Review
Novel Risk Factors for Atherosclerosis

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In the past several years, evidence has accumulated that factors other than conventional risk factors may contribute to the development of atherosclerosis. Conventional risk factors predict less than one half of future cardiovascular events. Furthermore, conventional risk factors may not have the same causal effect in different ethnic groups in whom novel risk factors may have a role. These newer risk factors for atherosclerosis include homocysteine, fibrinogen, impaired fibrinolysis, increased platelet reactivity, hypercoagulability, lipoprotein(a), small dense low-density lipoprotein cholesterol, and inflammatory-infectious markers. Identification of other markers associated with an increased risk of atherosclerotic vascular disease may allow better insight into the pathobiology of atherosclerosis and facilitate the development of preventive and therapeutic measures. In this review, we discuss the evidence associating these factors in the pathogenesis of atherosclerosis, the mechanism of risk, and the clinical implications of this knowledge.

Section snippets

Homocysteine

Considerable evidence has accumulated to implicate increased plasma homocysteine levels as a risk factor for atherosclerotic vascular disease.6 Homocysteine is a thiol-containing amino acid intermediate formed during the metabolism of methionine, an essential amino acid. In healthy persons, plasma homocysteine levels are between 5 and 15 μmol/L in the fasting state.7 Increased homocysteine plasma levels have been associated with aging,8 menopause,9 chronic renal insufficiency,10 low plasma

Fibrinogen

Several studies point to the importance of fibrinogen as a risk factor for atherosclerotic vascular disease. A meta-analysis of 6 prospective epidemiological studies confirmed the association of increased fibrinogen levels with subsequent MI or stroke.35 Persons with levels in the upper tertile had a relative risk of future cardiovascular disease that was 2.3 times higher than the risk in persons with levels in the lowest tertile. Of these 6 studies, only the Framingham Study included women36,

Impaired Fibrinolysis

The fibrinolytic system consists of plasminogen, which is converted to its active form plasmin by plasminogen activators, including tPA. A. Inhibitors of the system include plasminogen activator inhibitor type 1 (PAI-1) and plasmin inhibitors such as α2 -antiplasmin. In the Northwick Park Heart Study, fibrinolytic activity was measured by dilute blood clot lysis time at study entry in 1382 men, age 40 to 64 years, of whom 179 subsequently experienced episodes of CAD during a mean follow-up of

Platelet Reactivity

Platelet size, function, and number may be related to the risk of developing atherosclerotic cardiovascular events. Cross-sectional data from the Caerphilly Collaborative Heart Disease Study, in which platelet aggregation was measured in about 2000 men with no history of recent aspirin ingestion, demonstrated that patients with CAD had a significantly greater adenosine diphosphate-induced platelet aggregation compared with controls.67 Spontaneous platelet aggregation was a useful marker for

Hypercoagulability

An interesting feature of the hypercoagulable states is that they affect various vascular beds differently.80 Despite the predisposition to venous thrombosis, congenital deficiencies of antithrombin III, protein C, and protein are not associated with an increased incidence of arterial thrombosis or CAD.81 The factor V Leiden mutation is associated with venous thrombosis but not with atherosclerotic arterial disease, except perhaps in young women who smoke.82, 83 The prothrombin gene mutation

Lipoprotein(a)

Lipoprotein(a) refers to a family of lipoprotein particles similar to LDL in core lipid composition and in having apo B-100 as a surface apolipoprotein. In addition, Lp(a) possesses a unique glycoprotein, apo(a), which is bound to apo B-100.89 Lipoprotein(a) is associated with an increased risk of premature cardiovascular disease, but its physiological role remains obscure. Plasma levels vary widely among persons (about 1000-fold) but are stable within individuals, suggesting a strong heritable

Small Dense LDL

Low-density lipoprotein particles differ in size and density and have been divided into 2 distinct phenotypes: pattern B with a predominance of small dense LDL particles and pattern A with a higher proportion of large, more buoyant LDL particles.119 Small dense LDL particles tend to coexist with increased triglycerides and low HDL-C values, a combination that has been termed atherogenic dyslipidemia.119

Several retrospective studies have suggested that pattern B is associated with an increased

C-Reactive Protein

C-reactive protein, an acute phase reactant, is a marker for underlying systemic inflammation. Several studies have established an association between CRP and various manifestations of atherosclerosis. In a cross-sectional study, levels of CRP were associated with several other vascular risk factors, including smoking, hypertension, hypercholesterolemia, obesity, and diabetes.136 Levels of CRP were increased in chronic angina and in acute coronary syndromes.137 Increased CRP levels may predict

Infectious Agents

Recently, increasing interest has centered on the infectious theory of atherosclerosis. The hypothesis was initially proposed in the first 2 decades of the 20th century,150, 151 but it was not until the study by Fabricant et al152 in 1978, demonstrating development of atherosclerosis in chickens infected with the avian herpesvirus, that interest was rekindled. Subsequently, Chlamydia pneumoniae, Helicobacter pylori, Herpesvirus hominis, and cytomegalovirus have been implicated as primary

Conclusion

Atherosclerotic vascular disease is an exceedingly common disorder whose etiology is complex and multifactorial. Identifying new risk factors for atherosclerosis is important to enhance our understanding of its etiology, improve our ability to predict risk, and facilitate development of therapeutic and preventive approaches. Although pharmacological treatment is possible for several of the novel risk factors discussed in this article, prospective trial evidence to support such an approach is

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