Role of Inflammation and Infection in Vascular Disease

Relationship of infection, inflammation, and atherosclerosis has been a subject of intensive investigation in recent years. Potential mechanisms whereby chronic infections may play a role in atherogenesis are myriad. Chlamydia pneumoniae (Cp) infection in early life may accelerate atherosclerosis, leading to cardiovascular complications. Other infections, simultaneously occurring with Cp, may result in a synergistic effect to promote atherosclerosis. Chronic Helicobacter pylori infection is known to increase the pH level of the gastric juice and to decrease ascorbic acid levels, both of which will lead to a reduced folate absorption. Low folate hampers the methionine synthase reaction. This leads to an increased concentration of homocysteine in the blood, resulting in damage of endothelial cells. Cytomegalovirus (CMV) infection is associated with accelerated atherosclerosis following cardiac transplantation; several studies have found that patients with a previous CMV infection had a high independent risk of restenosis after coronary angiography. Inflammatory markers are independent predictors of cardiovascular and cerebrovascular events. Large population-based studies such as the study from the MONICA (MONItoring trends and determinants in CArdiovascular disease) Augsberg Center in Germany, the Atherosclerosis Risk in Communities Study, the Women’s Health Study, the Honolulu Heart Study, have also suggested the relation between the levels of CRP and risk of coronary disease. Over the past decade also another marker of inflammation has been studied; fibrinogen has been identified as an independent risk factor for CAD in several large prospective studies. All these studies suggested a new, possible role of markers of infection and inflammation beyond traditional cardiovascular risk factors, in the development and progression of atherosclerosis. However, the clinical and therapeutic implications of these results remain to be evaluated. Although antibiotic treatment of infections in CAD patients had no impact on mortality in large prospective trials, promising data is coming from smaller studies and further studies are needed to investigate the possibility to submit this category of high-risk patients to therapeutical approaches of primary prevention.     

Chlamydia pneumoniae accompanied by inflammation is associated with the progression of atherosclerosis in CAPD patients: a prospective study for 3 years.

BACKGROUND: The causes of accelerated atherosclerosis in end-stage renal disease (ESRD) patients are unknown, although recent studies have suggested that Chlamydia pneumoniae (Cp) infection and inflammation might be contributing factors. We aimed to evaluate the association of carotid atherosclerosis progression with Cp infection and inflammation in patients undergoing peritoneal dialysis (PD). METHODS: This is a prospective observational study. A total of 52 non-diabetic prevalent PD patients were included. The intima-media thickness of a common carotid artery (CCA-IMT) was measured at baseline and after 36 months by B-mode ultrasonography. Serum antibodies to Cp and inflammatory markers were obtained at the time of initial measurement of the CCA-IMT. RESULTS: CCA-IMT progressors (deltaCCA-IMT > or = 0.015 mm/year) had a higher prevalence of seropositivity for Cp IgA antibody, a higher level of Cp IgA antibodies indices, log IL-(interleukin-)6, and intercellular adhesion molecule-1 (ICAM-1) compared to the non-progressors (deltaCCA-IMT < 0.015 mm/year). On multivariate analysis, Cp IgA index and log IL-6 were independent risk a factors for CCA-IMT progression. Also, Cp IgA index had independent positive correlation with the magnitude of annual deltaCCA-IMT. Cp IgA antibody seropositive patients showed significantly higher mean annual deltaCCA-IMT than seronegative patients. Moreover, patients with both positive Cp IgA antibodies and elevated IL-6 above the median level showed higher deltaCCA-IMT than those with either factor alone. CONCLUSIONS: Our data showed that Cp and inflammation were significant risk factors of CCA-IMT change in PD patients. This study strengthens evidence that Cp is involved in the pathogenesis of atherosclerosis and also suggests that the effect of Cp infection under high inflammatory status might be a risk factor for progression of atherosclerosis.     

Update on C-reactive protein as a risk marker in cardiovascular disease

Atherosclerosis is characterized by a nonspecific local inflammatory process, which is accompanied by a systemic response. A number of prospective studies have convincingly demonstrated a strong and independent association between even slightly elevated concentrations of systemic markers of inflammation, like C-reactive protein (CRP), and cardiovascular events in initially healthy subjects and in patients with manifest atherosclerosis. Increased concentrations of CRP were also associated with recurrent instability after discharge, and with early and late complications after percutaneous interventions, bypass operation, and in patients with end-stage renal disease. Recent data have strengthened the role for CRP testing in primary prevention, and potentially new indications like glucose disorders have emerged. In addition, new experimental data suggest that CRP may not only be a risk marker, but may be directly involved in the pathogenesis of atherothrombosis. Testing the "inflammation hypothesis" now represents an important goal for clinical research of atherosclerosis.     

Active cytomegalovirus replication in patients with coronary disease

OBJECTIVES: To study the prevalence of active cytomegalovirus (CMV) infection in patients with stable and unstable conditions of coronary artery disease (CAD). DESIGN: Forty patients with acute coronary syndrome (ACS), 50 patients with stable angina and angiographically verified CAD (SA) and 50 clinically healthy controls were included. Monocytes were isolated from peripheral blood and CMV-RNA expression was determined by a nested RT-PCR assay. CMV IgM and IgG antibodies, interleukin-(IL)-6, IL-10 and CRP were measured in serum. RESULTS: The prevalence of active CMV infection was significantly higher in patients with ACS (15%) and in patients with SA (10%) compared with controls (2%) (p<0.001). The presence of an active CMV infection was associated with increased serum concentrations of IL-6. CONCLUSIONS: Active CMV infection was found to a larger extent in CAD patients than in healthy controls. The data indicate that CAD patients are more susceptible to reactivation of CMV and put new focus on the role of CMV in atherosclerosis.     

Coronary calcium in adults with type 1 diabetes: a stronger correlate of clinical coronary artery disease in men than in women

We studied the relationship of coronary artery calcification (CAC), a marker of coronary atherosclerosis, with prevalent clinical coronary artery disease (CAD) and established cardiovascular disease (CVD) risk factors in a type 1 diabetic population. At the 10-year follow-up examination of the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study cohort, 302 adults (mean age 38.1 +/- 7.8 years) received electron beam tomography (EBT) scanning of the heart and a clinical examination. Clinical CAD was defined as a confirmed history of myocardial infarction (MI), angiographic stenosis > or =50%, Pittsburgh EDC Study physician-diagnosed angina, or ischemic electrocardiogram (ECG). CAC correlated with most CVD risk factors. CAC had 84 and 71% sensitivity for clinical CAD in men and women, respectively, and 100% sensitivity for MI or obstructive CAD. A CACS cut point of 400 was the most efficient coronary calcium correlate of CAD. In subjects with angina only, CAC sensitivity was 83% in men and 46% in women. In logistic regression, CAC, ECG R-R variation, peripheral vascular disease, and Beck Depression Inventory independently correlated with prevalent CAD in men and overall. Except for CAC, the same variables independently correlated with CAD in women, and age also entered the model. CAC was an independent correlate of MI or obstructive CAD in both sexes and was the strongest independent correlate in men, but CAC was not independently associated with angina and ischemic ECG in either sex. It is concluded that EBT-detected CAC is strongly correlated with CAD in type 1 diabetes-particularly in men.     

Association between erectile dysfunction and coronary artery disease: Matching the right target with the right test in the right patient

INTRODUCTION: Evidence is accumulating in favour of a link between erectile dysfunction (ED) and coronary artery disease (CAD). This review attempts to identify which patients, among those with ED and no cardiovascular (CV) disease, should be screened for early, subclinical CAD, which coronary targets should be investigated, and which tests should be used. MATERIALS AND METHODS: A comprehensive evaluation of available published data included analysis of published full-length papers that were identified with Medline and Cancerlit from January 1988 to January 2006. RESULTS: Initial screening of patients with ED may adopt risk assessment office-based approaches to score patients into low, intermediate, or high risk of future cardiovascular events. Attention should be drawn to patients at intermediate risk. Targets for the assessment of subclinical CAD in this subset of patients should include both obstructive (flow-limiting) and nonobstructive (non-flow-limiting) CAD. Some tests address obstructive atherosclerosis by directly assessing coronary flow reserve (i.e., standard exercise stress test, rest/stress myocardial scintigraphy or echocardiography). Other tests are general measures of atherosclerosis burden (not necessarily obstructive) either in the coronary circulation (i.e., coronary calcium score by electron-beam computed tomography), or in extracoronary vessels (i.e., ankle brachial index, carotid intima-media thickness by B-mode ultrasound) as surrogate markers of CAD. Although a systematic use of these measures of nonobstructive atherosclerosis burden has not yet been recommended in the guidelines for coronary risk assessment, their use is progressively being extended from the research area to clinical practice. CONCLUSIONS: ED is definitely a vascular disorder and all men with ED should be considered at risk of CV disease until proven otherwise. Available risk assessment charts should be used to stratify (low, intermediate, and high) the coronary risk score in each patient with ED.     

Effect of glycemic control on markers of subclinical atherosclerosis in patients with type 2 diabetes mellitus: A review

Cardiovascular disease is the predominant cause of death in type 2 diabetes mellitus (T2DM). Evidence suggests a strong association between duration and degree of hyperglycemia and vascular disease. However, large trials failed to show cardiovascular benefit after intensive glycemic control, especially in patients with longer diabetes duration. Atherosclerosis is a chronic and progressive disease, with a long asymptomatic phase. Subclinical atherosclerosis, which is impaired in T2DM, includes impaired vasodilation, increased coronary artery calcification (CAC), carotid intima media thickness, arterial stiffness, and reduced arterial elasticity. Each of these alterations is represented by a marker of subclinical atherosclerosis, offering a cost-effective alternative compared to classic cardiac imaging. Their additional use on top of traditional risk assessment strengthens the predictive risk for developing coronary artery disease (CAD). We, herein, review the existing literature on the effect of glycemic control on each of these markers separately. Effective glycemic control, especially in earlier stages of the disease, attenuates progression of structural markers like intima-media thickness and CAC. Functional markers are improved after use of newer anti-diabetic agents, such as incretin-based treatments or sodium-glucose co-transporter-2 inhibitors, especially in T2DM patients with shorter disease duration. Larger prospective trials are needed to enhance causal inferences of glycemic control on clinical endpoints of CAD.     

When and how to start prevention of atherosclerosis? Lessons from the Cardiovascular Risk in the Young Finns Study and the Special Turku Coronary Risk Factor Intervention Project

This review provides an up-to-date summary of findings from two ongoing population-based, prospective studies conducted in Finland: The Cardiovascular Risk in Young Finns Study, and the Special Turku Coronary Risk Factor Intervention Project (STRIP), which have contributed significantly to the scientific literature concerning the childhood origin of cardiovascular disease, and whether prevention efforts in adults can be expanded to young people. From the Young Finns Study, we summarize evidence demonstrating childhood risk factors to be associated with both risk factors and preclinical markers of atherosclerosis in adulthood, and from STRIP, we summarize evidence showing that supervised dietary counseling of a low saturated fat diet effectively decreases exposure to cardiovascular risk factors without affecting growth and development of healthy children and adolescents. The evidence available from these studies supports that the ability to prevent or delay the risk of premature atherosclerosis and its clinical sequelae later in life lies in maintaining a low lifetime risk by preventing the development of risk factors in early life.     

Homocysteine,endothelial dysfunction,and coronary artery disease: emerging strategy for secondary prevention

Atherosclerosis is an important medical problem of the 21st century, but traditional risk factors could only account for 50% of the problem. Hyperhomocysteinemia is emerging as an independent atherosclerosis risk factor, associated with folate deficiency, renal failure, and relative deficiency of MTHFR (C677T polymorphism) or other enzymes depending on gender, age, and smoking status. Hyperhomocysteinemia has been reported to occur in 11-22% of western people, in 3-5% of normal asymptomatic Chinese subjects aged 18-70 years in Hong Kong, Macau, Sydney, and San Francisco, 23-36% of Chinese in Hong Kong with premature coronary artery disease, and 29% of a nonselective series of coronary subjects in Hong Kong. Evidence is accumulating that documents its associations with atherosclerosis disease in both case-control observations and prospective cohort studies, in vitro experiments, and in vivo experimental models in both animals and human subjects, as well as the successful improvement by homocysteine-lowering of endothelial function as surrogate atherosclerosis endpoints in asymptomatic human and coronary patients (secondary prevention). A number of large scale homocysteine-lowering trials are currently underway for stroke and heart attacks prevention. Collectively these trials will include more than 65,000 patients at high-risk for cardiovascular and stroke events, and should provide a reliable evidence-base for prevention.     

FIRST INTERNATIONAL SYMPOSIUM ON CARDIOVASCULAR SCIENCE—FROM BENCH TO BEDSIDE

Abstract Atherosclerosis is an important medical problem of the 21^st century, but traditional risk factors could only account for 50% of the problem. Hyperhomocysteinemia is emerging as an independent atherosclerosis risk factor, associated with folate deficiency, renal failure, and relative deficiency of MTHFR (C677T polymorphism) or other enzymes depending on gender, age, and smoking status. Hyperhomocysteinemia has been reported to occur in 11–22% of western people, in 3–5% of normal asymptomatic Chinese subjects aged 18–70 years in Hong Kong, Macau, Sydney, and San Francisco, 23–36% of Chinese in Hong Kong with premature coronary artery disease, and 29% of a nonselective series of coronary subjects in Hong Kong. Evidence is accumulating that documents its associations with atherosclerosis disease in both case‐control observations and prospective cohort studies, in vitro experiments, and in vivo experimental models in both animals and human subjects, as well as the successful improvement by homocysteine‐lowering of endothelial function as surrogate atherosclerosis endpoints in asymptomatic human and coronary patients (secondary prevention). A number of large scale homocysteine‐lowering trials are currently underway for stroke and heart attacks prevention. Collectively these trials will include more than 65,000 patients at high‐risk for cardiovascular and stroke events, and should provide a reliable evidence‐base for prevention.     

Inflammation, metabolic syndrome, erectile dysfunction, and coronary artery disease: common links

OBJECTIVE: Erectile dysfunction (ED) may be the early clinical manifestation of a generalized vascular disease and carries an independent risk for cardiovascular events. Low-grade subclinical inflammation affects endothelial function and is involved in all stages of the atherosclerotic process. This review identifies potential pathophysiologic links among low-grade inflammation, ED, metabolic syndrome, and coronary artery disease (CAD) and presents the clinical implications in terms of ED diagnosis, assessment of patient risk, and therapy. METHODS: A comprehensive evaluation was performed for available published data in full-length papers that were identified in MedLine up to July 2007. RESULTS: Studies support an association between metabolic syndrome, ED, and increased inflammatory state. Increased circulating levels of inflammatory and endothelial-prothrombotic compounds are related to the presence and severity of ED. Specific inflammatory biomarkers and their combination appear to have the potential to aid ED diagnosis or exclusion. ED and CAD may confer a similar unfavorable impact on the inflammatory and prothrombotic state, whereas ED adds an incremental activation on top of CAD; these findings have important implications for cardiovascular risk. Lifestyle and risk factor modification, as well as pharmacologic therapy, are associated with anti-inflammatory effects. CONCLUSIONS: Low-grade systemic inflammation could be an important element of the association between metabolic syndrome, ED, and CAD. Its individualized assessment may be a valuable tool for ED diagnosis, risk assessment, and rationalized therapeutic approach especially in patients with ED who have metabolic syndrome and carry an intermediate risk for future cardiovascular events.     

Association between Systemic Calcified Atherosclerosis and Bone Density

Both atherosclerosis and osteoporosis are responsible for significant morbidity and mortality, are independent predictors of cardiovascular disease (CVD) events, and may share common regulatory mechanisms as well as histopathology. Multiple reports of weak or null relationships between traditional CVD risk factors and calcified atherosclerosis have heightened interest in novel predictors of arterial calcium. One such hypothesis is for an inverse relationship between bone mineral density (BMD) and calcified coronary atherosclerosis. Although contrary findings have been reported, the majority of cross-sectional and all prospective studies have demonstrated a significant inverse association between arterial calcium deposits and BMD. The few studies that include men are equivocal, and, to date, no study has investigated the relationship between BMD and systemic arterial calcium. The aim of this study was to test the hypothesis that lumbar BMD is significantly associated with the presence of arterial atherosclerotic calcium in the carotid, coronary, and iliac vascular beds as well as the aorta.     

Infections and Atherosclerosis

More than a century ago, inflammation and infection were considered to have atherogenic effects. During last century, however, this hypothesis was completely abandoned, and the old idea that coronary heart disease (CHD) possibly has an infectious etiology has only re-emerged in recent years. Both viral and bacterial pathogens have been proposed to be associated with the inflammatory changes found in atherosclerosis. Herpes group viruses, especially cytomegalovirus (CMV) and herpes simplex virus type 1 (HSV1), have been associated with both atherosclerosis and restenosis. Helicobacter pylori and dental infections have also been linked to CHD, but the evidence is strongest for a respiratory tract bacterium, Chlamydia pneumoniae. The association was originally found in seroepidemiological studies, but the presence of organisms in atherosclerotic lesions, the first animal studies and preliminary successful intervention trials with antibiotics suggest that C. pneumoniae may have a pathogenetic role in the disease. The causal relationship has not yet been proven, but ongoing large intervention trials and research on pathogenetic mechanisms may lead to the use of antimicrobial agents in the treatment of CHD in the future.     

Infections and atherosclerosis

More than a century ago, inflammation and infection were considered to have atherogenic effects. During last century, however, this hypothesis was completely abandoned, and the old idea that coronary heart disease (CHD) possibly has an infectious etiology has only re-emerged in recent years. Both viral and bacterial pathogens have been proposed to be associated with the inflammatory changes found in atherosclerosis. Herpes group viruses, especially cytomegalovirus (CMV) and herpes simplex virus type 1 (HSV1), have been associated with both atherosclerosis and restenosis. Helicobacter pylori and dental infections have also been linked to CHD, but the evidence is strongest for a respiratory tract bacterium, Chlamydia pneumoniae. The association was originally found in seroepidemiological studies, but the presence of organisms in atherosclerotic lesions, the first animal studies and preliminary successful intervention trials with antibiotics suggest that C. pneumoniae may have a pathogenetic role in the disease. The causal relationship has not yet been proven, but ongoing large intervention trials and research on pathogenetic mechanisms may lead to the use of antimicrobial agents in the treatment of CHD in the future.     

Long-term outcome of cytomegalovirus infection in simultaneous pancreas–kidney transplant recipients without ganciclovir prophylaxis

As cytomegalovirus (CMV) infection frequently occurs in simultaneous pancreas kidney transplantation (SPKT), most centers use general ganciclovir prophylaxis. The aim of the study was to analyze the impact of CMV in a patient cohort with preemptive therapy only. Incidence, course and risk factors of CMV infection were retrospectively analyzed in 94 adult SPK recipients without prophylaxis. Patients with asymptomatic pp65-antigenemia were treated preemptively with intravenous ganciclovir for 14 days. Survival rates after 1, 3, and 5 years were 98%, 97%, and 94% for patients, 96%, 94%, and 88% for renal grafts and 88%, 85%, and 82% for pancreas grafts. CMV infections occurred in 51% of patients and CMV syndrome in 16%. No tissue-invasive disease was observed. Thirty-eight per cent of patients with CMV infection developed a recurrence. Risk factors for CMV in multivariate analysis were the D+/R- constellation, acute rejections, anti-rejection therapy and coronary heart disease. CMV had no impact on patient or graft survival, occurrence of acute or chronic rejection and bacterial infections. Preemptive therapy seems to be safe and effective in SPK recipients, but as the present study was retrospective, prospective randomized studies are needed to confirm our results.     

Athérosclérose et connectivitesAtherosclerosis and connective tissue disease.

Large increases in mortality related to premature atherosclerosis with coronary artery disease and stroke have been reported in patients with systemic lupus erythematosus (SLE), antiphospholipid syndrome (APLS), or rheumatoid arthritis (RA). Studies found relative risks of 5 for myocardial infarction, 6 to 10 for stroke in SLE patients, and 3.6 for cardiovascular deaths in RA patients. The main risk factors for atherosclerosis included not only the classic factors identified in epidemiological studies such as the Framingham study (advanced age, high cholesterol levels, hypertension, diabetes mellitus, and obesity), but also prolonged glucocorticoid therapy, long duration of SLE, postmenopausal status, and heart failure. SLE per se is an independent risk factor. The current pathogenic hypothesis for atherosclerosis involves an inflammatory response (erythrocyte sedimentation rate, C-reactive protein, and fibrin), autoantibodies, immune complexes (containing antibodies to phospholipids, to oxidized LDLs, and to endothelial cells), cytokine-producing activated T cells, and bacterial or viral infections responsible for an immune response against heat shock proteins (endogenous HSP60 and its equivalent, bacterial HSP65). Early risk factor intervention and effective control of inflammation should be incorporated into the management of connective tissue disease with the goal of protecting patients against atherosclerosis.     

Atherosclerosis and connective tissue diseases.

Large increases in mortality related to premature atherosclerosis with coronary artery disease and stroke have been reported in patients with systemic lupus erythematosus (SLE), antiphospholipid syndrome (APLS), or rheumatoid arthritis (RA). Studies found relative risks of 5 for myocardial infarction, 6 to 10 for stroke in SLE patients, and 3.6 for cardiovascular deaths in RA patients. The main risk factors for atherosclerosis included not only the classic factors identified in epidemiological studies such as the Framingham study (advanced age, high cholesterol levels, hypertension, diabetes mellitus, and obesity), but also prolonged glucocorticoid therapy, long duration of SLE, postmenopausal status, and heart failure. SLE per se is an independent risk factor. The current pathogenic hypothesis for atherosclerosis involves an inflammatory response (erythrocyte sedimentation rate, C-reactive protein, and fibrin), autoantibodies, immune complexes (containing antibodies to phospholipids, to oxidized LDLs, and to endothelial cells), cytokine-producing activated T cells, and bacterial or viral infections responsible for an immune response against heat shock proteins (endogenous HSP60 and its equivalent, bacterial HSP65). Early risk factor intervention and effective control of inflammation should be incorporated into the management of connective tissue disease with the goal of protecting patients against atherosclerosis.     

C-reactive protein: a new risk assessment tool for cardiovascular disease

Recent research has focused on the use of high-sensitivity C-reactive protein (hs-CRP), a marker of inflammation, in the detection of patients at increased risk for cardiovascular disease. Several prospective studies have demonstrated that hs-CRP is an independent predictor of future risk for cardiovascular events among healthy individuals, as well as among patients with acute coronary syndromes. In addition, because half of all cardiovascular events occur in persons with low to average levels of low-density lipoprotein cholesterol, hs-CRP may aid in identifying patients at high risk for a first cardiovascular event who might otherwise be missed by lipid screening alone. Thus, hs-CRP is a potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. The Centers for Disease Control and Prevention and the American Heart Association have therefore proposed joint guidelines for the use of hs-CRP in determining cardiovascular disease risk. The author reviews numerous studies examining the prognostic value of hs-CRP and outlines ongoing efforts to assess the effect of statin therapy in healthy individuals with low levels of low-density lipoprotein cholesterol and high levels of hs-CRP.     

Athérosclérose et connectivites

Large increases in mortality related to premature atherosclerosis with coronary artery disease and stroke have been reported in patients with systemic lupus erythematosus (SLE), antiphospholipid syndrome (APLS), or rheumatoid arthritis (RA). Studies found relative risks of 5 for myocardial infarction, 6 to 10 for stroke in SLE patients, and 3.6 for cardiovascular deaths in RA patients. The main risk factors for atherosclerosis included not only the classic factors identified in epidemiological studies such as the Framingham study (advanced age, high cholesterol levels, hypertension, diabetes mellitus, and obesity), but also prolonged glucocorticoid therapy, long duration of SLE, postmenopausal status, and heart failure. SLE per se is an independent risk factor. The current pathogenic hypothesis for atherosclerosis involves an inflammatory response (erythrocyte sedimentation rate, C-reactive protein, and fibrin), autoantibodies, immune complexes (containing antibodies to phospholipids, to oxidized LDLs, and to endothelial cells), cytokine-producing activated T cells, and bacterial or viral infections responsible for an immune response against heat shock proteins (endogenous HSP60 and its equivalent, bacterial HSP65). Early risk factor intervention and effective control of inflammation should be incorporated into the management of connective tissue disease with the goal of protecting patients against atherosclerosis.     

Exercise and carotid atherosclerosis.

OBJECTIVES: Both carotid atherosclerosis or increased carotid intima-media thickness (IMT) are common manifestations of generalized atherosclerosis, closely associated with increased risk of stroke and myocardial infarction. Despite the predominant involvement of physical activity in cardiovascular prevention and rehabilitation strategies, its role in carotid atherosclerosis progression is less evaluated. The aim of our study was to review the literature for the contribution of increased physical activity or structured exercise to the prevention and treatment of carotid atherosclerosis. MATERIALS/METHODS: A systematic review was performed of all cross-sectional, interventional, prospective or retrospective, clinical studies. Using the following terms: carotid atherosclerosis, intima-media thickness, physical activity, exercise, life-style, stroke, cardiovascular risk factors, we searched MEDLINE and EMBASE databases from 1985 to 2007. Carotids ultrasonography and relevant quantitative indexes were prerequisites for our search. RESULTS: The majority of cross-sectional studies have demonstrated that physical inactivity is associated with increased carotid IMT, while structured lifestyle interventions have conferred inconsistent results on the progression of carotid thickening. The increment of cardiorespiratory fitness and the modification of numerous cardiovascular risk factors, such as hyperglycemia, insulin resistance, hyperlipidemia, hypertension and obesity provide plausible mechanisms by which exercise training may suppress the evolution of carotid atherosclerosis. CONCLUSIONS: It remains questionable whether long-term exercise can decelerate the development of carotid atherosclerosis. Perhaps increased physical activity suppresses the overall cardiovascular risk and hence curtails the progression of carotid atherosclerosis. If carotid artery disease is regarded as a coronary artery disease equivalent, it is reasonable to recommend similar patterns of physical activity in patients with subclinical or manifest carotid atherosclerosis as for those with coronary atherosclerosis.