CatellierD, . C-reactive protein and incident coronary heart disease in the Atherosclerosis Risk in Communities (ARIC) study. Am Heart J2002;144:233–238.
11.
MazoyerE, DrouetL, SoriaC, . Risk factors and outcomes for atherothrombotic disease in French patients: the RIVAGE study. RIsque VAsculaire Group d'Etude. Thromb Res1999;95:163–176.
12.
RidkerPM, GlynnRJ, HennekensCH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation1998;97:2007–2011.
13.
National Cholesterol Education Program (NCEP). Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report. Circulation2002;106:3143–3421.
14.
PearsonT, MensahG, AlexanderRW, . Markers of Inflammation and Cardiovascular Disease. Application to Clinical and Public Health Practice. A Statement for Healthcare Professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation2003;107:499–511.
15.
MattilaKJ, ValtonenVV, NieminenMS, . Role of infection as a risk factor for atherosclerosis, myocardial infarction, and stroke. Clin Infect Dis1998;26:719–734.
16.
Espinola-KleinC, RupprechtH, BlankenbergS, . Impact of infectious burden on progression of carotid atherosclerosis. Stroke2002;33:2581–2586.
17.
SpenceD, NorrisJ. Infection, inflammation, and atherosclerosis. Stroke2003;34:333–334.
18.
MagyarMT, SzikszaiZ, BallaJ, . Early-onset carotid atherosclerosis is associated with increased intima-media thickness and elevated serum levels of inflammatory markers. Stroke2003;34:58–63.
19.
HashimotoH, KitagawaK, HougakuH, . C-reactive protein is an independent predictor of the rate of increase in early carotid atherosclerosis. Circulation2001;104:63–67.
20.
SellmayerA, LimmertT, HoffmannU. High sensitivity C-reactive protein in cardiovascular risk assessment. Int Angiol2003;22:15–23.
21.
MurataM, IdeT. Determination of cholesterol in sub-nanomolar quantities in biological fluids by high-performance liquid chromatography. J Chromatogr1992;579:329–333.
22.
MontagneP, LarocheP, CuilliereML, . Microparticle-enhanced nephelometric immunoassay for human C-reactive protein. J Clin Lab Anal1992;1:24–29.
23.
MyersGL, RifaiN, TracyR, . CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: report from the laboratory science discussion group. Circulation2004;110:e545–549.
24.
VonClauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol1957;17:231–237.
25.
ImperatoreG, RiccardiG, IovineC, . Plasma fibrinogen: a new factor of the metabolic syndrome. A population-based study. Diabetes Care1998;21:649–654.
26.
RidkerPM, KundsinRB, StampferMJ, . Prospective study of Chlamydia pneumoniae IgG seropositivity and risks of future myocardial infarction. Circulation1999;99:1161–1164.
27.
PatelP, MendallMA, CarringtonD. Association of Helicobacter pylori and Chlamydia pneumoniae infection with coronary heart disease. BMJ1995;331:711–714.
28.
MuhlesteinJB. Chronic infection and coronary artery disease. Med Clin North Am2000;84:123–148.
29.
PignoliP, TremoliE, PoliA, . Intimal plus medial thickness of the arterial wall. A direct measurement with ultrasound imaging. Circulation1986;74:1399–1406.
30.
2003 European Society of Hypertension. Society of Cardiology Guidelines for the Management of Arterial Hypertension. J Hypertens2003;21:1011–1053.
31.
PasceriV, ChangJ, WillersonJT, . Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation2000;102:2165–2168.
32.
RidkerPM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation2001;103:1813–1818.
33.
GreenlandP, SmithSC, GrundySM. Improving coronary heart disease risk assessment in asymptomatic people. Role of traditional risk factors and non invasive cardiovascular tests. Circulation2001;104:1863–1867.
34.
BardRL, KalsiH, RubenfireMD, . Effect of carotid atherosclerosis screening on risk stratification during primary cardiovascular disease prevention. Am J Cardiol2004;93:1030–1032.
35.
CoppolaG, CorradoE, MuratoriI, . Increased levels of C-reactive protein and fibrinogen influence the risk of vascular events in patients with NIDDM. Int J Cardiol2006;106:16–20.
36.
KheraA, de LemosJA, PeshockRM, . Relationship between C-reactive protein and subclinical atherosclerosis: the Dallas Heart Study. Circulation2006;113:38–43.
37.
RidkerPM, RifaiN, RoseL, . Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med2002;347:1557–1565.
38.
WangTJ, GonaP, LarsonMG, . Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med2006;355:2631–2639.
39.
CaoJJ, ArnoldAM, ManolioTA, . Association of carotid artery intima-media thickness, plaques, and C-reactive protein with future cardiovascular disease and all-cause mortality: the Cardiovascular Health Study. Circulation2007;116:32–38.
40.
MichalsenA, LehmannN, PithanC, . Mediterranean diet has no effect on markers of inflammation and metabolic risk factors in patients with coronary artery disease. Eur J Clin Nutr2006;60:478–485.
41.
García-LordaP, BullóM, BalanzàR, . C-reactive protein, adiposity and cardiovascular risk factors in a Mediterranean population. Int J Obes (Lond)2006;30:468–474.
42.
SchillingerM, ExnerM, MlekuschW, . Inflammation and Carotid Artery-Risk for Atherosclerosis Study (ICARAS). Circulation2005;111:2203–2209.
43.
Alvarez GarciaBA, RuizC, ChaconP, . High-sensitivity C-reactive protein in high-grade carotid stenosis: risk marker for unstable carotid plaque. J Vasc Surg2003;38:1018–1024.
44.
RidkerP, RifaiN, PfefferM, . Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation1999;100:230–235.
45.
JialalD, SteinD, BalisD, . Effect of hydroxymethyl glutaryl coenzyme A reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation2001;103:1933–1935.
46.
AlbertMA, DanielsonE, RifaiN, , PRINCE Investigators. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA2001;286:64–70.
47.
NissenSE, TuzcuEM, SchoenhagenP, , Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) Investigators. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med2005;352:29–38.
