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Biologic markers as predictors of cardiovascular disease
Biologic Markers as Predictors of Cardiovascular Disease William H. Frishman, MD, Valhalla, New York
Epidemiologic data obtained over the past 30 years suggest that a number of new biologic markers are associated with increased risk for cardiovascular disease. These include indices related to (1) altered glucose metabolism, particularly insulin resistance; (2) hyperlipidemia; (3) elevated levels of lipoprotein(a) and homocysteine; (4) increased levels of molecules reflecting decreased fibrinolysis and increased activation of the coagulation cascade; (5) elevations in cell adhesion molecules and other markers of endothelial function; and (6) elevations in molecules associated with infection, inflammation, and vascular remodeling. Changes in molecules associated with increased risk usually occur in clusters. This clustering suggests that effective treatment of one marker may have positive effects on multiple markers. Indeed, several studies have demonstrated that therapies designed to reduce hyperlipidemia may also lower the plasma levels of factors associated with increased coagulation and reduced fibrinolysis. Thus, careful assessment of patient risk factors, and the development of therapies directed toward chains of markers associated with increased risk, may significantly alter the course of cardiovascular disease. Am J Med. 1998;104(6A):18S–27S. © 1998 by Excerpta Medica, Inc.
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ardiovascular disease is a leading cause of morbidity and mortality in Western society.1 Largescale epidemiologic studies and reviews of the literature carried out over the last 30 years have identified a number of new risk factors for the development of cardiovascular disease.2–5 In fact, it has been suggested that as many as 250 factors may be associated with the development of coronary artery disease (CAD).6 A number of traditional risk factors for CAD, such as advanced age, male gender, obesity, diabetes, physical inactivity, elevated blood pressure, and smoking, can be identified during routine physical examination and medical history taking.4,7,8 Such a simple measurement as the ankle–arm ratio of systolic blood pressure is also a very good index of cardiovascular risk and mortality.9,10 However, other markers for increased cardiovascular risk can be detected only by careful laboratory evaluation. Of these, the best known is elevated serum lipids, particularly elevated low-density lipoprotein (LDL) cholesterol and triglycerides.4,11,12 Molecules whose relation to cardiovascular disease has been established more recently include those associated with abnormal coagulation and reduced fibrinolysis, with cardiovascular remodeling and/or inflammation, homocysteine, cell adhesion molecules, and markers of infection (Table 1). This article will (1) review the relations between biologic markers and increased cardiovascular risk; (2) discuss, where possible, the mechanisms by which specific marker molecules associated with increased risk promote vascular injury that may lead to cardiovascular events; and, finally, (3) review potential interventions that may decrease risk associated with these biologic markers.
SERUM LIPIDS AND CARDIOVASCULAR DISEASE
From the Department of Medicine, New York Medical College and Westchester Medical Center, Valhalla, New York. Requests for reprints should be addressed to William H. Frishman, MD, New York Medical College, Department of Medicine, Munger Pavilion, Valhalla, New York 10595. 18S © 1998 by Excerpta Medica, Inc. All rights reserved.
Total Cholesterol, Triglycerides, LDL, and High-Density Lipoprotein A large number of epidemiologic studies have documented the relation between elevated serum lipids (elevated total cholesterol, triglycerides, and LDL) and the development of cardiovascular disease.1,2,8,13,14 They have also established that lower levels of high-density lipoprotein (HDL) are associated with increased risk.1,14 The oxidative metabolism of LDL appears to be the final common pathway in the relation between hyperlipidemia and the development of atherosclerosis.15 When 0002-9343/98/$19.00 PII S0002-9343(98)00184-3
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Table 1. New Cardiovascular Risk Factors Apolipoprotein E Apolipoprotein C-III Lipoprotein(a) Plasminogen activator inhibitor (PAI) Tissue plasminogen activator (tPA) Factors VII and VIII von Willebrand’s factor Cell adhesion molecules Insulin resistance Homocysteine Infection (e.g., Chlamydia pneumoniae) Inflammation Serum ferritin Transforming growth factor b1 Vitamin D
LDL is oxidized by oxygen free radicals, macrophages become differentiated and migrate; this in turn phagocytizes the oxidized LDL (Figure 1). When macrophages become filled with oxidized LDL, they become the foam cells that are typically observed in early atherosclerotic lesions. Under continuing oxidative stress, the foam cells necrose and their toxic contents are released into the in-
timal space. This process stimulates an inflammatory response in which neutrophils and additional macrophages are recruited to the lesion site. This recruitment, along with both smooth muscle and neointimal proliferation, ultimately results in plaque formation.14 Local atherosclerotic plaque can make the affected coronary artery susceptible to abnormal vasoconstriction, which can lead to angina, plaque rupture, and acute coronary syndrome.14 Oxidized LDL is also involved in a number of other atherogenic processes, including activation of the coagulation cascade (Table 2). A variety of interventions have been employed to lower both LDL and oxidized LDL. Several large-scale studies have demonstrated the effectiveness of lowering LDL in both primary and secondary prevention programs. The Scandinavian Simvastatin Survival Study (4S) showed that the addition of the lipid-lowering agent simvastatin to a lipid-lowering diet in 4,444 patients with angina or previous myocardial infarction significantly reduced the risk of death, coronary death, and major coronary events over a median follow-up of 5.4 years.16 The Cholesterol and Recurrent Events (CARE) trial evaluated the effects of adding pravastatin to dietary therapy in 4,159 patients with a history of myocardial infarction, total cholesterol
Table 2. Involvement of Oxidized LDL in Atherosclerosis ● ● ● ● ● ● ● ●
Causes chemotaxis of monocytes Stimulates monocyte differentiation to macrophage Inhibits motility of macrophages at the site Produces cytotoxicity Stimulates macrophage uptake of LDL Induces immunogenicity (produces antibodies to oxidized LDL) Increases vasomotor tone Induces hypercoagulability
LDL 5 low-density lipoprotein Reprinted with permission from Mayo Clin Proc.14
Figure 1. Mechanisms by which the oxidation of low-density lipoprotein (LDL) may contribute to atherogenesis. (Reprinted with permission from N Engl J Med.15 q 1989 Massachusetts Medical Society.) June 22, 1998
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levels ,240 mg/dL, and LDL levels of 115–174 mg/dL.17 Such treatment significantly lowered the risk of fatal coronary events or nonfatal myocardial infarctions, the requirements for coronary bypass surgery and angioplasty, and the frequency of stroke. The best evidence supporting lipid-lowering therapy for primary prevention comes from the West of Scotland Study.18 This trial included 6,595 men with mean total cholesterol and LDL levels of 272 mg/dL and 190 mg/dL, respectively. Treatment with 40 mg/day of pravastatin resulted in significant decreases in nonfatal myocardial infarctions or death due to coronary artery disease. Therapy directed toward lowering LDL may also be important in reducing the activity of another molecule, cholesterol ester transfer protein (CETP). This molecule plays a key role in the transfer of cholesterol esters among different lipoproteins, and increased CETP is associated with lower levels of HDL cholesterol.19,20 Thus, high CETP activity is considered to promote atherosclerosis.20 Recent results have demonstrated that effective lipidlowering therapy can substantially reduce CETP activity.21 Agents that inhibit the oxidation of LDL may also be effective in reducing the risk of cardiovascular events. Antioxidants that may be relevant in preventing the development of atherosclerosis include vitamin E, carotene, vitamin C, flavonoids, and selenium. Vitamin E may be the most important antioxidant relative to atherosclerosis. Two large prospective studies that included .120,000 men and women reported a 40% decrease in CAD risk among individuals who consumed .200 IU of vitamin E daily.22,23 The size of LDL particles may also influence cardiovascular risk. Although there is not complete agreement, smaller LDL particles are thought to be associated with increased risk.24 –26 Importantly, therapy that effectively lowers LDL in patients with hyperlipidemia may not influence the size distribution for LDL particles. For example, Kontopoulos et al27 recently reported that simvastatin effectively lowered LDL in patients with familial hyperlipidemia but that it did not change LDL particle size. In contrast, ciprofibrate and the combination of ciprofibrate plus simvastatin did increase the size of LDL particles in patients with this condition. Apolipoprotein Phenotype Apolipoprotein E (apoE) phenotype is a major determinant of total cholesterol and LDL. ApoE appears in 3 major isoforms, E2, E3, and E4, which are coded by the corresponding alleles, «2, «3, and «4.28 The «4 allele appears to be correlated with the greatest risk for coronary artery disease. It is associated with significantly increased risk in women and in both sexes combined after adjustment for traditional risk factors and lipids.29 20S
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Table 3. Approaches to Lowering Lp(a) Levels Mode Diet HMG-CoA reductase inhibitors Resins Fibrates Neomycin Niacin Neomycin and niacin Estrogen replacement LDL apheresis
Effect 0 0 0 5–15%2 2 24%2 2 38%2 2 45%2 2 14–50%2 2 40–60%2 2
Anticoagulants (acetylsalicylic acid, others) and antioxidants (vitamins E, C, carotene) have been suggested either to prevent potential thrombogenic effect of high Lp(a) level or to decrease its oxidation (which makes it more atherogenic). LDL 5 low-density lipoprotein; Lp(a) 5 lipoprotein(a). Reprinted with permission from Can J Cardiol.40
ApoC-III is another major lipoprotein whose levels are positively correlated with cardiovascular disease.30,31 Effective lipid-lowering therapy with either a statin or gemfibrozil has been shown to result in substantial reductions in apoC-III in patients with hyperlipidemia.32–34 Lipoprotein(a) Lipoprotein a (Lp[a]) is now established as a significant and independent risk factor for the development of ischemic heart disease, CAD, and myocardial infarction.35–38 Lp(a) is similar to an LDL particle but is attached to apolipoprotein a (apo[a]). Apo(a) exhibits considerable genetically determined interindividual variation in size and is homologous to plasminogen.39 This homology has suggested a prothrombogenic role for Lp(a). It has been proposed that the strong association between elevated Lp(a) and the development of cardiovascular disease is due to the accumulation of apo(a) in the vascular wall and in atherosclerotic plaques and the potential inhibition of plasminogen and thus fibrinolysis by Lp(a).37 Small (#500 kiloDaltons [kDa]) isoforms of Lp(a) are effective inhibitors of plasminogen activation, while larger isoforms (.500 kDa) have little or no activity in this system.37 Thus, Lp(a) would appear to be an important link between 2 apparently distinct classes of risk factors for the development of cardiovascular disease: elevated serum lipids and reduced fibrinolytic activity. Treatment approaches that appear to effectively lower high Lp(a) levels include drug therapy with fibrates, neomycin, or niacin; estrogen replacement therapy; and LDL apheresis (Table 3).40,41 Duriez et al39 have reported that long-term fluvastatin therapy significantly reduces Lp(a) in hypercholesterolemic patients. Frohlich40 has suggested that the cardiovascular risk associated with Lp(a) can be significantly reduced by decreasing patients’ LDL to ,3 mmol/L.
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Figure 2. The binding of fibrinogen to its platelet integrin receptor aIIb b3 (glycoproteins IIb/IIIa complex), a key event in the linking of platelets and the formation of platelet thrombi. (Reprinted with permission from Thromb Haemost.46)
FACTORS ASSOCIATED WITH FIBRINOLYSIS AND COAGULATION Several biologic markers associated with decreased fibrinolysis and increased activation of the coagulation cascade have been associated with elevated cardiovascular risk. The best known of these markers is fibrinogen. However, abnormal levels of other molecules, such as Factors VII and VIII and von Willebrand’s factor (vWF), have also been linked to increased risk. Fibrinogen and the Fibrinolytic System Both cardiovascular risk and the severity of CAD are directly related to the level of plasma fibrinogen.42– 44 Cardiovascular risk factors such as smoking, elevated serum triglyceride levels, and decreased HDL:total cholesterol ratio are positively correlated with increased fibrinogen.43,45 It has been suggested that an increased level of plasma fibrinogen is a marker for cardiovascular disease because it reflects an inflamed condition of the vascular wall that may be associated with increased levels of other inflammatory cytokines, including interleukin (IL)-6 and
tumor necrosis factor a (TNFa).42 Fibrinogen contributes to platelet aggregation by binding to its platelet integrin receptor and may thus play a critical role in thrombus formation (Figure 2).46 Elevated fibrinogen levels also may contribute to cardiovascular risk by increasing blood viscosity.47 Plasma levels of fibrinogen can be decreased by lifestyle changes and smoking cessation.48 Recent studies have also shown that plasma fibrinogen levels can be significantly reduced by treatment with bezafibrate.49 Urokinase therapy can reduce plasma fibrinogen levels in patients with endstage CAD.50 Fibrinogen-stimulated platelet aggregation can be inhibited by new agents that block its glycoprotein (Gp)IIb/IIIa receptors on platelets. These include monoclonal antibodies, snake venom proteins, small peptides, and peptidomimetics.51 There is also evidence that increased levels of plasminogen activator inhibitor (PAI) and tissue plasminogen activator (tPA) antigen are associated with elevated cardiovascular risk.52,53 Both of these markers may be associated with reduced fibrinolysis and thus increased risk of thrombosis.53
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Figure 3. Proposed relation between insulin resistance and other risk factors for coronary heart disease. (Reprinted with permission from Physiol Rev.68)
Coagulation Factors Both Factor VII and activated Factor VII (Factor VIIa) have been associated with increased risk for cardiovascular disease.54,55 It has been suggested that elevated levels of Factor VIII and vWF may increase the risk for acute stroke.56 In the Atherosclerosis Risk in Communities (ARIC) study, fibrinogen, white blood cells, Factor VIII, and von Willebrand’s factor were significantly associated with increased risk of coronary artery disease.57 However, after adjustment for other risk factors, these hemostatic factors appeared to be of limited value in predicting risk in healthy adults. Oral anticoagulant therapy with low-dose warfarin and aspirin has been shown to produce a significant decrease in plasma levels of Factor VIIa, but there is a rebound to above-baseline concentrations of this coagulation factor after cessation of treatment.54
[ICAM-1], vascular cell adhesion molecule-1 [VCAM1]), and chemotactic factors.58 – 60 In atherogenesis, blood monocytes adhere to and migrate beneath the endothelium.61 The recent observation that elevated white blood cells may be associated with increased cardiovascular risk is consistent with this model.57 There may be a link between cigarette smoking and the expression of cell adhesion molecules. Shen and associates61 showed that a condensate of cigarette smoke induced the expression of several cell adhesion molecules by human umbilical vein endothelial cells. Elevated levels of cell adhesion molecules are also associated with hyperlipidemia, and aggressive lipid-lowering therapy appears to have only limited effects on their concentrations.62
Cell Adhesion Molecules Adhesion molecules and receptors play a key role in thrombosis, restenosis after percutaneous transluminal coronary angioplasty, atherosclerosis, and reperfusion injury.58 It is thought that these molecules mediate the interaction of circulating mononuclear leukocytes with the vascular endothelium, an early event in atherosclerosis. This interaction is initiated when cytokine-activated endothelial cells express cell adhesion molecules (e.g., Pselectin, E-selectin, intercellular adhesion molecule-1
Diabetes is a well-established risk factor for the development of cardiovascular disease.63,64 Both insulin resistance and the resultant hyperinsulinemia are associated with increased risk.65,66 Epidemiologic studies have clearly established elevated fasting serum insulin as an independent predictor of cardiovascular disease67; this hormone may cause hypertrophy of blood vessel walls, with narrowing of the lumen of resistance vessels.66 These changes may be a direct effect of insulin or insulininduced growth factors (IGF) such as IGF-1.66
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ALTERATIONS IN GLUCOSE METABOLISM
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Table 4. Factors Influencing Homocysteine Levels I. Genetics A. Transsulfuration abnormalities: diminished or absent cystathionine-beta-synthase activity (chromosome 21) B. Remethylation abnormalities 1. Abnormal methylenetetrahydrofolate reductase (absent or thermolabile variant) 2. Abnormal methionine synthase II. Age/gender A. Homocysteine increases with age B. Homocysteine levels: men . age-matched women C. Postmenopausal women: homocysteine levels increase III. Renal function: homocysteine increases with increased creatinine IV. Nutrition A. Vitamin B6 deficiency B. Vitamin B12 deficiency C. Folate deficiency V. Disease states A. Severe psoriasis, associated with increased homocysteine levels (possibly related to lower folate levels) B. Cancer, acute lymphoblastic leukemia, elevated levels C. Chronic renal failure, increased homocysteine, lowered with dialysis VI. Medications A. Increase homocysteine 1. Methotrexate, depletes 5-methyltetrahydrofolate 2. Azaribine, vitamin B6 antagonist 3. Nitrous oxide, inactivates vitamin B12 4. Phenytoin, interferes with folate metabolism 5. Carbamazepine, interferes with folate metabolism 6. Estrogen-containing oral contraceptives, induce vitamin B6 deficiency B. Decrease homocysteine: penicillamine, metabolically stable cysteine analogue Reprinted with permission from J Am Coll Cardiol.71 q 1996 American College of Cardiology.
The combination of insulin resistance and compensatory hyperinsulinemia predisposes patients to a number of other risk factors for cardiovascular disease, including glucose intolerance, increased plasma triglycerides, decreased HDL, small LDL particles, higher circulating levels of PAI, and increased blood pressure (Figure 3).68 There is, at present, no information on how treatment directed solely at lowering serum insulin may affect cardiovascular risk.
HOMOCYSTEINE Hyperhomocysteinemia is an independent risk factor for the development of atherosclerosis and is associated with a number of other cardiovascular risk factors, including
male gender, old age, smoking, high blood pressure, elevated cholesterol, and lack of exercise.69 –71 Homocysteine is formed during the metabolism of the essential amino acid methionine, and levels of this molecule can be influenced by alterations in concentrations of folate, vitamin B6, cobalamin, or the activities of various enzymes that participate in its remethylation or transsulfuration.71 The increased cardiovascular risk associated with elevated homocysteine levels may result from its direct cytotoxic effects on endothelial cells, its stimulation of increased platelet adhesion, and/or its promotion of procoagulant activity.71 A summary of factors influencing homocysteine levels is provided in Table 4. Plasma homocysteine levels can be reduced by administering folic acid, either alone or with vitamins B6 and B12.71 However, the routine use of vitamin B12 to treat patients with normal homocysteine levels may need to be reconsidered because of a recent observation that increased levels of this vitamin may be associated with elevated risk for mortality and cardiovascular disease.72,73
INFECTION AND INFLAMMATION Infection and inflammation are also more recently identified and thus perhaps less well-known risk factors for cardiovascular disease.74 Specific pathogens associated with increased risk include Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, and herpes class viruses.74 –77 The potential mechanisms whereby bacterial or viral infection might lead to vascular pathology arise from the inflammatory response to infection. Endotoxins released by bacteria are potent activators of inflammatory reactions. They stimulate monocytes and increase the secretion of cytokines such as IL-1 and TNF. Bacterial infection and endotoxin release are also associated with increased thrombocyte adherence, reduced levels of antithrombin III, and down-regulation of the fibrinolytic system.74 Endotoxin may also raise levels of thromboxane2, inhibit tissue plasminogen activation, decrease lipoprotein lipase activity, and damage endothelial cells.74 The metabolic consequences of infection, including altered glucose and lipid metabolism as well as electrolyte disturbances, may also contribute to increased cardiovascular risk.74 As noted above, inflammation may result in the increased expression of cell adhesion molecules by endothelial cells. It also has been suggested that high levels of another marker of endothelial cell injury, thrombomodulin, may be associated with increased cardiovascular risk.78 However, in a small-scale study, mean plasma thrombomodulin levels were similar in patients with and without electrocardiographic signs of ischemic heart disease.79
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FERRITIN, GROWTH FACTOR, AND VITAMIN D Increased serum ferritin has been associated with increased risk of myocardial infarction in Finnish men, and it has been suggested that this relation may be due to the fact that iron catalyzes the formation of oxygen free radicals.80,81 However, elevated levels of serum ferritin were not associated with risk of new coronary events in a prospective US study of men and women with and without CAD.82 A recent epidemiologic study has shown that transforming growth factor-b1 (TGF-b1), a multifunctional cytokine that plays an important role in tissue repair and regeneration after injury, is a significant and independent risk factor for cardiovascular disease.83 Most importantly, TGF-b1 appears to stimulate production of extracellular matrix, which may lead to tissue fibrosis.83 It is reasonable to suggest that elevation of TGF-b1 is not a primary event in the sequence of events leading to CAD, but rather that increased levels of this cytokine are part of the complex metabolic response to vascular damage. Another recent study has demonstrated that levels of 1,25-vitamin D are inversely correlated with vascular calcification in patients at moderate and high risk for coronary artery disease.84 This relation may provide an explanation for the long-observed positive relation between osteoporosis and vascular calcification. Cardiovascular remodeling associated with normal aging or inflammatory processes is characterized by increased arterial stiffness, a possible mechanism in the initiation and progression of atherosclerosis and hypertension.85,86 As might be expected, arterial stiffness has now been suggested as a risk factor for the development of cardiovascular disease. There is some evidence that lowsodium diets and regular endurance exercise training can reduce arterial stiffness in older patients.85
RELATIONS AMONG BIOLOGIC MARKERS ASSOCIATED WITH INCREASED CARDIOVASCULAR RISK Changes in the biologic markers associated with increased cardiovascular risk do not occur in isolation. Rather, epidemiologic studies have demonstrated strong positive correlations among the levels of these biologic markers. The clustering of abnormalities related to carbohydrate and lipid metabolism, and the association between serum lipids and markers of fibrinolysis, provide excellent examples of these relations. As noted above, there is strong evidence that insulin resistance and the resultant compensatory hyperinsulinemia predispose patients toward a cluster of abnormalities including glucose intolerance, increased plasma triglycerides, smaller LDL particles, and higher levels of PAI-1.68 This cluster of risk factors is referred to as syn24S
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drome X, and all of its manifestations have been shown to be associated with increased risk for cardiovascular disease.68 Several investigators have noted significant positive relations between elevated lipids and changes in markers of fibrinolysis and coagulation. Hyperlipidemia has been associated with increased Factor VII activity, elevated levels of PAI-1, and reduced fibrinolysis.87– 89 As noted earlier, Lp(a), which consists of an LDL particle linked to a plasminogen-like molecule and is a strong inhibitor of fibrinolysis, may provide a key link between lipid and fibrinolytic abnormalities in patients with cardiovascular disease.37 There also may be a relation between carbohydrate metabolism and homocysteine in patients with cardiovascular disease. Homocysteine levels are significantly increased in patients with noninsulin-dependent diabetes (NIDDM) and macrovascular disease compared with NIDDM patients without macroangiopathy.90,91 Plasma homocysteine levels may also be elevated in patients with NIDDM versus healthy controls regardless of the presence of macrovascular disease.91 Given the relation between insulin resistance, altered lipid metabolism, hyperlipidemia, and reduced fibrinolysis, it is tempting to suggest that many of the biomarkers associated with increased cardiovascular risk may be traced back to insulin resistance. Indeed, in their review of cardiovascular risk factors, O’Keefe et al14 suggested that insulin resistance may underlie many of the risk factors associated with cardiovascular disease. Further support for this view has been provided by Salomaa and associates,92 who demonstrated that impaired glucose metabolism may also be associated with arterial stiffness. Increased fasting plasma glucose levels were significantly correlated with arterial stiffness in both black and white patients and in men and women, regardless of the presence of diabetes. It has also been noted that as much as 70% of the interindividual variability in insulin resistance is nongenetically determined and associated with such variables as body weight, sedentary lifestyle, and elevated blood glucose.14,93
CONCLUSIONS A large number of biologic markers are associated with increased cardiovascular risk. Moreover, changes in levels of specific molecules associated with increased risk are likely to occur together. The clustering of risk factors suggests that effective treatment of one may have positive effects on others. In fact, this has proved to be the case. Several studies have demonstrated that therapies designed to reduce hyperlipidemia may also decrease plasma levels of Factor VII and PAI-1.1 Such results support the proposal that the careful assessment of patient risk factors, and the development of new therapies directed toward key elements in chains of biologic markers
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associated with increased risk, can significantly alter the course of cardiovascular disease. Further evaluation of older treatments such as N-3 fatty acids (fish oil), which may influence a large number of the biologic markers discussed in this review, is also warranted.72 The identification of new risk factors in ongoing largescale studies such as the Honolulu Heart Program, ARIC, the Framingham Heart Study, and the Strong Heart Study as well as the proposed Subclinical Cardiovascular Disease Study will offer even more opportunities for intervention.94 It will also be important to determine the degree to which one intervention and reduction in one factor influences levels of other risk-related biomarkers. This information will permit the design of simple and cost-effective treatment programs with the potential to normalize levels of multiple biomarkers associated with increased risk for CAD.
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Monitored Atherosclerosis Regression Study (MARS). Arterioscler Thromb. 1994;14:1906 –1913. Alaupovic P, Mack WJ, Knight-Gibson C, Hodis HN. The role of triglyceride-risk lipoprotein families in the progression of atherosclerotic lesions as determined by sequential coronary angiography from a controlled clinical trial. Arterioscler Thromb Vasc Biol. 1997;17:715–722. Yang CY, Gu ZQ, Xie YH. Effects of gemfibrozil on verylow-density lipoprotein composition and low-density lipoprotein size in patients with hypertriglyceridemia or combined hyperlipidemia. Atherosclerosis. 1996;126:105–116. Reguero JJR, Cubero GI, Celada MM, et al. Interrelationships between lipoprotein(a) and other cardiovascular risk factors. Cardiology. 1995;86:432– 435. Heinimann K, Stahelin HB, Perrig-Chiello P, et al. Lipoprotein(a) and plasma lipids in 429 elderly and very old subjects: significance as risk factor, effect of nutrition and life style. (Abstr.) Schweiz Med Wochenschr. 1996;126: 1487. Chapman MJ, Huby T, Nigon F, Thillet J. Lipoprotein(a): implication in atherothrombosis. Atherosclerosis. 1994;110: S69 –S75. Weber M, McNicoll S, Marcil M, et al. Metabolic factors clustering, lipoprotein cholesterol, apolipoprotein B, lipoprotein (a) and apolipoprotein E phenotypes in premature coronary artery disease in French Canadians. Can J Cardiol. 1997;13:253–260. Duriez P, Dallongeville J, Fruchart JC. Lipoprotein(a) as a marker for coronary heart disease. Br J Clin Prac. 1996; 77A:54 – 61. Frohlich JJ. Lipoproteins and homocyst(e)ine as risk factors for atherosclerosis: assessment and treatment. Can J Cardiol. 1995;11(suppl 11):18C–23C. Sirtori CR. New targets for lipid lowering and atherosclerosis prevention. Pharmacol Ther. 1995;67:433– 447. de Maat MPM, Pietersma A, Kofflard M, et al. Association of plasma fibrinogen levels with coronary artery disease, smoking and inflammatory markers. Atherosclerosis. 1996; 121:185–191. Wang XL, Wang J, McCredie RM, Wilcken DEL. Polymorphisms of factor V, factor VII, and fibrinogen genes. Relevance to severity of coronary artery disease. Arterioscler Thromb Vasc Biol. 1997;17:246 –251. Bolibar I, Kienast J, Thompson SG, et al. Relation of fibrinogen to presence and severity of coronary artery disease is independent of other coexisting heart disease. Am Heart J. 1993;125:1601–1605. Fogari R, Zoppi A, Marasi G, et al. Associations between plasma fibrinogen levels and cardiovascular risk factors in hypertensive men. J Cardiovasc Risk. 1994;1:341–345. Hawiger J. Mechanisms involved in platelet vessel wall interaction. Thromb Haemost. 1995;74:369 –372. Heinrich J, Assmann G. Fibrinogen and cardiovascular risk. J Cardiovasc Risk. 1995;2:197–205. Eber B, Schumacher M. Fibrinogen: its role in the hemostatic regulation in atherosclerosis. Semin Thromb Hemost. 1993;19:104 –107. de Faire U, Ericsson CG, Grip L, et al. Secondary preventive potential of lipid-lowering drugs. The Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT). Eur Heart J. 1996;17(suppl F):37– 42. Schoebel FC, Jax TW, Fischer Y, et al. Antithrombotic treatment in stable coronary syndromes: long-term intermittent urokinase therapy in end-stage coronary artery disease and refractory angina pectoris. Heart. 1997;77:13–17. June 22, 1998
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51. Coller BS, Anderson K, Weisman HF. New antiplatelet agents: platelet GPIIb/IIIa antagonists. Thromb Haemost. 1995;74:302–308. 52. Smith FB, Lee AJ, Rumley A, et al. Tissue-plasminogen activator, plasminogen activator inhibitor and risk of peripheral arterial disease. Atherosclerosis. 1995;115:35– 43. 53. Schleiffer T, Hellstern P, Freitag M, Brass H. Plasminogen activator inhibitor 1 activity and lipoprotein(a) in nephropathic patients with non-insulin-dependent diabetes mellitus versus patients with nondiabetic nephropathy. Haemostasis. 1994;24:49 –54. 54. Raskob GE, Durica SS, Morrissey JH, et al. Effect of treatment with low-dose warfarin-aspirin on activated factor VII. Blood. 1995;85:3034 –3039. 55. Kario K, Matsuo T, Miyata T. Activated factor VII as a new cardiovascular risk factor of atherothrombotic disease. Jap J Clin Pathol. 1995;43:1201–1208. 56. Catto AJ, Grant PJ. Risk factor for cerebrovascular disease and the role of coagulation and fibrinolysis. Blood Coagul Fibrinolysis. 1995;6:497–510. 57. Folsom AR, Qu KK, Rosamond WD, et al. Prospective study of hemostatic factors and incidence of coronary heart disease. The Atherosclerosis Risk in Communities (ARIC) study. Circulation. 1997;96:1102–1108. 58. Frishman WH, Weisen S, Lerro KA, et al. Innovative drug targets for treating cardiovascular disease: adhesion molecules, cytokines, neuropeptide Y, and bradykinin. In: Frishman WH, Sonnenblick EH, eds. Cardiovascular Pharmacotherapeutics. New York: The McGraw-Hill Companies, 1997:881–905. 59. Caulin-Glaser T, Watson CA, Pardi R, Bender JR. Effects of 17 beta-estradiol on cytokine-induced endothelial cell adhesion molecule expression. J Clin Invest. 1996;98:36 – 42. 60. Sluiter W, Pietersma A, Lamers JM, Koster JF. Leukocyte adhesion molecules on the vascular endothelium: their role in the pathogenesis of cardiovascular disease and the mechanisms underlying their expression. J Cardiovasc Pharmacol. 1993;22(suppl 4):S37–S44. 61. Shen Y, Rattan V, Sultana C, Kalra VK. Cigarette smoke condensate-induced adhesion molecule expression and transendothelial migration of monocytes. Am J Physiol. 1996;270:H1624 –H1633. 62. Hackman A, Yasunori A, Insull W Jr, et al. Levels of soluble cell adhesion molecules in patients with dyslipidemia. Circulation. 1996;93:1334 –1338. 63. Howard BV. Risk factors for cardiovascular disease in individuals with diabetes. The Strong Heart Study. Acta Diabetol. 1996;33:180 –184. 64. Ruiz J, Thillet J, Huby T, et al. Association of elevated lipoprotein(a) levels and coronary heart disease in NIDDM patients. Relationship with apolipoprotein(a) phenotypes. Diabetologia. 1994;37:585–591. 65. Stern MP. Perspectives in diabetes: diabetes and cardiovascular disease. The common soil hypothesis. Diabetes. 1995;44:369 –374. 66. Mediratta S, Fozailoff A, Frishman WH. Insulin resistance in systemic hypertension: pharmacotherapeutic implications. J Clin Pharmacol. 1995;35:943–956. 67. Dhawan J, Bray CL, Warburton R, et al. Insulin resistance, high prevalence of diabetes, and cardiovascular risk in immigrant Asians: genetic or environmental effect? Br Heart J. 1994;72:413– 421. 68. Reaven GM. Pathophysiology of insulin resistance in human disease. Physiol Rev. 1995;75:473– 486. 69. Tonstad S, Refsum H, Ueland PM. Association between
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plasma total homocysteine and parental history of cardiovascular disease in children with familial hypercholesterolemia. Circulation. 1997;96:1803–1808. Nygard O, Vollset SE, Refsum H, et al. Total plasma homocysteine and cardiovascular risk profile: the Hordaland Homocysteine Study. JAMA. 1995;274:1526 –1533. Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol. 1996;27:517– 527. Frishman WH, Fan SC, Boczko J, Husain J. Fish oils, the B vitamins, and folic acid as cardiovascular protective agents. In: Frishman WH, Sonnenblick EH, eds. Cardiovascular Pharmacotherapeutics. New York: The McGraw-Hill Companies, 1997:511–534. Zeitlin A, Frishman WH, Chang CJ. The association of vitamin B12 and folate blood levels with mortality and cardiovascular morbidity incidence in the old old: the Bronx Aging Study. Am J Ther. 1997;4:275–281. Nieminen MS, Mattila K, Valtonen V. Infection and inflammation as risk factors for myocardial infarction. Eur Heart J. 1993;14(suppl K):12–16. Ramirez JA, the Chlamydia pneumoniae/Atherosclerosis Study Group. Isolation of Chlamydia pneumoniae from the coronary artery of a patient with coronary atherosclerosis. Ann Intern Med. 1996;125:979 –982. Zhou YF, Leon MB, Waclawiw MA, et al. Association between prior cytomegalovirus infection and the risk of restenosis after coronary atherectomy. N Engl J Med. 1996;335: 624 – 630. Murray LJ, Bamford KB, O Reilly DPJ, et al. Helicobacter pylori infection: relation with cardiovascular risk factors, ischaemic heart disease, and social class. Br Heart J. 1995; 74:497–501. Gris JC, Granger B, Vecina F, et al. Increased cardiovascular risk factors and features of endothelial activation and dysfunction in dialyzed uremic patients. Kidney Int. 1994; 46:807– 813. Nilsson TK, Hellsten G, Amiral J. Plasma thrombomodulin concentrations in relation to cardiovascular risk factors in a population sample. Blood Coagul Fibrinolysis. 1993;4:455– 458. Salonen JT, Nyysso¨nen K, Korpela H, et al. High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation. 1992;86:803– 811. Sempos CT, Looker AC, Gillum RF. Iron and heart disease: the epidemiologic data. Nutr Rev. 1996;54:73– 84.
82. Aronow WS, Ahn C. Three-year follow-up shows no association of serum ferritin levels with incidence of new coronary events in 577 persons aged $62 years. Am J Cardiol. 1996;78:678 – 679. 83. Wang XL, Liu S-X, Wilcken DEL. Circulating transforming growth factor b1 and coronary artery disease. Cardiovasc Res. 1997;34:404 – 410. 84. Watson KE, Abrolat ML, Malone LL, et al. Active serum vitamin D levels are inversely correlated with coronary calcification. Circulation. 1997;96:1755–1760. 85. Hodes RJ, Lakatta EG, McNeil CT. Another modifiable risk factor for cardiovascular disease? Some evidence points to arterial stiffness. J Am Geriatr Soc. 1995;43:581–582. 86. Arnett DK, Evans GW, Riley WA. Arterial stiffness: a new cardiovascular risk factor? Am J Epidemiol. 1994;140:669 – 682. 87. Kario K, Matsuo T. High factor-VII activity in the elderly is related to vascular disease through activation of the coagulation system. J Cardiovasc Risk. 1994;1:165–171. 88. Daae LNW, Kierulf P, Landaas S, Urdal P. Cardiovascular risk factors: interactive effects of lipids, coagulation and fibrinolysis. Scand J Clin Lab Invest. 1993;215:19 –27. 89. Andersen P. Hypercoagulability and reduced fibrinolysis in hyperlipidemia: relationship to the metabolic cardiovascular syndrome. J Cardiovasc Pharmacol. 1992;20(suppl 8): S29 –S31. 90. Araki A, Sako Y, Ito H. Plasma homocysteine concentrations in Japanese patients with non-insulin-dependent diabetes mellitus: effect of parenteral methylcobalamin treatment. Atherosclerosis. 1993;103:149 –157. 91. Munshi MN, Stone A, Fink L, Fonseca V. Hyperhomocysteinemia following a methionine load in patients with noninsulin-dependent diabetes mellitus and macrovascular disease. Metabolism. 1996;45:133–135. 92. Salomaa V, Riley W, Kark JD, et al. Non-insulin-dependent diabetes mellitus and fasting glucose and insulin concentrations are associated with arterial stiffness indexes. The ARIC study. Circulation. 1995;91:1432–1443. 93. Austin MA, King M-C, Vranizan KM, Krauss RM. Atherogenic lipoprotein phenotype: a proposed genetic marker for coronary heart disease risk. Circulation. 1990;82:495–506. 94. Braunwald E. Shattuck lecture— cardiovascular medicine at the turn of the millennium: triumphs, concerns, and opportunities. N Engl J Med. 1997;337:1360 –1369.
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Epidemiologic data obtained over the past 30 years suggest that a number of new biologic markers are associated with increased risk for cardiovascular disease. These include indices related to (1) altered glucose metabolism, particularly insulin resistance; (2) hyperlipidemia; (3) elevated levels of lipoprotein(a) and homocysteine; (4) increased levels of molecules reflecting decreased fibrinolysis and increased activation of the coagulation cascade; (5) elevations in cell adhesion molecules and other markers of endothelial function; and (6) elevations in molecules associated with infection, inflammation, and vascular remodeling. Changes in molecules associated with increased risk usually occur in clusters. This clustering suggests that effective treatment of one marker may have positive effects on multiple markers. Indeed, several studies have demonstrated that therapies designed to reduce hyperlipidemia may also lower the plasma levels of factors associated with increased coagulation and reduced fibrinolysis. Thus, careful assessment of patient risk factors, and the development of therapies directed toward chains of markers associated with increased risk, may significantly alter the course of cardiovascular disease. Am J Med. 1998;104(6A):18S–27S. © 1998 by Excerpta Medica, Inc.
C
ardiovascular disease is a leading cause of morbidity and mortality in Western society.1 Largescale epidemiologic studies and reviews of the literature carried out over the last 30 years have identified a number of new risk factors for the development of cardiovascular disease.2–5 In fact, it has been suggested that as many as 250 factors may be associated with the development of coronary artery disease (CAD).6 A number of traditional risk factors for CAD, such as advanced age, male gender, obesity, diabetes, physical inactivity, elevated blood pressure, and smoking, can be identified during routine physical examination and medical history taking.4,7,8 Such a simple measurement as the ankle–arm ratio of systolic blood pressure is also a very good index of cardiovascular risk and mortality.9,10 However, other markers for increased cardiovascular risk can be detected only by careful laboratory evaluation. Of these, the best known is elevated serum lipids, particularly elevated low-density lipoprotein (LDL) cholesterol and triglycerides.4,11,12 Molecules whose relation to cardiovascular disease has been established more recently include those associated with abnormal coagulation and reduced fibrinolysis, with cardiovascular remodeling and/or inflammation, homocysteine, cell adhesion molecules, and markers of infection (Table 1). This article will (1) review the relations between biologic markers and increased cardiovascular risk; (2) discuss, where possible, the mechanisms by which specific marker molecules associated with increased risk promote vascular injury that may lead to cardiovascular events; and, finally, (3) review potential interventions that may decrease risk associated with these biologic markers.
SERUM LIPIDS AND CARDIOVASCULAR DISEASE
From the Department of Medicine, New York Medical College and Westchester Medical Center, Valhalla, New York. Requests for reprints should be addressed to William H. Frishman, MD, New York Medical College, Department of Medicine, Munger Pavilion, Valhalla, New York 10595. 18S © 1998 by Excerpta Medica, Inc. All rights reserved.
Total Cholesterol, Triglycerides, LDL, and High-Density Lipoprotein A large number of epidemiologic studies have documented the relation between elevated serum lipids (elevated total cholesterol, triglycerides, and LDL) and the development of cardiovascular disease.1,2,8,13,14 They have also established that lower levels of high-density lipoprotein (HDL) are associated with increased risk.1,14 The oxidative metabolism of LDL appears to be the final common pathway in the relation between hyperlipidemia and the development of atherosclerosis.15 When 0002-9343/98/$19.00 PII S0002-9343(98)00184-3
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Table 1. New Cardiovascular Risk Factors Apolipoprotein E Apolipoprotein C-III Lipoprotein(a) Plasminogen activator inhibitor (PAI) Tissue plasminogen activator (tPA) Factors VII and VIII von Willebrand’s factor Cell adhesion molecules Insulin resistance Homocysteine Infection (e.g., Chlamydia pneumoniae) Inflammation Serum ferritin Transforming growth factor b1 Vitamin D
LDL is oxidized by oxygen free radicals, macrophages become differentiated and migrate; this in turn phagocytizes the oxidized LDL (Figure 1). When macrophages become filled with oxidized LDL, they become the foam cells that are typically observed in early atherosclerotic lesions. Under continuing oxidative stress, the foam cells necrose and their toxic contents are released into the in-
timal space. This process stimulates an inflammatory response in which neutrophils and additional macrophages are recruited to the lesion site. This recruitment, along with both smooth muscle and neointimal proliferation, ultimately results in plaque formation.14 Local atherosclerotic plaque can make the affected coronary artery susceptible to abnormal vasoconstriction, which can lead to angina, plaque rupture, and acute coronary syndrome.14 Oxidized LDL is also involved in a number of other atherogenic processes, including activation of the coagulation cascade (Table 2). A variety of interventions have been employed to lower both LDL and oxidized LDL. Several large-scale studies have demonstrated the effectiveness of lowering LDL in both primary and secondary prevention programs. The Scandinavian Simvastatin Survival Study (4S) showed that the addition of the lipid-lowering agent simvastatin to a lipid-lowering diet in 4,444 patients with angina or previous myocardial infarction significantly reduced the risk of death, coronary death, and major coronary events over a median follow-up of 5.4 years.16 The Cholesterol and Recurrent Events (CARE) trial evaluated the effects of adding pravastatin to dietary therapy in 4,159 patients with a history of myocardial infarction, total cholesterol
Table 2. Involvement of Oxidized LDL in Atherosclerosis ● ● ● ● ● ● ● ●
Causes chemotaxis of monocytes Stimulates monocyte differentiation to macrophage Inhibits motility of macrophages at the site Produces cytotoxicity Stimulates macrophage uptake of LDL Induces immunogenicity (produces antibodies to oxidized LDL) Increases vasomotor tone Induces hypercoagulability
LDL 5 low-density lipoprotein Reprinted with permission from Mayo Clin Proc.14
Figure 1. Mechanisms by which the oxidation of low-density lipoprotein (LDL) may contribute to atherogenesis. (Reprinted with permission from N Engl J Med.15 q 1989 Massachusetts Medical Society.) June 22, 1998
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levels ,240 mg/dL, and LDL levels of 115–174 mg/dL.17 Such treatment significantly lowered the risk of fatal coronary events or nonfatal myocardial infarctions, the requirements for coronary bypass surgery and angioplasty, and the frequency of stroke. The best evidence supporting lipid-lowering therapy for primary prevention comes from the West of Scotland Study.18 This trial included 6,595 men with mean total cholesterol and LDL levels of 272 mg/dL and 190 mg/dL, respectively. Treatment with 40 mg/day of pravastatin resulted in significant decreases in nonfatal myocardial infarctions or death due to coronary artery disease. Therapy directed toward lowering LDL may also be important in reducing the activity of another molecule, cholesterol ester transfer protein (CETP). This molecule plays a key role in the transfer of cholesterol esters among different lipoproteins, and increased CETP is associated with lower levels of HDL cholesterol.19,20 Thus, high CETP activity is considered to promote atherosclerosis.20 Recent results have demonstrated that effective lipidlowering therapy can substantially reduce CETP activity.21 Agents that inhibit the oxidation of LDL may also be effective in reducing the risk of cardiovascular events. Antioxidants that may be relevant in preventing the development of atherosclerosis include vitamin E, carotene, vitamin C, flavonoids, and selenium. Vitamin E may be the most important antioxidant relative to atherosclerosis. Two large prospective studies that included .120,000 men and women reported a 40% decrease in CAD risk among individuals who consumed .200 IU of vitamin E daily.22,23 The size of LDL particles may also influence cardiovascular risk. Although there is not complete agreement, smaller LDL particles are thought to be associated with increased risk.24 –26 Importantly, therapy that effectively lowers LDL in patients with hyperlipidemia may not influence the size distribution for LDL particles. For example, Kontopoulos et al27 recently reported that simvastatin effectively lowered LDL in patients with familial hyperlipidemia but that it did not change LDL particle size. In contrast, ciprofibrate and the combination of ciprofibrate plus simvastatin did increase the size of LDL particles in patients with this condition. Apolipoprotein Phenotype Apolipoprotein E (apoE) phenotype is a major determinant of total cholesterol and LDL. ApoE appears in 3 major isoforms, E2, E3, and E4, which are coded by the corresponding alleles, «2, «3, and «4.28 The «4 allele appears to be correlated with the greatest risk for coronary artery disease. It is associated with significantly increased risk in women and in both sexes combined after adjustment for traditional risk factors and lipids.29 20S
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Table 3. Approaches to Lowering Lp(a) Levels Mode Diet HMG-CoA reductase inhibitors Resins Fibrates Neomycin Niacin Neomycin and niacin Estrogen replacement LDL apheresis
Effect 0 0 0 5–15%2 2 24%2 2 38%2 2 45%2 2 14–50%2 2 40–60%2 2
Anticoagulants (acetylsalicylic acid, others) and antioxidants (vitamins E, C, carotene) have been suggested either to prevent potential thrombogenic effect of high Lp(a) level or to decrease its oxidation (which makes it more atherogenic). LDL 5 low-density lipoprotein; Lp(a) 5 lipoprotein(a). Reprinted with permission from Can J Cardiol.40
ApoC-III is another major lipoprotein whose levels are positively correlated with cardiovascular disease.30,31 Effective lipid-lowering therapy with either a statin or gemfibrozil has been shown to result in substantial reductions in apoC-III in patients with hyperlipidemia.32–34 Lipoprotein(a) Lipoprotein a (Lp[a]) is now established as a significant and independent risk factor for the development of ischemic heart disease, CAD, and myocardial infarction.35–38 Lp(a) is similar to an LDL particle but is attached to apolipoprotein a (apo[a]). Apo(a) exhibits considerable genetically determined interindividual variation in size and is homologous to plasminogen.39 This homology has suggested a prothrombogenic role for Lp(a). It has been proposed that the strong association between elevated Lp(a) and the development of cardiovascular disease is due to the accumulation of apo(a) in the vascular wall and in atherosclerotic plaques and the potential inhibition of plasminogen and thus fibrinolysis by Lp(a).37 Small (#500 kiloDaltons [kDa]) isoforms of Lp(a) are effective inhibitors of plasminogen activation, while larger isoforms (.500 kDa) have little or no activity in this system.37 Thus, Lp(a) would appear to be an important link between 2 apparently distinct classes of risk factors for the development of cardiovascular disease: elevated serum lipids and reduced fibrinolytic activity. Treatment approaches that appear to effectively lower high Lp(a) levels include drug therapy with fibrates, neomycin, or niacin; estrogen replacement therapy; and LDL apheresis (Table 3).40,41 Duriez et al39 have reported that long-term fluvastatin therapy significantly reduces Lp(a) in hypercholesterolemic patients. Frohlich40 has suggested that the cardiovascular risk associated with Lp(a) can be significantly reduced by decreasing patients’ LDL to ,3 mmol/L.
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Figure 2. The binding of fibrinogen to its platelet integrin receptor aIIb b3 (glycoproteins IIb/IIIa complex), a key event in the linking of platelets and the formation of platelet thrombi. (Reprinted with permission from Thromb Haemost.46)
FACTORS ASSOCIATED WITH FIBRINOLYSIS AND COAGULATION Several biologic markers associated with decreased fibrinolysis and increased activation of the coagulation cascade have been associated with elevated cardiovascular risk. The best known of these markers is fibrinogen. However, abnormal levels of other molecules, such as Factors VII and VIII and von Willebrand’s factor (vWF), have also been linked to increased risk. Fibrinogen and the Fibrinolytic System Both cardiovascular risk and the severity of CAD are directly related to the level of plasma fibrinogen.42– 44 Cardiovascular risk factors such as smoking, elevated serum triglyceride levels, and decreased HDL:total cholesterol ratio are positively correlated with increased fibrinogen.43,45 It has been suggested that an increased level of plasma fibrinogen is a marker for cardiovascular disease because it reflects an inflamed condition of the vascular wall that may be associated with increased levels of other inflammatory cytokines, including interleukin (IL)-6 and
tumor necrosis factor a (TNFa).42 Fibrinogen contributes to platelet aggregation by binding to its platelet integrin receptor and may thus play a critical role in thrombus formation (Figure 2).46 Elevated fibrinogen levels also may contribute to cardiovascular risk by increasing blood viscosity.47 Plasma levels of fibrinogen can be decreased by lifestyle changes and smoking cessation.48 Recent studies have also shown that plasma fibrinogen levels can be significantly reduced by treatment with bezafibrate.49 Urokinase therapy can reduce plasma fibrinogen levels in patients with endstage CAD.50 Fibrinogen-stimulated platelet aggregation can be inhibited by new agents that block its glycoprotein (Gp)IIb/IIIa receptors on platelets. These include monoclonal antibodies, snake venom proteins, small peptides, and peptidomimetics.51 There is also evidence that increased levels of plasminogen activator inhibitor (PAI) and tissue plasminogen activator (tPA) antigen are associated with elevated cardiovascular risk.52,53 Both of these markers may be associated with reduced fibrinolysis and thus increased risk of thrombosis.53
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Figure 3. Proposed relation between insulin resistance and other risk factors for coronary heart disease. (Reprinted with permission from Physiol Rev.68)
Coagulation Factors Both Factor VII and activated Factor VII (Factor VIIa) have been associated with increased risk for cardiovascular disease.54,55 It has been suggested that elevated levels of Factor VIII and vWF may increase the risk for acute stroke.56 In the Atherosclerosis Risk in Communities (ARIC) study, fibrinogen, white blood cells, Factor VIII, and von Willebrand’s factor were significantly associated with increased risk of coronary artery disease.57 However, after adjustment for other risk factors, these hemostatic factors appeared to be of limited value in predicting risk in healthy adults. Oral anticoagulant therapy with low-dose warfarin and aspirin has been shown to produce a significant decrease in plasma levels of Factor VIIa, but there is a rebound to above-baseline concentrations of this coagulation factor after cessation of treatment.54
[ICAM-1], vascular cell adhesion molecule-1 [VCAM1]), and chemotactic factors.58 – 60 In atherogenesis, blood monocytes adhere to and migrate beneath the endothelium.61 The recent observation that elevated white blood cells may be associated with increased cardiovascular risk is consistent with this model.57 There may be a link between cigarette smoking and the expression of cell adhesion molecules. Shen and associates61 showed that a condensate of cigarette smoke induced the expression of several cell adhesion molecules by human umbilical vein endothelial cells. Elevated levels of cell adhesion molecules are also associated with hyperlipidemia, and aggressive lipid-lowering therapy appears to have only limited effects on their concentrations.62
Cell Adhesion Molecules Adhesion molecules and receptors play a key role in thrombosis, restenosis after percutaneous transluminal coronary angioplasty, atherosclerosis, and reperfusion injury.58 It is thought that these molecules mediate the interaction of circulating mononuclear leukocytes with the vascular endothelium, an early event in atherosclerosis. This interaction is initiated when cytokine-activated endothelial cells express cell adhesion molecules (e.g., Pselectin, E-selectin, intercellular adhesion molecule-1
Diabetes is a well-established risk factor for the development of cardiovascular disease.63,64 Both insulin resistance and the resultant hyperinsulinemia are associated with increased risk.65,66 Epidemiologic studies have clearly established elevated fasting serum insulin as an independent predictor of cardiovascular disease67; this hormone may cause hypertrophy of blood vessel walls, with narrowing of the lumen of resistance vessels.66 These changes may be a direct effect of insulin or insulininduced growth factors (IGF) such as IGF-1.66
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ALTERATIONS IN GLUCOSE METABOLISM
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Table 4. Factors Influencing Homocysteine Levels I. Genetics A. Transsulfuration abnormalities: diminished or absent cystathionine-beta-synthase activity (chromosome 21) B. Remethylation abnormalities 1. Abnormal methylenetetrahydrofolate reductase (absent or thermolabile variant) 2. Abnormal methionine synthase II. Age/gender A. Homocysteine increases with age B. Homocysteine levels: men . age-matched women C. Postmenopausal women: homocysteine levels increase III. Renal function: homocysteine increases with increased creatinine IV. Nutrition A. Vitamin B6 deficiency B. Vitamin B12 deficiency C. Folate deficiency V. Disease states A. Severe psoriasis, associated with increased homocysteine levels (possibly related to lower folate levels) B. Cancer, acute lymphoblastic leukemia, elevated levels C. Chronic renal failure, increased homocysteine, lowered with dialysis VI. Medications A. Increase homocysteine 1. Methotrexate, depletes 5-methyltetrahydrofolate 2. Azaribine, vitamin B6 antagonist 3. Nitrous oxide, inactivates vitamin B12 4. Phenytoin, interferes with folate metabolism 5. Carbamazepine, interferes with folate metabolism 6. Estrogen-containing oral contraceptives, induce vitamin B6 deficiency B. Decrease homocysteine: penicillamine, metabolically stable cysteine analogue Reprinted with permission from J Am Coll Cardiol.71 q 1996 American College of Cardiology.
The combination of insulin resistance and compensatory hyperinsulinemia predisposes patients to a number of other risk factors for cardiovascular disease, including glucose intolerance, increased plasma triglycerides, decreased HDL, small LDL particles, higher circulating levels of PAI, and increased blood pressure (Figure 3).68 There is, at present, no information on how treatment directed solely at lowering serum insulin may affect cardiovascular risk.
HOMOCYSTEINE Hyperhomocysteinemia is an independent risk factor for the development of atherosclerosis and is associated with a number of other cardiovascular risk factors, including
male gender, old age, smoking, high blood pressure, elevated cholesterol, and lack of exercise.69 –71 Homocysteine is formed during the metabolism of the essential amino acid methionine, and levels of this molecule can be influenced by alterations in concentrations of folate, vitamin B6, cobalamin, or the activities of various enzymes that participate in its remethylation or transsulfuration.71 The increased cardiovascular risk associated with elevated homocysteine levels may result from its direct cytotoxic effects on endothelial cells, its stimulation of increased platelet adhesion, and/or its promotion of procoagulant activity.71 A summary of factors influencing homocysteine levels is provided in Table 4. Plasma homocysteine levels can be reduced by administering folic acid, either alone or with vitamins B6 and B12.71 However, the routine use of vitamin B12 to treat patients with normal homocysteine levels may need to be reconsidered because of a recent observation that increased levels of this vitamin may be associated with elevated risk for mortality and cardiovascular disease.72,73
INFECTION AND INFLAMMATION Infection and inflammation are also more recently identified and thus perhaps less well-known risk factors for cardiovascular disease.74 Specific pathogens associated with increased risk include Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, and herpes class viruses.74 –77 The potential mechanisms whereby bacterial or viral infection might lead to vascular pathology arise from the inflammatory response to infection. Endotoxins released by bacteria are potent activators of inflammatory reactions. They stimulate monocytes and increase the secretion of cytokines such as IL-1 and TNF. Bacterial infection and endotoxin release are also associated with increased thrombocyte adherence, reduced levels of antithrombin III, and down-regulation of the fibrinolytic system.74 Endotoxin may also raise levels of thromboxane2, inhibit tissue plasminogen activation, decrease lipoprotein lipase activity, and damage endothelial cells.74 The metabolic consequences of infection, including altered glucose and lipid metabolism as well as electrolyte disturbances, may also contribute to increased cardiovascular risk.74 As noted above, inflammation may result in the increased expression of cell adhesion molecules by endothelial cells. It also has been suggested that high levels of another marker of endothelial cell injury, thrombomodulin, may be associated with increased cardiovascular risk.78 However, in a small-scale study, mean plasma thrombomodulin levels were similar in patients with and without electrocardiographic signs of ischemic heart disease.79
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FERRITIN, GROWTH FACTOR, AND VITAMIN D Increased serum ferritin has been associated with increased risk of myocardial infarction in Finnish men, and it has been suggested that this relation may be due to the fact that iron catalyzes the formation of oxygen free radicals.80,81 However, elevated levels of serum ferritin were not associated with risk of new coronary events in a prospective US study of men and women with and without CAD.82 A recent epidemiologic study has shown that transforming growth factor-b1 (TGF-b1), a multifunctional cytokine that plays an important role in tissue repair and regeneration after injury, is a significant and independent risk factor for cardiovascular disease.83 Most importantly, TGF-b1 appears to stimulate production of extracellular matrix, which may lead to tissue fibrosis.83 It is reasonable to suggest that elevation of TGF-b1 is not a primary event in the sequence of events leading to CAD, but rather that increased levels of this cytokine are part of the complex metabolic response to vascular damage. Another recent study has demonstrated that levels of 1,25-vitamin D are inversely correlated with vascular calcification in patients at moderate and high risk for coronary artery disease.84 This relation may provide an explanation for the long-observed positive relation between osteoporosis and vascular calcification. Cardiovascular remodeling associated with normal aging or inflammatory processes is characterized by increased arterial stiffness, a possible mechanism in the initiation and progression of atherosclerosis and hypertension.85,86 As might be expected, arterial stiffness has now been suggested as a risk factor for the development of cardiovascular disease. There is some evidence that lowsodium diets and regular endurance exercise training can reduce arterial stiffness in older patients.85
RELATIONS AMONG BIOLOGIC MARKERS ASSOCIATED WITH INCREASED CARDIOVASCULAR RISK Changes in the biologic markers associated with increased cardiovascular risk do not occur in isolation. Rather, epidemiologic studies have demonstrated strong positive correlations among the levels of these biologic markers. The clustering of abnormalities related to carbohydrate and lipid metabolism, and the association between serum lipids and markers of fibrinolysis, provide excellent examples of these relations. As noted above, there is strong evidence that insulin resistance and the resultant compensatory hyperinsulinemia predispose patients toward a cluster of abnormalities including glucose intolerance, increased plasma triglycerides, smaller LDL particles, and higher levels of PAI-1.68 This cluster of risk factors is referred to as syn24S
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drome X, and all of its manifestations have been shown to be associated with increased risk for cardiovascular disease.68 Several investigators have noted significant positive relations between elevated lipids and changes in markers of fibrinolysis and coagulation. Hyperlipidemia has been associated with increased Factor VII activity, elevated levels of PAI-1, and reduced fibrinolysis.87– 89 As noted earlier, Lp(a), which consists of an LDL particle linked to a plasminogen-like molecule and is a strong inhibitor of fibrinolysis, may provide a key link between lipid and fibrinolytic abnormalities in patients with cardiovascular disease.37 There also may be a relation between carbohydrate metabolism and homocysteine in patients with cardiovascular disease. Homocysteine levels are significantly increased in patients with noninsulin-dependent diabetes (NIDDM) and macrovascular disease compared with NIDDM patients without macroangiopathy.90,91 Plasma homocysteine levels may also be elevated in patients with NIDDM versus healthy controls regardless of the presence of macrovascular disease.91 Given the relation between insulin resistance, altered lipid metabolism, hyperlipidemia, and reduced fibrinolysis, it is tempting to suggest that many of the biomarkers associated with increased cardiovascular risk may be traced back to insulin resistance. Indeed, in their review of cardiovascular risk factors, O’Keefe et al14 suggested that insulin resistance may underlie many of the risk factors associated with cardiovascular disease. Further support for this view has been provided by Salomaa and associates,92 who demonstrated that impaired glucose metabolism may also be associated with arterial stiffness. Increased fasting plasma glucose levels were significantly correlated with arterial stiffness in both black and white patients and in men and women, regardless of the presence of diabetes. It has also been noted that as much as 70% of the interindividual variability in insulin resistance is nongenetically determined and associated with such variables as body weight, sedentary lifestyle, and elevated blood glucose.14,93
CONCLUSIONS A large number of biologic markers are associated with increased cardiovascular risk. Moreover, changes in levels of specific molecules associated with increased risk are likely to occur together. The clustering of risk factors suggests that effective treatment of one may have positive effects on others. In fact, this has proved to be the case. Several studies have demonstrated that therapies designed to reduce hyperlipidemia may also decrease plasma levels of Factor VII and PAI-1.1 Such results support the proposal that the careful assessment of patient risk factors, and the development of new therapies directed toward key elements in chains of biologic markers
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associated with increased risk, can significantly alter the course of cardiovascular disease. Further evaluation of older treatments such as N-3 fatty acids (fish oil), which may influence a large number of the biologic markers discussed in this review, is also warranted.72 The identification of new risk factors in ongoing largescale studies such as the Honolulu Heart Program, ARIC, the Framingham Heart Study, and the Strong Heart Study as well as the proposed Subclinical Cardiovascular Disease Study will offer even more opportunities for intervention.94 It will also be important to determine the degree to which one intervention and reduction in one factor influences levels of other risk-related biomarkers. This information will permit the design of simple and cost-effective treatment programs with the potential to normalize levels of multiple biomarkers associated with increased risk for CAD.
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