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Revista médica de Chile

versión impresa ISSN 0034-9887

Rev. méd. Chile v.129 n.10 Santiago oct. 2001

http://dx.doi.org/10.4067/S0034-98872001001000016 

Non-traditional risk factors for Atherosclerosis

Mónica Acevedo MD*, Rodrigo Tagle MD**,
Conrad Simpfendorfer MD*

Correspondencia a: Conrad Simpfendorfer MD. The Cleveland Clinic Foundation. 9500 Euclid Avenue, Cleveland, Ohio 44195, USA. Phone: (216) 444 2082; Fax: (216) 444 8646; E-mail: simpfec@ccf.org

During the last 10 years, several "non-traditional" risk markers for atherosclerosis have been identified. Among them, new markers of lipoprotein metabolism (ie lipoprotein [a]), endothelial dysfunction (ie homocysteine), hemostasis (ie fibrinogen) and inflammation (ie C-reactive protein) have been linked to an excessive risk of cardiovascular disease. These factors should help the clinician to better identify individuals at risk of premature atherosclerotic disease and/or improve the predictive value of established risk factors for atherosclerosis. Finally, these factors are expected to improve the knowledge in the pathophysiology of cardiovascular diseases, and perhaps to impact future therapeutic decisions. In this review article, we will analyze the markers in which there are at least some evidence to support their acceptance as "non-traditional risk factors" for atherosclerotic disease (Rev Méd Chile 2001; 129: 1212-21).
(Key Words: Atherosclerosis; C-reactive protein; Fibrinogen; Homocysteine; Lipoprotein (a); Risk factors)

Factores de riesgo no-tradicionales en la aterosclerosis

Durante los últimos 10 años se han identificado varios marcadores de riesgo "no-tradicionales" para la aterosclerosis. Entre ellos, se ha relacionado con un riesgo excesivo de enfermedad cardiovascular a nuevos marcadores del metabolismo de lipoproteínas (ej: lipoproteína [a]), disfunción endotelial (ej: homocisteína), hemostasis (ej: fibrinógeno) e inflamación (ej: proteína C-reactiva). Estos factores deberían ayudar al clínico a identificar mejor los individuos con riesgo de una enfermedad aterosclerótica prematura y/o mejorar el valor predictivo de los factores de riesgo de aterosclerosis ya conocidos. Finalmente, se espera que estos factores aumenten el conocimiento de la fisiopatología y el diagnóstico de las enfermedades cardiovasculares y, tal vez, tengan impacto en futuras decisiones terapéuticas. En este artículo de revisión se analizan aquellos marcadores sobre los cuales existen algunas evidencias que apoyen su aceptación como "factores no-tradicionales de riesgo" para la enfermedad aterosclerótica.

Manuscrito preparado por invitación de los Editores de la Revista. Recibido el 10 de agosto de 2001.
El Dr. Simpferdorfer es miembro del Comité Asesor Internacional de la Revista Médica de Chile.
Departments of Cardiology* and Hypertension-Nephrology**, The Cleveland Clinic Foundation, Cleveland, Ohio, USA.

During the last decades great progress has been made in the pathophysiology, diagnosis and treatment of cardiovascular (CV) diseases. Currently, it is well known that atherosclerotic disease is treatable, that plaque progression can be stabilized and that risk factor modification can influence the clinical expression of vascular disease. For these reasons, current disease prevention strategies have focused on the treatment of the traditional risk factors for coronary artery disease (CAD), such as to reduce elevated cholesterol levels and LDL-C, control elevated blood pressure and glucose levels, promote cigarette smoking cessation and weight loss and increase physical activity. However, these traditional risk factors do not fully explain why some people may experience a CV event and others do not. Almost 25% of patients with premature CV disease do not have any established risk factors1. Based on growing evidence, the Bethesda Conference1 in 1996 acknowledged other conditions, such as left ventricular hypertrophy, hyperhomocysteinemia, elevated lipoprotein (a) (Lp {a}), hypertriglyceridemia, oxidative stress, and hyperfibrinogenemia as other possible risk factors for CV disease. New markers of lipoprotein metabolism, endothelial dysfunction, fibrinolysis, and inflammation have been linked to an excessive risk of CV disease. Further, these markers could better predict clinical events alone or in association with traditional risk factors.

We, herein, will review some of these markers, the so-called "non-traditional risk factors of CV disease". For the purpose of this review we will focus on markers in which there is enough evidence in the literature to consider them risk factors for atherosclerotic disease.

FIBRINOGEN

Fibrinogen was first related to cardiovascular diseases (CVD) in the 1950s, when its levels were found to be elevated in patients with CAD2. Since then, several prospective studies have demonstrated that fibrinogen is strongly and independently associated with subsequent CV events (including fatal and non-fatal CVD and total mortality), stroke and the extension of coronary atherosclerosis3-5. In 1980, Meade et al6 first described fibrinogen as a risk factor for CAD and mortality when the results of the Northwick Park Heart Study were published. They demonstrated, in 1511 men, that high fibrinogen levels were associated with an 84% increased risk for fatal and/or non-fatal CV events. After this first report, several studies including the Framingham Study7 and the Munster Study8 corroborated that fibrinogen levels were associated with CV events. In a review of the results of some of these epidemiologic studies, Ernst and Resch9 in 1993 concluded that high fibrinogen levels were an independent risk factor for CAD with a 2-3 fold increase in CV risk. In a more recent meta-analysis, Maresca et al10 further confirmed these results. They showed that the overall estimate of risk of a CV event in subjects with plasma fibrinogen levels in the higher tertile was twice as high as that of subjects in the lower tertile (odds ratio= 1.99, p <0.05).

Fibrinogen levels are positively associated with the "classic" risk factors for ischemic heart disease, such as advanced age, elevated LDL-C and triglycerides, low HDL-C, obesity, smoking, physical inactivity, family history of premature CAD and history of hypertension or diabetes, suggesting that it may be the mechanism by which these risk factors may exert their effect11. As an example, in the Framingham Study7, almost 50% of the CV risk attributable to smoking was mediated by an increase in fibrinogen levels. Data from the European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study (ECAT)12 showed that in patients with high cholesterol levels, the risk of coronary events and sudden death rose with increasing levels of fibrinogen and the risk was low when fibrinogen levels were low, independent of cholesterol values (Figure 1A). Other factors and medications affecting fibrinogen plasma levels are summarized in Table 1.


Figure 1 A and B. Incidence of coronary events during two years of follow-up according to concentrations of fibrinogen, C-reactive protein, and total cholesterol.

Panel A shows the risk of coronary events according to fibrinogen and total cholesterol concentrations. Panel B shows the risk according to fibrinogen and C-reactive protein concentrations combined, as compared with total cholesterol concentrations. The concentrations of these variables are divided into three categories (lower, middle and higher), each containing a third of the sample, according to their respective distributions. In panel B, "intermediate" refers to all combinations of fibrinogen and C-reactive protein concentrations other than lower-lower or higher-higher. The values used to divide the sample into thirds were 2.71 and 3.31 g per liter of fibrinogen, 5.79 and 6.80 mmol per liter (224 and 263 mg per deciliter) for cholesterol, and 0.88 and 2.17 mg per liter for C-reactive protein. The number of coronary events and the number of patients at risk are shown for each group. Only patients for whom data on both fibrinogen and total cholesterol concentrations were available are included in the analyses.

(Reproduced with permission from N Engl J Med 1995; 332: 635-41. Copyright(c) 1995 Massachusetts Medical Society. All rights reserved).

There are many mechanisms by which elevated fibrinogen levels may promote thrombosis and progression of atherosclerosis. Fibrinogen is the major determinant of blood viscosity and therefore, can affect the rheological properties of blood13. Fibrinogen also binds activated platelets via glycoprotein IIb-IIIa promoting platelet aggregation13. Elevated fibrinogen levels enhance fibrin formation and subsequent platelet-rich thrombi, which can stimulate both smooth muscle-cell proliferation and atherosclerotic plaque growth14. But, fibrinogen is also an acute phase-reactant and as such, its synthesis is increased during vascular injury. If elevated fibrinogen levels are cause or consequence of the vascular damage in these patients has not been fully elucidated. Fibrin (ogen) degradation products may also stimulate macrophages to produce interleukin-6, which in the liver increases fibrinogen synthesis11.

The association between fibrinogen and CV disease, even though, strong and biologically plausible, has failed to demonstrate to be causal. Despite this fact, fibrinogen has demonstrated to be useful in global CV risk assessment. In the ECAT study, fibrinogen alone and in association to CRP, another acute phase reactant and marker of increased CV risk, proved to enhance significantly the predicted value of high cholesterol levels (Figure 1B).

Several interventions have been demonstrated to reduce fibrinogen levels. General measures include smoking cessation and exercise11,15. Among drugs, fibrates have been proven to decrease fibrinogen levels15. Statins, however, have not consistently been shown to reduce fibrinogen levels16,17.

In summary, fibrinogen has proved to be a strong and independent predictor of CV events in patients with and without manifest vascular disease. Prospective studies demonstrating that the reduction of fibrinogen levels has a positive impact on clinical CV outcomes are warranted.

HOMOCYSTEINE

Homocysteine (Hcy) is a thiol (sulfhydryl) containing amino acid that plays an important role in methionine and folate metabolism. Homocysteine is metabolized by 2 pathways: when methionine stores are enough, Hcy enters the transsulfuration pathway and is converted to cysteine in a reaction catalyzed by vitamin B6-dependent-cystathionine ß-synthase. On the other hand, when methionine conservation is necessary, Hcy receives a methyl group from N5 methyl-tetrahydrofolate (catalyzed by the enzyme N5, N10 methylenetetrahydrofolate reductase) and is converted to methionine by methionine synthase (demethylation). The cofactor in this last reaction is vitamin B1218.

Elevated Hcy levels may be secondary to genetic and acquired abnormalities in the enzymes that participate in the metabolism of Hcy or deficiencies in folic acid, vitamin B6, or vitamin B12 (Table 2). Severe hyperhomocysteinemia is rare. However, mild hyperHcy can occur in approximately 5-7% of the general population and in 15-40% of patients with prevalent CVD19. The definition of elevated Hcy levels is not standardized and usually levels between 5-15 µmol/L are considered normal19.


Severe hyperhomocysteinemia was first reported to be related to atherosclerosis and vascular thrombosis in 1969 by McCully20. Since then, several cross sectional, case-control and prospective studies have suggested that even mild to moderate elevations of Hcy levels (>16 µmol/L) represent an independent risk factor for coronary, cerebral and peripheral atherosclerosis9,21-24. The British United Provident Association Study21 showed a very strong and graded association between Hcy quartiles and CV death during a follow up of 8.7 years. Comparing death rates for the subjects with Hcy values in the highest versus the lowest quartile gave a relative risk (RR) of 2.9 after adjustments. The Framingham's Elderly cohort22 reported a significant RR of 1.54 for all-cause death, independently of traditional risk factors. More recent epidemiologic data, however, have yielded to controversial results25-28. The positive relationship between Hcy and CVD or death was not found in 5 large prospective cohort studies. In the Multiple Risk Factor Intervention Trial (MRFIT), Evans et al27 (in 712 patients followed for 20 years) did not find a significant association between Hcy quartile (³15 versus £14.9 µmol/L) and the combined end point of fatal and non fatal CAD. These findings were corroborated by the results of the Caerphilly cohort29 in which the adjusted odds ratio for the top Hcy quintile versus the lower quintiles was 1.03 (p=0.8) after a long term follow up. Population heterogeneity, assays, duration of follow up and degree of adjustment for confounders have been proposed as possible explanations for the differences in the results.

Elevated Hcy levels are associated with traditional risk factors for CVD, such as elevated cholesterol levels and particularly smoking, hypertension and impaired renal function. Thus, adjustment for these factors are important to assure that Hcy has an independent relation to CVD.

The mechanism(s) by which elevated Hcy causes vascular damage is (are) still largely unknown30. Several in vitro and in vivo studies have suggested that elevated Hcy levels can impair endothelial function through the generation of potent reactive oxygen intermediates and impaired bioavailability of nitric oxide18. High Hcy may also induce smooth muscle cell proliferation and increase LDL oxidation. On the other hand, Hcy can also interfere with the fibrinolytic system through the modulation of annexin II, the endothelial receptor for tissue plasminogen activator31. Finally, it was recently demonstrated in Apo E deficient mice that elevated Hcy levels induce enhanced expression/activity of key participants in vascular inflammation and atherogenesis such as NF (kappa) B, TNF-alpha, advanced glycation end products, VCAM-1, tissue factor and matrix metalloproteinase-9. These effects were not seen when the mice were pre- treated with Hcy lowering vitamins32.

Treatment of hyperhomocysteinemia will depend on the underlying cause (Table 2). In general, folic acid is the preferred treatment. In patients with chronic renal failure higher doses of folic acid and B vitamins are needed18,19.

In conclusion, emerging evidence supports a positive, graded and biologically plausible association between Hcy levels and risk for CV disease. The results of ongoing large randomized trials with multivitamin therapy to reduce Hcy levels will clarify whether the decrease in Hcy levels associates with a reduction in risk for CVD.

C-REACTIVE PROTEIN

It is now well recognized that atherosclerosis is an inflammatory disease33. From the earliest atherosclerotic lesion, the fatty streak, to the ruptured plaque, inflammation plays a crucial role. For this reason, plenty of research has been done in order to identify inflammatory markers to better predict CV risk. Among these markers, C-reactive protein (CRP) has been the most studied.

C-reactive protein is an acute-phase protein produced in the liver by the influence of tumor necrosis factor alpha or interleukin-1 or 6 in response to an acute or chronic infection or injury34. Recently, a high sensitivity assay for CRP has been developed (hs-CRP). This assay has let to discriminate that CRP levels within the low normal range represent a low grade inflammation status. These low normal levels are not detected by traditional assays. However, there are some limitations in measuring hs-CRP. As an acute phase reactant, hs-CRP increases with acute infection or trauma. When this is the case, the recommendation is to wait 2-3 weeks until the acute infection is over to avoid misclassification of hs-CRP levels35. The same increase in hs-CRP is seen after an episode of acute ischemia, in which hs-CRP levels rise significantly35.

Several large prospective epidemiological studies have demonstrated that elevated hs-CRP plasma levels are strong and independent predictors of myocardial infarction (MI), stroke, peripheral arterial disease, and CV death in apparently healthy individuals. In patients with prevalent CAD, high hs-CRP levels are also associated with elevated vascular event rates. In the Physician's Health Study36, in 543 apparently healthy men who subsequently developed MI, stroke or venous thrombosis, hs-CRP levels were higher when compared to men without vascular events. Patients in the highest hs-CRP quartile (≥2.1 mg/L) had almost three times the risk of MI (RR=2.9, p<0.001) and two times the risk for stroke (RR=1.9, p=0.02) than the men in the lowest quartile (≤0.55 mg/L). These results were not altered after adjustment for other CV risk factors. In addition, in a study of 965 patients with acute coronary syndromes enrolled in the Fragmin during Instability in Coronary Artery Disease Study (FRISC)37, stratification by baseline hs-CRP levels (<2, 2-10, >10 mg/L) showed that there was a graded risk of mortality at 5 months with CRP. An updated meta-analyses38, including 14 prospective studies (11 population-based and 3 in patients with pre-existing CVD), found a RR for future CV events of 2 (95% CI= 1.6-2.5) in the general population and 1.5 (95% CI= 1.1-2.1) in patients with prevalent CVD when individuals in the top third of hs-CRP where compared to those in the bottom third (Figure 2). No heterogeneity among the studies was noted, giving consistency to the predictive value of hs-CRP among different groups of patients.


Figure 2. Prospective studies of C-reactive protein and coronary heart disease. Risk ratios compare top and bottom thirds of baseline measurements. Black squares indicate the risk ratio in each study, with the size of square proportional to number of cases. The combined risk ratio and its 95% confidence interval are indicated by unshaded diamonds for subtotals and shaded diamonds for total. All studies adjusted for age, sex, smoking, and some other standard vascular risk factors; the first 3 studies also adjusted for markers of socioeconomic status. (Reproduced from BMJ 2000; 321: 199-204 with permission from the BMJ Publishing Group).

C-reactive protein is positively associated with age, body mass index (BMI), smoking, history of diabetes and fibrinogen levels12,39. Current smokers for example, have hs-CRP levels that are twice as high as non smokers39. Also, increased hs-CRP levels are seen in post-menopausal women receiving hormone replacement therapy and obese people35.

The increasing interest in hs-CRP as a risk factor comes from studies that have demonstrated that CRP confers risk above that of an altered lipid profile. In a prospective study in women, Ridker et al40 showed that hs-CRP was the strongest predictor of CV risk (RR of 4.4 for highest vs lowest quartile) compared to lipoprotein (a), Hcy levels, total cholesterol and LDL-C levels and total cholesterol: HDL-C (TC:HDL-C) ratio. In the multivariate analysis, only hs-CRP levels and TC/HDL-C ratio proved to have and independent predictive value after adjustments for traditional risk factors. Further, it has been recently proposed that hs-CRP may have the potential to improve CV global risk-prediction strategies35. Thus, men with both hs-CRP and TC:HDL-C ratio in the highest quintile represent a very high-risk group for CV events (RR almost 9) compared to those with both parameters in the lowest quintiles35. But, hs-CRP could also have a predictive role among patients defined as low-risk by traditional global risk-assessment strategies. As an example, among women without any traditional risk factors present, and therefore, classified as low-risk for CV endpoints, hs-CRP has been demonstrated as the strongest predictor of future CV events41. Even more interesting have been the results of the recently published substudy of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)42. In this substudy, statin therapy was highly effective in reducing the CV risk in patients with elevated hs-CRP and relatively low lipid levels. However, there is no evidence yet to suggest that the reduction of hs-CRP plasma levels will translate in a reduction of CV events.

The mechanism by which CRP confers an elevated risk for CV disease has not been fully elucidated. Experimental studies suggest that CRP may contribute directly to vascular damage43. Ligand-bound CRP has the ability to activate the complement system and has been found in atherosclerotic vessels and infarcted myocardium43,44. CRP, also, both upregulates adhesion molecule expression on endothelial cells45 and stimulates tissue factor production by macrophages. Finally, recent experimental data has suggested that CRP can mediate LDL uptake by macrophages without biochemical modification of LDL46.

Data from clinical trials using acetyl salicylic acid47 and statin therapy48 have demonstrated that risk reductions in CV outcomes are greater in patients with elevated hs-CRP levels. Four different statins have been shown to be effective in reducing hs-CRP levels49,50. Interestingly, the hs-CRP-percent reduction achieved was similar among the different agents and independent of LDL-C levels.

In summary, hs-CRP represents an independent and modifiable marker of CV events. Among primary prevention subjects, hs-CRP could be a complementary risk marker for global risk assessment35.

LIPOPROTEIN (A)

Lipoprotein (a) (Lp (a) represents a class of lipoprotein particles similar to LDL. Like LDL, it has a cholesterol-phospholipid core and an associated protein Apo B100, but it differentiates from LDL by the presence of another protein, a glycoprotein called apo(a), which is attached to Apo B100 by a disulfide bridge. Apo(a) has structural similarity with plasminogen but it is catalytically inactive and therefore, it can not be cleaved by plasminogen activators51,52. Plasma concentrations of Lp(a) are mostly genetically determined. Elevated Lp(a) levels are the most common familial lipoprotein disorder in patients with premature CAD53. High Lp(a) levels are also seen in patients with renal insufficiency, nephrotic syndrome and kidney transplantation.

Currently, routine Lp(a) testing in the general population is not recommended, as there is no standardization of Lp(a) measurements available yet.

Lp(a) was first identified as a plasma antigen in 1963 by Berg54. Since then, several case-control and prospective studies have been published55. Most of these studies have shown that elevated Lp(a) (>20-40 mg/dL) is an independent risk factor for coronary and cerebrovascular disease51,56. In the Framingham Offspring Study57 for example, Lp(a) was associated with an increased CV risk of 1.9 (95% CI= 1.2-1.9) in both men and women. By contrast, in the Physician's Health Study58, no association was found between Lp(a) and the risk for MI. Similar results were reported by the Quebec Cardiovascular Study59, which showed that elevated Lp(a) was not an independent risk factor for CAD. Explanations for these contradictory results may include collection and storage of the samples and differences in Lp(a) assays51. However, a recent meta-analyses55, including 27 published prospective studies (18 population-based and 9 with pre-existing CAD) and involving 5436 cases with a mean follow up of 10 years, demonstrated a moderate and independent association of Lp(a) and CAD with a RR of 1.6 (p <0.00001) for the combined endpoint of death or non fatal MI for individuals in the top tertile compared to those in the bottom tertile.

The specific mechanism for the atherogenicity of Lp(a) has not been elucidated. The pathogenic role of Lp(a) can be mainly secondary to both its similarity to LDL (proatherogenic) and plasminogen (prothrombotic). Lp(a) is present in the arterial vessel wall of atherosclerotic lesions51,52. There, Lp(a) may undergo oxidative modification (as LDL) and thus, may contribute to foam cell formation. It has also been suggested that the atherogenicity of Lp(a) depends or at least it is enhanced by LDL, such as when LDL levels are low, high Lp(a) is no longer atherogenic. Lp(a) has been shown to interfere with the lysis of clots in vivo and in vitro experiments. Lp(a) competes with plasminogen for binding to cell surfaces in general, and to annexin II (endothelial cell plasminogen tissue plasminogen activator-tPA co-receptor) in particular. Another potential mechanism by which Lp(a) may affect fibrinolysis results from the upregulation of plasminogen-activator-inhibitor-1 and therefore, may impair plasminogen activation52. In addition, Lp(a) may promote atherogenesis through growth factor activity and vascular cell proliferation through its inhibitory action on transforming growth factor ß. Finally, Lp(a) may increase the adhesion of circulating monocytes to the endothelial cell surface and may stimulate monocyte chemotactic activity in endothelial cells51,52.

The most common recommendation for individuals with high Lp(a) levels is to first target LDL-C. Lowering of LDL-C reduces the atherogenic effect of Lp(a)51. Other treatments that primarily lower Lp(a) levels are estrogen therapy and nicotinic acid. Statins per se do not lower Lp(a) levels.

In conclusion, Lp(a) is an independent and moderately strong risk factor for atherosclerotic disease. Measurement of Lp(a) levels should be considered in patients with family history of premature CAD which is not explained by traditional risk factors. Pharmacologic therapy should be considered in these subjects.

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