Nontraditional Cardiovascular Risk Factors

Nontraditional Cardiovascular Risk Factors SUZANNE OPARIL, MD;* ALBERT OBERMAN, MD, MPHt

ABSTRACT: A number of newer, "nontraditional" cardiovascular risk factors have been identified based on recent studies of the pathogenesis of atherosclerosis and atherothrombotic cardiovascular events. These include chronic inflammation and its markers, such as C-reactive protein; homocysteine; oxidative stress or endothelial dysfunction; lipoprotein Lp (a); psychosocial factors, such as environmental stress and responsiveness to stress; plasma insulin levels and markers of insulin resistance; and activation of the renin-angiotensin system, which is in part a function of polymorphisms in genes for components of the system, such as angiotensinogen and the angiotensin II type 1 receptor. The strength of the associations of the newer risk factors with cardiovascular therapy are currently being tested. This review will briefly discuss evidence that these risk factors are related to cardiovascular disease. KEY INDEXING TERMS: Cardiovascular risk factor; C-reactive protein; Homocysteine; Lipoprotein Lp (a); Stress; Insulin; Angiotensin; Oxidative stress. [Am J Med Sci 1999;317(3):193-207.]

P

opulation-based studies, such as the Framingham Heart Study, have given rise to the concept that specific factors, both genetic and environmental, modifiable and nonmodifiable, increase the risk of developing cardiovascular disease. 1 The 27th Bethesda Conference: Matching the Intensity of Risk Factor Management with the Hazard for Coronary Disease Events has classified proposed cardiovascular risk factors into four categories based on descending levels of evidence to support the efficacy

From the *Vascular Biology and Hypertension Program, Division of Cardiovascular Disease and tthe Division of Preventive Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama. Correspondence: Suzanne Oparil, M.D., The University of Alabama at Birmingham, Department of Medicine, Division of Cardiovascular Disease, Vascular Biology and Hypertension Program, 1038 Zeigler Research Building, 703 South 19th Street, Birmingham, AL 35294-0007 (E-mail: [email protected]). THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

of direct management in reducing cardiovascular disease morbidity and mortality (Table 1). Most attention in the literature has focused on the traditional risk factors in Category I and II (Table 2). These risk factors are strongly associated with cardiovascular morbidity and mortality and are amenable to lifestyle modification and/or pharmacologic therapy. Thrombogenic factors, including fibrinogen, are equally associated with cardiovascular events and mortality and are responsive to pharmacologic therapy. However, because measurement of these factors has not been standardized sufficiently to be clinically useful, and also because they are not known to be responsive to lifestyle modification, thrombogenic factors do not usually appear high on the list of traditional cardiovascular risk factors. Newer, "nontraditional" cardiovascular risk factors, such as those in category III, have been identified based on recent studies of the pathogenesis of atherosclerosis and atherothrombotic cardiovascular events. These include chronic inflammation and its markers, such as C-reactive protein; homocysteine; oxidative stress or endothelial dysfunction; lipoprotein Lp (a); psychosocial factors, such as environmental stress and responsiveness to stress; plasma insulin levels and markers of insulin resistance; and activation of the renin-angiotensin system, which is in part a function of polymorphisms in genes for components of the system, such as angiotensinogen and the angiotensin II, type 1 (AT l ) receptor. These newer risk factors are just beginning to be examined in populations, and the strength of their associations with cardiovascular events and responsiveness to lifestyle modification or pharmacologic therapy are currently being tested in observational and interventional studies. Definitive clinical trial evidence that intervening on these factors will prevent cardiovascular events does not yet exist. Gathering additional data on these nontraditional risk factors is of critical importance, because preliminary evidence suggests that they may be highly prevalent in high-risk populations. This review will briefly discuss evidence that these risk factors are related to cardiovascular disease. Chronic Inflammation

Inflammation clearly plays a role in the pathogenesis of chronic atherosclerotic disease and perhaps of 193

Nontraditional Cardiovascular Risk Factors

Table 1. Proposed Risk Factor Categories I. Risk factors for which interventions have been proved to reduce the incidence of coronary artery disease events. II. Risk factors fot which interventions are likely, based on our current pathophysiologic understanding and on epidemiologic and clinical trial evidence, to reduce the incidence of coronary artery disease events. III. Risk factors clearly associated with an increase in coronary artery disease risk, which, if modified, might lower the incidence of coronary artery disease events. IV. Risk factors associated with increased risk but that cannot be modified or whose modification would be unlikely to change the incidence of coronary disease events.

Reprinted from the 27th Bethesda Conference. Matching the Intensity of Risk Factor Management with the Hazard for Coronary Disease Events. 1995 Sep 14-15. JAm Coll Cardiol1996;27:9571047. Copyright © 1996 Elsevier Science.

acute atherothrombotic events as well.2-5 The efficacy of therapy with aspirin, which has antiinflammatory as well as antiplatelet properties, in reducing cardiovascular events provides indirect support for this hypothesis. Plasma levels of C-reactive protein, which is an acute phase reactant synthesized by the liver and a marker for systemic inflammation, are elevated in patients with acute myocardial infarction (MI)6,7 or acute ischemia. s C-reactive protein is also predictive of recurrent ischemia in patients hospitalized for unstable angina, 7 of MI in patients with angina, 9 and of fatal coronary disease in men with multiple risk factors, including smoking. lO The lability of plasma C-reactive protein measurements (they, as well as other acute phase reactants increase after acute ischemias and during/ immediately after cigarette smokinglO,ll ) has traditionally been thought to limit their usefulness as predictors of subsequent cardiovascular disease and/or events in high-risk subjects. A recent report from the Physicians' Health Study tested the hypotheses that inflammation increases and aspirin treatment decreases the risk of a first thrombotic event. 4 The investigators measured plasma C-reactive protein as a marker for systemic inflammation in 543 apparently healthy men in whom MI, stroke, or venous thrombosis subsequently developed, lind in 543 study participants who did not report vascular disease during a follow-up period of> 8 years. Subjects were randomly assigned to receive aspirin or placebo at the beginning of the trial. Baseline plasma C-reactive protein concentrations were higher among men who went on to have MI or ischemic stroke, but not venous thrombosis, than among men without vascular events (Table 3). The men in the quartile with the highest C-reactive protein values had three times the risk of MI and two times the risk of ischemic stroke of the men in the lowest quartile (Figure 1). Risks were stable over

194

long periods, were not modified by smoking, and were independent of other risk factors, including diabetes, family history of premature coronary artery disease, smoking status, body mass index, blood pressure, plasma lipids [total or high-density lipoprotein (HDL) cholesterol, triglycerides, lipoprotein (a)], t-PA antigen, D-dimer, fibrinogen, or homocysteine. The increased risk related to elevations in C-reactive protein levels was stable over the 8-year follow-up period and was observed among nonsmokers, providing evidence that the effect of C-reactive protein on vascular risk is not simply the result of cigarette smoking. Aspirin use was associated with significant reductions in the risk of MI among men in the highest quartile but with only small, nonsignificant reductions among these in the lowest quartile (Figure 1), perhaps reflecting the anti-inflammatory properties of aspirin. Thus, plasma concentrations of C-reactive protein in apparently healthy men predict the risk of future MI and stroke, but not of venous thromboembolism, which suggests that the relationship of inflammation to vascular risk may be limited to the arterial circulation. The reduction in risk of a first MI associated with the use of aspirin seems to be directly related to the level of C-reactive protein, which raises the possibility that anti-inflammatory agents may have clinical benefits in preventing cardiovascular disease. As pointed out by Ridker et aI, these findings indicate that C-reactive protein is a long-term marker of risk for cardiovascular events occurring years after the index observation, which suggests that the cardiovascular effects of inflammation are likely mediated through a chronic process and excludes the possibility that undetected acute illness at baseline was responsible for the increased cardiovascular risk observed in participants with elevated baseline C-reactive protein levels. Further, the observation that the benefits of aspirin are dependent on the presence of inflammation, as assessed by the plasma concentration of C-reactive protein, suggests the hypothesis that C-reactive protein and other markers of inflammation may be useful in identifying persons most likely to benefit from use of aspirin (and possibly other antiinflammatory agents) in the prevention of cardiovascular disease. A subsequent report from the same cohort showed that among apparently healthy male physicians, elevated baseline levels of C-reactive protein predict future risk of developing symptomatic peripheral arterial disease. 12 The highest levels of C-reactive protein were found among study participants who required surgical revascularization in addition to developing intermittent claudication. These data provide further evidence that C-reactive protein may serve as a molecular marker for atherosclerosis outside the coronary and cerebral vascular beds and March 1999 Volume 317 Number 3

Oparil and Oberman

Table 2. Cardiovascular Risk Factors: The Evidence Supporting Their Association with Disease, the Usefulness of Measuring Them and Their Responsiveness to Intervention Response to Evidence for Association with CVD Risk Factor

Epidemiologic

Clinical Trials

Clinical Measurement Useful?

Category I (risk factors for which interventions have been proved to lower CVD risk) Cigarette smoking +++ ++ +++ LDL cholesterol +++ +++ +++ High fat/cholesterol diet +++ ++ ++ Hypertension +++ +++ +++ (stroke) Left ventricular + +++ ++ hypertrophy Thrombogenic factors + +++ +++ (fibrinogen) (aspirin, (fibrinogen) warfarin) Category II (risk factors for which interventions are likely to lower CVD risk) Diabetes mellitus +++ + +++ Physical inactivity +++ ++ ++ HDL cholesterol +++ + +++ Triglycerides; small, ++ ++ +++ dense LDL +++ +++ Obesity Post-menopausal status +++ +++ (women) Category III (risk factors associated with increased CVD risk that, if modified, might lower risk) ++ + +++ Psychosocial factors Lipoprotein(a) + + Homocysteine ++ + Oxidative stress + No alcohol consumption +++ ++

Nonpharmacologic Therapy

+++ ++ ++ +

Pharmacologic Therapy

++ +++ +++ ++

+

+++ (aspirin, warfarin)

++ ++ ++ ++

+++

++

+ +++

+ ++ + ++

+ +++

+ ++ ++

Category IV (risk factors associated with increased CVD risk, but which cannot be modified) Age +++ +++ Male sex +++ +++ Low socioeconomic +++ +++ status Family history of early+++ +++ onset CVD

CVD, cardiovascular disease; +, weak, somewhat consistent evidence; + +, moderately strong, rather consistent evidence; + + +, very strong, consistent evidence; -, evidence poor or nonexistent. Reprinted from the 27th Bethesda Conference. Matching the Intensity of Risk Factor Management with the Hazard for Coronary Disease Events. 1995 Sep 14-15. JAm CoIl Cardiol1996;27:957-1047. Copyright © 1996 Elsevier Science.

that higher levels of C-reactive protein correlate with more extensive disease. Mechanisms that have been suggested to relate levels of C-reactive protein to atherosclerosis and atherothrombotic events include chronic infections of the arterial wall, chronic systemic infections, overexpression . of cytokines and chemoattractant factors in the vasculature, and bronchial inflammation caused by smoking (Figure 2). C-reactive protein may have procoagulant effects related to its ability to enhance expression of tissue factor. It has been localized in blood vessel walls, binds to neutrophils, and can activate complement. Importantly, C-reactive protein and peptides derived from it may be involved in processes related to shedding of some THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

cellular adhesion molecules, which may facilitate in the adhesion and transmigration of leukocytes across the endothelial wall, an early event in the pathogenesis of atherosclerosis.1 2 ,13 The role of cellular adhesion molecules as potential cardiovascular risk factors will be discussed in the context of endothelial dysfunction. Coronary heart disease has been associated with a variety of gram-negative bacterial infections leg, Helicobacter pylori and Chlamydia pneumoniael; herpesvirus infections, particularly cytomegalovirus (CMV); and with clinical markers of chronic dental infection, including severe periodontal disease and missing teeth. 5 ,14 The epidemiological (generally based on antibody measurements in populations) 195

Nontraditional Cardiovascular Risk Factors

Table 3. Base-line Plasma Concentrations of C-Reactive Protein in Study Participants Who Remained Free of Vascular Disease during Follow-up (Control Subjects) and Those in Whom Myocardial Infarction, Stroke, or Venous Thrombosis Developed (Patients) Plasma C-Reactive Protein Cardiovascular Disease during Follow-up

None (n = 543) Any vascular event (n = 543) Myocardial infarction (n = 246) Any stroke (n = 196) Ischemic stroke (n = 154) Venous thrombosis (n = 101)

Geometric Mean

P-Value

mglL 1.10

Median

~

mg/L 1.13

1.37

<0.001

1.40

<0.001

1.48

<0.001

1.51

<0.001

1.30

0.03

1.36

0.03

1.36

0.01

1.38

0.02

1.24

0.22

1.26

0.34

and clinical (based on detection of bacteria or viruses in atheromas or blood vessels) evidence for associations between infections with H. pylori, C. pneu-

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Quartile of Plasma C-Reactive Protein Figure 1. Relative risk of a first myocardial infarction associated with base-line plasma concentrations of C-reactive protein, stratified according to randomized assignment to aspirin or placebo therapy. Analyses are limited to events occurring before the unblinding of the aspirin component of the Physicians' Health Study. The reduction in the risk of myocardial infarction associated with the use of aspirin was 13.9% in the first (lowest) quartile of C-reactive protein values, 33.4% in the second quartile, 46.3% in the third quartile, and 55.7% in the fourth (highest) quartile. (Reprinted with permission from Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973-9. Copyright © 1997 the Massachusetts Medical Society. All rights reserved.)

196

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/ AtherOgenVess Plaque rupture ~Is

Autoimmunity / Hsp60 cross-reactivity with bacterial antigens

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Classic risk factors HDL cholesterol t Rbrinogen t Triglycerides

Systemic Inflammation t C-reactive protein t Leucocyte count t Cytokines Figure 2. Postulated mechanisms to link infections and vascular disease. Hsp, heat-shock protein. (Reprinted with permission from Danesh J, Collins R, and Peto R. Chronic infections and coronary heart disease: is there a link? Lancet 1997;350:430-6. Copyright © 1997 The Lancet Ltd.)

moniae, and cytomegalovirus and coronary heart disease has recently been reviewed. 5 A variety of mechanisms that act either acutely, thus precipitating plaque rupture, or chronically, promoting plaque growth, have been proposed to link chronic infections with coronary heart disease (Figure 2).5 These include direct effects of infectious agents on the arterial wall, causing endothelial injury, smooth muscle cell proliferation, and local inflammation, as well as indirect effects of chronic inflammation, including toxic effects of cross-reactive antibodies and effects on cardiovascular risk factors, such as lipids, clotting factors, oxidative metabolites, and homocysteine. 5 H. pylori

(j) CI:

(

P-Value

(Reprinted with permission from Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973-9. Copyright © 1997 the Massachusetts Medical Society. All rights reserved.)

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Infection of arterial wall Smooth-muscle proliferation associated with p53 inactivation Local inflammation

More than 20 epidemiologic studies, all of which included fewer than 100 cases and 100 controls, have reported on the association between H. pylori antibody titers and either coronary heart disease or stroke. These studies are limited by small size and, in most cases, by a failure to adjust for a number of confounding factors that are strongly associated with both H. pylori infection and coronary heart disease, including low socioeconomic status. Thus, there is a need for large prospective studies that can both reduce selection bias and assess infection before the onset of clinical disease. Pathological evidence relating H. pylori to atherosclerotic vascular disease is relatively weak. The only study published as yet (others are in progress) in which H. pylori DNA was sought in atheroscleMarch 1999 Volume 317 Number 3

Oparil and Oberman

rotic arteries did not find ip5 Evidence linking seropositivity for H. pylori with markers of inflamm ation, such as C-reactive protein and fibrinogen, that have themselves been associated with vascular disease, is inconsistent and inconclusive.1 6 Similarly, associations between H. pylori and traditional cardiovascular risk factors have been weak (triglycerides and HDL) or nonexistent. 5,17 A mechanism that has been hypothesized to relate H. pylori to vascular disease is an autoimmune response to endogenous heat-shock protein 60, an endothelial antigen that is also expressed by H. pylori. ls C. pneumoniae

Epidemiologic case studies have consistently found two-fold or higher odds ratios for developing coronary heart disease or stroke in individuals with antibodies to C.pneumoniae. 5 These studies, limited by inconsistencies in methods of measuring antibody levels, failure to adjust for known confounders, and a lack of understanding of risk factors for C. pneumoniae infection, point to a need for large prospective studies using more rigorously standardized methods. Mechanistic evidence relating C. pneumoniae, a common respiratory pathogen, to atherosclerotic vascular disease is strong. 19 C. pneumoniae can infect and reproduce in human smooth muscle cells, coronary artery endothelial cells, and macrophages,5,2o whereas inoculation of C. pneumoniae into transgenic mice and rabbits can induce vascular lesions that resemble early atherosclerosis. 5,21 C. pneumoniae DNA, antigen and/or elementary bodies have been identified in a high percentage (~ 50%) of atheromatous lesions, but in only 5% of control samples of human arterial tissue in 13 published studies summarized by Danesh et al. 5 Viable C. pneumoniae organisms have been cultured from coronary artery specimens of heart transplant recipients 22 and carotid endarterectomy specimens 23 but not from normal vascular tissue. The presence of C. pneumoniae in the atherosclerotic vessels was not correlated with serum antibody titers. These findings suggest that local infection with C. pneumoniae may playa role in the pathogenesis of atherosclerosis. Two small trials of antibiotic therapy have been carried out to test the clinical significance of C. pneumoniae infection in the natural history of patients with ischemic heart disease. 24 ,25 Short-term treatment with oral azithromycin in seropositive male survivors of acute MI resulted in a four-fold reduction in risk of cardiovascular events at 18 months of follow-up.24 Azithromycin-treated patients were also more likely to manifest decreases in antibody titers than placebo-treated patients. The Randomized Trial of Roxithromycin in Non-Q-Wave Coronary Syndromes (ROXIS) pilot study produced similar findings: roxithromycin treatment of paTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

tients with unstable angina or non-Q-wave myocardial infarction was associated with a statistically significant reduction in the primary composite triple endpoint rates (ischemic cardiac death, MI, and severe recurrent ischemia) at 6 months of follow-up. 25 These provocative findings hold promise of an effective and efficient new modality for the secondary prevention of coronary heart disease, but raise many questions. Whether the beneficial effects of the antibiotics used in these studies were related to eradication or suppression of infection in the coronary arteries, thus stabilizing active plaques by reducing inflammation and the tendency to hypercoagulation, remains to be determined, as does the generalizability of these results. Another critical issue raised by these studies is the relationship between serum antibody levels, direct infection of the atherosclerotic plaque by C. pneumoniae and risk of adverse cardiovascular events. Further data from large-scale clinical trials are needed to identify reliable markers for C. pneumoniae infection of blood vessels, to define the role of C. pneumoniae in vascular damage, and, most importantly, to determine the efficacy of antibiotic treatment in preventing cardiovascular events and the progression of atherosclerotic disease. CMV and Other Herpesviruses

Epidemiologic studies have reported two-fold or higher odds ratios for developing cardiovascular disease in people with antibodies to CMV.5 These studies are subject to the limitations previously described for epidemiologic associations between other infectious agents and atherosclerotic disease. Moreover, the majority of cases examined in these studies involved atypical forms of vascular disease, such as transplant stenosis, postatherectomy restenosis, and extracoronary lesions, which may differ in their pathogenesis from native coronary-artery atherosclerosis. Mechanistic evidence linking CMV and other herpesviruses with vascular pathology is provocative, but weaker than that for C. pneumoniae. There is little evidence that CMV antibody titers are related to classic cardiovascular risk factors or plasma markers of inflammation, and CMV has not been detected in atheromatous lesions more frequently than in control vessels, although use of sensitive techniques such as polymerase chain reaction has increased the yield in atheromatous disease. 5 However, herpesviruses can alter cholesterol metabolism in smooth muscle cells, activate coagulation factors, and elicit the expression of cytokines, chemokines, and cellular adhesion molecules in the vessel wall, processes that can accelerate atherosclerosis and/or trigger cardiovascular events. CMVinfected rats develop a more robust neointimal response to vascular injury than noninfected animals, which supports the functional significance of these in vitro mechanisms. 26 Further, herpesviruses can 197

Nontraditional Cardiovascular Risk Factors

Methyl acceptors Phosphotidylethanolamine Guanidinoacetate Neurotransmitters (dopamine etc) Proteins (myelin etc) DNA RNA

Methylated acceptors

Polyamines

I

S-AdenosylATP methionine ~ Glycine 3 Proteins (MetIJyITHF Inhibition) /' Sarcosine

Jdf

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Phosphatidylcholine S-A.denosylCreatine Homocysteine Methylated neurotransmitters ~ Methylated proteins ~ 6 Methylated DNA 4 Betaine Methylated RNA Homocysteine Serine ~

PLP

r

THF

2

MethylTHF

19

a-I
The occurrence of arterial lesions in people with elevated circulating homocysteine levels was first noted in 1969 by McCulley.28 He described progressive arterial disease, often resulting in death from thrombosis in a vital organ, in children with homocystinuria, a rare inborn error of metabolism with an autosomal recessive mode of inheritance related to a deficiency in cystathionine /3-synthase (Figure 3). The vascular damage in these patients is thought to be a direct toxic effect of extremely elevated (>200 ILmollL, compared with normal values of 4-17 ILmollL) circulating levels of homocysteine on the endothelium, platelets, and the coagulation cascade. Homocysteine also potentiates the auto-oxidation of low-density lipoprotein (LDL) cholesterol, interferes with nitric oxide-mediated vascular relaxation, and stimulates smooth muscle cell proliferation and 198

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:d FAD 1

B6

Taurlne- -

8

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Fot 8 ,2 , ate Methylene THF

Cystathionine

PLP

*;

{~serine

Methionine

Figure 3. Homocysteine metabolism. Enzyme reactions that are regulated by vitamin Bs and 5-methyltetrahydrofolate (MethTHF) are indicated by large arrows. Enzymes: (1) 5,10-methylenetetrahydrofolate reductase; (2) methionine synthase; (3) Sadenosylmethionine synthase; (4) S-adeno8ylhomocysteine hydrolase; (5) cystathionine beta synthase; (6) betaine:homocysteine methyltransferase; (7) glycine N-s; (8) serine hydroxymethylase; (9) cystathionase. Folic acid and vitamin B12 are co-enzymes in the remethylation pathway2,S (folic acid is a substrate in this metabolic pathway as well); vitamin Bs is a cofactor for the enzyme cystathionine J3-synthase in the trans-sulfuration pathway.5,9 (Modified from Folic acid, in Selhub J, Rosenburg IH, editors. Present knowledge in nutrition. Washington (DC): International Life Sciences Institute; 1996. p. 206-19. Copyright © 1996 International Life Sciences Institute.)

S04-

elastolytic processes in the arterial wall. These mechanisms may contribute to the positive association between homocysteine levels and systolic and diastolic hypertension that has been reported,29,30 as well as to the pathogenesis of accelerated atherosclerosis. More recently, a number of much more common causes of elevated homocysteine levels have been identified, including deficient levels of folic acid and vitamin B6 in the diet,31 an autosomal recessive mutation in 5,10-methylene-tetrahydrofolic acid reductase, mutations in methionine synthase, and heterozygous cystathionine /3-synthase deficiency.32 The mutation in the methylene-tetrahydrofolate reductase gene is extremely common: approximately 50% of the population is heterozygous and 11% homozygous for this defect. 33 Although the homocysteine levels in these people are only slightly elevated above normal and are far below those observed in homocystinurics, they are strongly associated with the development of atherosclerosis. Case control studies involving thousands of patients with coronary, peripheral, and cerebral vascular disease compared with disease-free controls have found hyperhomocysteinuria in 20-30% of vascular disease patients but only 2% of control subjects.34 Prospective studies have given rise to similar findings. In the Physicians Health Study, male phyMarch 1999 Volume 317 Number 3

Oparil and Oberman

sicians without apparent vascular disease at entry but with homocysteine levels in the top 5% had a 3.4-fold greater risk of MI or cardiac death than those in the lower 90% after adjustment for other cardiovascular risk factors.35 Subsequent prospective studies defined a graded risk of atherosclerotic disease and events, including MI and stroke, across the normal range of homocysteine concentrations. 36 - 38 The European Concerted Action Project assessed the magnitude of the vascular disease risk associated with increased plasma homocysteine levels and examined interactions between elevated plasma homocysteine levels and conventional risk factors in a case-control study.39 Cases and controls were enrolled from 19 centers in nine European countries. Cases included people with evidence of coronary, cerebral, or peripheral vascular disease. The rela-

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I Figure 5. Relative risks of vascular disease in groups defined by the presence or absence of classic risk factors and elevated plasma total homocysteine levels (adjusted for age and sex). (Reprinted with permission from Graham 1M, Daly LE, Refsum HM, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA 1997;277:1775-81. Copyright © 1997 The American Medical Association.)

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Figure 4. Quantitative analysis of studies of total homocysteine (tHcy) and vascular disease presented as odds ratios (ORs) with 95% CIon a log scale based on a 5-p,mol/L increase in tHcy. An OR greater than 1.0 indicates that elevated tHcy levels increase the risk for vascular disease. For each study, the OR estimate was calculated from the mean levels of tHcy in cases and controls by the linear discriminant function method. Unless indicated, ORs are for both males (M) and females. The "Summary, All" included all studies in each figure, and the "Summary, High Quality" included only those studies classified as high quality. N, prospective nested case-control studies; P, population-based case-control studies; C, cross-sectional studies; 0, other case-control studies. (Reprinted with permission from Boushey CJ, Beresford SA, Omenn GS, et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA 1995;274:1049-57. Copyright © 1995 the American Medical Association.) THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

o

2

3

4

5

6

Years Figure 6. Estimated survival among patients with coronary artery disease, according to plasma total homocysteine levels. The figure shows estimated survival for 55-year-old male former smokers with three-vessel disease, a left ventricular ejection fraction of 55%, a creatinine level of 1.5 mgldL (130 p,mol/L), and a total cholesterol level of 241 mg per deciliter (6.24 mmol per liter) at four different total homocysteine levels. Survival curves have been estimated in a stratified Cox regression analysis. (Reprinted with permission from Nygard 0, Nordrehaug JE, Refsum H, et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997;337;230-6. Copyright © 1997 The Massachusetts Medical Society. All rights reserved.)

199

Nontraditional Cardiovascular Risk Factors

tive risk of vascular disease in the top quintile compared with the bottom four quintiles of the fasting total homocysteine distribution was 2.2, and methionine loading, which stresses the metabolic pathway responsible for the irreversible degradation of homocysteine, identified an additional 27% of high risk cases. This level of risk was equivalent to that of hypercholesterolemia or smoking and applied to all categories of vascular disease. These findings are consistent with the previous estimate that the odds ratio for developing coronary artery disease of a 5 p,mollL increment in plasma homocysteine is 1.6 for men and 1.8 for women, equivalent to an increase in total cholesterol level of 0.5 p,mollL (19 mg/dL) (Figure 4).34 The overall risk estimate for increased homocysteine levels was independent of other risk factors, but the study did reveal strong interactions between homocysteine levels, smoking, and hypertension, the latter interaction being particularly strong in women (Figure 5). The common denominator in this relationship may be endothelial damage, which is characteristic of each risk factor independently. A recent report from Norway has assessed the prognostic value of homocysteine levels in patients with established coronary artery disease. 4o Five hundred and eighty-seven patients with angiographically confirmed coronary artery disease, most of whom underwent revascularization, were observed for an average of 4.6 years. Survival was closely related to plasma homocysteine levels (Figure 6). After 4 years, 4% of patients with homocysteine levels < 9 p,mollL had died, compared with 25% of those with levels > 25 p,mollL. The relation between homocysteine levels and mortality was graded, remained robust even when adjusted for potential confounders (history of MI, left ventricular ejection fraction, and serum creatinine), and was further strengthened when death due to cardiovascular disease (78% of all deaths) was the end point. Further, the relation between homocysteine level and mortality was apparent within a few months of the baseline coronary angiogram (Figure 6). The finding that plasma homocysteine level was the strongest modifiable risk factor for overall mortality and mortality due to cardiovascular causes in this population of high risk patients emphasizes the need for trials of homocysteine-lowering therapy in the prevention of cardiovascular outcomes. Reduced circulating levels of folic acid and/or vitamin B6 are associated with elevated homocysteine levels, in part because folic acid is used in the remethylation of homocysteine and vitamin B6 is a cofactor for cystathionine J3-synthase in the transsulfuration pathway (Figure 3). Supplementation of the diet above the recommended daily allowance with folate alone or with folate and vitamin B6 has been shown to reduce homocysteine levels. 41 In this

200

6-week placebo-controlled study of 100 men with hyperhomocysteinemia, folic acid supplementation (650 p,g) reduced plasma homocysteine concentrations by 42% (P < 0.001). A combination of folate, vitamin B 12 , and vitamin B6 was no more effective than folate alone, reducing homocysteine levels by 50%. These results, which have been supported by subsequent larger trials, provide strong evidence that folate deficiency is an important cause of hyperhomocysteinemia and that folate supplementation is effective in reducing homocysteine levels. The European Concerted Action Project has explored the interrelationships between homocysteine, folate, vitamins B12 and B6 and vascular disease to evaluate the role of these nutrients as risk factors for atherosclerosis. 42 Low red-cell folate and vitamin B6 levels were associated with increased risk of vascular disease independent of traditional risk factors. The increased risk associated with low folate levels was explained in part by increases in homocysteine, whereas the relationship between vitamin B6 and atherosclerosis was independent ofhomocysteine. The causes offolate and B6 deficiency were not defined in this study (ie, it is unclear whether dietary inadequacy or metabolic abnormalities played the major role). Nevertheless, these abnormalities in circulating nutrient levels can be readily reversed by administration of folic acid alone or folic acid and vitamin B6.41,43 Vitamin B12 levels are influenced more by absorption than intake, and vitamin B12 administration is recommended, not because of its effects on homocysteine levels (which are minor), but mainly to prevent hematologic disorders from arising in folic-acid-deficient persons. The Nurses' Health Study has provided prospective data relating intake of folate and vitamin B6 to the incidence of nonfatal MI and fatal coronary heart disease over 14 years offollow-up.44 Based on food frequency questionnaires, the largest single source of folate was multivitamins. The age-adjusted relative risk of coronary heart disease was 0.53 for women in the highest quintile of folate intake compared with the lowest; after controlling for other cardiovascular risk factors and dietary components, the relative risks for the highest vs. lowest quintiles of dietary intake were 0.69 for folate, 0.67 for vitamin B 6, and 0.55 for both folate and B6. Relative risk of coronary heart disease was reduced to 0.76 in women who used multiple vitamins regularly. Even though the average intakes offolate and vitamin B6 in this population exceeded the national average, there was a graded reduction in risk with higher intakes, and maximum benefit seemed to require folate intakes of ;:::400 p,g/day. These findings, taken together with the established role of folate in preventing neural-tube-closure defects, strongly support the recommendation for consumption of at least 400 p,g of folate/day. Nevertheless, March 1999 Volume 317 Number 3

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the limitations inherent in observational studies are such that controlled prospective interventional trials are needed to test the hypothesis that lowering homocysteine levels can reduce atherosclerotic events. Endothelial Dysfunction

Both traditional cardiovascular risk factors (such as cigarette smoking, hyperlipidemia, and hypertension) and nontraditional risk factors (such as inflammation, homocysteine, and oxidative stress) are thought to initiate the atherosclerotic process by damaging the endothelium. The ability to identify markers of early endothelial damage thus offers promise for predicting cardiovascular morbidity and mortality. Candidate markers for endothelial damage include endothelin-I, which is released from injured endothelial cells; nitric oxide and its metabolites, which depend on a healthy endothelium for their production and are thus reduced in response to endothelial damage; and cell adhesion molecules, which are expressed by activated endothelium. The selectins are a family of adhesive molecules that capture leukocytes and tether them to the endothelium. E-selectin is particularly interesting because it is synthesized and released into the circulation only by activated endothelial cells, so that the demonstration of soluble E-selectin in the blood is conclusive evidence of endothelial activation. 45- 47 E-selectin is more sensitive than such conventional markers of endothelial activation as thrombomodulin, endothelin-I, and von Willebrand factor antigen because these are also produced in non-endothelial cells. Overproduction of E-selectin and other adhesion molecules traps leukocytes in the blood vessel wall. These activated leukocytes then release free radicals and cytokines, such as interleukin-I and tumor necrosis factor, which in turn enhance Eselectin expression on the endothelial surface and stimulate release of various growth factors, which mediate the vascular injury process. Research in oxidative stress and mechanisms of endothelial damage is growing rapidly, and it is likely that new markers of endothelial dysfunction will soon be identified. Thrombogenic Factors

Because atherothrombotic events are triggered by intravascular clotting, it is reasonable to expect that clotting factors should be predictors of cardiovascular risk. Fibrinogen has been known to be increased in patients with ischemic heart disease for 50 years.48 A meta-analysis ofthe relationship between fibrinogen levels and the subsequent incidence of MI, stroke, and peripheral arterial occlusive diseases in six prospective epidemiologic studies showed a positive relationship between fibrinogen and MI and stroke in all studies [odds ratio, 2.3; 95% THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

confidence interval (Cl) 1.9-2.8)].49 Although fibrinogen is related to many other cardiovascular risk factors, it is also a major independent risk factor that plays a mechanistic role in both the progression of atherosclerosis and the pathogenesis of acute thromboembolic events. Further, fibrinogen has been shown to be higher in blacks than in whites and higher in persons with cardiovascular disease or increased carotid intimal-medial thickness than in persons who are disease free in the Atherosclerotic Risk in Communities (ARIC) cohort. 5o ,51 Other proteins involved in the procoagulant/antithrombolytic process that have been related to cardiovascular risk include von Willebrand factor, which mediates platelet adhesion to exposed subendothelium, thus promoting the role of platelets at the site of vascular injury; ~-thromboglobulin, a marker of platelet activation; plasminogen activator-I (PAl-I), which protects clots from rapid lysis by binding to circulating tissue-type plasminogen activator (t-PA); factors VII and VIII; protein C; and anti-thrombin IIJ.52-55 In the ARIC cohort, participants with cardiovascular disease had higher levels offactor VIII, von Willebrand factor, and fibrinogen than those without disease; the other thrombogenic factors were less consistently associated with prevalent cardiovascular disease. 51 A subsequent study, also carried out in the ARIC cohort, found statistically significant but weak positive associations between six of the major hemostatic factors (fibrinogen, factor VII, factor VIII, von Willebrand factor, antithrombin III, and protein C) and family risk score for coronary heart disease in men; four ofthese (fibrinogen, factor VII, factor VIII, and von Willebrand factor) were associated with family risk score in women. 52 Although these associations were weak and further attenuated after adjustments for lifestyle and biochemical covariates, these findings provide evidence that hemostatic factors, like traditional cardiovascular risk factors, are expressed at higher levels in people with family histories of heart disease. To test the hypothesis that defective fibrinolysis contributes to the progression of atherosclerotic lesions, the relationship between blood levels of PAl-I, t-PA, and D-dimer with carotid artery intima-media thickness as an index of early atherosclerosis was assessed in a subset of the ARIC cohort. 53 This cross-sectional case-control study involving 457 pairs of cases (those with intima-media thickness above the 90th percentile) and control subjects (those with intima-media thickness below the 75th percentile) found that all three fibrinolytic parameters were significantly higher in cases than in controls. Further, the odds ratios for carotid atherosclerosis showed increasing trends across quartiles of PAl-I, t-PA, and D-dimer concentrations, which supports the hypothesis that thrombosis and fibri201

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nolysis play a role early in the atherosclerotic process. Together with previous reports of high levels of PAl-l in patients with coronary atherosclerosis and acute coronary syndromes,54 these data support a role for thrombolytic factors, particularly PAl-I, as risk factors for coronary artery disease and coronary events. The potential role of markers of platelet activation as cardiovascular risk factors has been debated because, although many studies have shown increased platelet activation in patients with atherosclerotic disease, the temporal relationship between platelet activation and the development of atherosclerosis is unclear. To test whether platelet activation contributes to the progression of early atherosclerotic lesions, plasma concentrations of two specific markers of platelet activation, l3-thromboglobulin and platelet factor 4, have been measured in 459 cases with increased carotid wall thickness and 459 matched controls selected from the ARIC cohort. 55 Participants had no acute vascular symptoms or known cardiovascular disease. Mean values of both markers were significantly higher in cases than in controls, but when analyzed by quartiles using conditioned logistic regression, only l3-thromboglobulin showed a significant association with wall thickness. The odds ratio was significantly higher for the top quartile of l3-thromboglobulin compared to the other 3 quartiles for white men (2.3; CI 1.1-2.5) but not for white women (1.4; CI 0.6-3.0) or blacks (1.0; CI 0.4-2.5). These data suggest that l3-thromboglobulin may be a risk factor/marker for early atherosclerosis in some gender/ethnic groups and not others. Further, these observational data do not distinguish between the possibilities that platelet activation may be either a cause or a consequence of atherosclerotic disease in this setting. Lipoprotein Lp (a)

In addition to the traditional lipoprotein cardiovascular risk factors, lipoprotein Lp (a), an LDL particle that is linked to apolipoprotein (a) and shares partial homology with plasminogen, has recently been linked to increased risk of MI, stroke, and restenosis of saphenous vein coronary grafts and of native coronary arteries after balloon angioplasty.56-6o Lipoprotein Lp (a) is both prothrombotic and atherogenic. Because of its structural homology with plasminogen, lipoprotein Lp (a) accelerates thrombosis and interferes with fibrinolysis by competing with plasminogen for binding sites on cells and molecules, including fibrin. Lipoprotein Lp (a) colocalizes with fibrin in atherosclerotic plaques and binds to plasmin-degraded fibrin in vitro. 61 ,62 Further, homocysteine increases the affinity oflipoprotein Lp (a) for fibrin.63 Lipoprotein Lp (a) is internalized by macrophages and has been identified in macrophage-rich areas within atherosclerotic

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Psychosocial Factors

R;'k~~LD_m

~

Symptoms Time to

Hostility Depression Type A Job strain Drug abuse

Perception and action

ER

MI

Anger Acute stress

Outcome

Depression Lack of social support

Figure 7. Relationship between psychosocial factors that have been identified as risk factors for cardiovascular disease and cardiovascular symptoms, events, and outcomes.

plaques. 64 Lipoprotein Lp (a) can induce monocyte chemotactic activity in endothelial cells, a property that it shares with oxidized LDL and that could contribute to its atherogenicity.62,65 Lipoprotein Lp (a) promotes atherosclerosis through interactions with LDL cholesterol: lipoprotein Lp (a) binds to endothelium and extracellular matrix, resulting in localized cholesterol accumulation; it potentiates the oxidative susceptibility of LDL cholesterol, in part by inducing oxygen-derived free radical formation in monocytes; and causes endothelial dysfunction (impaired endothelium-dependent vasodilation) in persons with familial hypercholesterolemia. 66,67 Lipoprotein Lp (a), particularly in the setting of hypercholesterolemia, seems to be a predictor of premature coronary artery disease. Lipoprotein Lp (a) excess is the most common familial lipoprotein disorder in patients with premature coronary artery disease. 68 In the Framingham Offspring Study, lipoprotein Lp (a) was an independent predictor of coronary heart disease risk in men younger than 55 years and in women. 57 The magnitude of the population attributable risk for coronary heart disease associated with lipoprotein Lp (a) excess was similar to the increased risk attributed to hypercholesterolemia and low HDL cholesterol levels. In contrast, lipoprotein Lp (a) is a relatively weak predictor of coronary heart disease events in unselected populations. The Lipid Research Clinics Coronary Primary Prevention Trial studied the relationship between lipoprotein Lp (a) excess and coronary heart disease in 3806 middle aged men with hypercholesterolemia. 69 Lipoprotein Lp (a) levels were higher in participants with coronary events than in controls, but lipoprotein Lp (a) excess was a weaker risk factor than tobacco use or low HDL cholesterol levels. Similar results were reported in the British United Provident Association study and the Gottingen Risk Incidence and Prevalence Study (GRIPS).7o,71 Further, the Physician's Health Study found no association between lipoprotein Lp (a) levels and risk of MI. 72 A limitation of this study in assessing the predictive value oflipoprotein Lp (a) is March 1999 Volume 317 Number 3

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that half of the participating physicians received aspirin, which may have blunted its prothrombotic effects. In contrast, cross-sectional data from the ARIC Study demonstrated an association oflipoprotein Lp (a) levels with preclinical atherosclerotic disease, as assessed by extracranial carotid artery intima-media wall thickness, and in stroke or transient ischemic attack. 73-75 Lipoprotein Lp (a) levels in blacks were twice those in whites in the ARIC cohort, but the risk of preclinical and clinical cardiovascular disease was positively related to lipoprotein Lp (a) levels in both races and genders. Lipoprotein Lp (a) was an independent risk factor for carotid thickness in men, but in women the relationship was affected by the presence of other risk factors and was stronger when smoking and diabetes was present. 75 Psychosocial Factors

Psychosocial factors that have been implicated as risk factors for cardiovascular disease include type A personality traits such as hostility and anger, depression, job strain, and other socioeconomic stresses (Figure 7).76-82 Conversely, preliminary evidence suggests that the personality trait of submissiveness may be protective against coronary events, particularly in women. 83 Specific aspects of the type A personality pattern, such as hostility and anger, are now considered to be specific predictors of disease. Controlled studies have begun to validate the anecdotal impression that emotionally stressful events and anger immediately precede and seem to trigger the onset of acute MI. 77 The Determinants of Myocardial Infarction Onset Study, a case-crossover study involving 1623 patients with acute MI, demonstrated that episodes of self-reported anger were associated with a transient doubling of the baseline risk of the onset of MI in the subsequent 2 hours. The Veteran's Administration Normative Aging Study found a three-fold increase in relative risk of total coronary heart disease (nonfatal MI and fatal coronary heart disease) and of combined incident coronary events, including angina pectoris, among men who reported the highest levels of anger over a 7-year follow-up period. 78 Further, total (potential for) hostility scores on structured interviews have been shown to predict (odds ratio, 2.5; CI 1.03-5.32) restenosis after balloon angioplasty.79 The latter findings suggest that angerlhostility are associated with the pathogenesis of atherosclerosis, as well as of acute cardiovascular events. Further, it was recently shown that the combination of "negative affectivity" and social inhibition predicts cardiac events independently of traditional cardiovascular risk factors. 81 ,82 The biological mechanisms by which anger can increase the risk of coronary events include increases in circulating catecholamines, myocardial THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

oxygen demand, heart rate, vasospasm, platelet aggregability, and coagulability ofthe blood. These are similar to the cardiovascular responses to mental stress and sudden heavy physical exertion (not graded exercise, which elicits favorable cardiovascular responses), other triggers of MI. 84,85 Higher levels of self-reported anger induced by an anger recall task have been shown to produce coronary vasoconstriction in diseased vessels,80 and a recalled anger task has been shown to be more potent than other mental stressors or exercise' in eliciting myocardial ischemia, as measured by a reduction in left ventricular ejection fraction in patients with coronary artery disease. 86 It has been postulated that angerinduced hemodynamic stresses may disrupt unstable atherosclerotic plaques, thus precipitating acute MI.87 Interestingly, aspirin seems to mitigate the effects of anger on coronary heart disease risk, supporting a role for platelet aggregation and thrombus formation in this process. A limitation of the studies relating anger and hostility to coronary heart disease and events is that they were based on predominantly white male cohorts. Further investigation is needed to examine this association in women and in nonwhite populations. Mental stress has been shown to trigger myocardial ischemia and cardiac arrhythmias, and responses to psychosocial stressors, including workrelated stressors, may affect the development of cardiovascular disease and the precipitation of acute events. 88 - 90 In particular, increased environmental stress and altered stress responses have been related to hypertension and related cardiovascular disease in blacks. Cardiovascular reactivity, assessed by alterations in blood pressure and peripheral vascular resistance, is enhanced in blacks in response to physical and mental stressors such as cold, orthostasis, isometric exercise, treadmill testing, reaction time tasks, and video games. Heightened cardiovascular responses to mental stress in black adolescents have been shown to predict the development of essential hypertension, at least in the short term. 91 Normotensive blacks have a greater increase in muscle sympathetic nerve activity in response to cold presser testing than agematched, normotensive whites, a direct demonstration of enhanced stress-induced sympathetic activation. 92 Higher levels of environmental stress, coupled with enhanced vascular reactivity/sympathetic nervous system activity may lead to earlier vascular hypertrophy in blacks than in whites, resulting in sustained increases in peripheral resistance with consequent elevation of blood pressure. Longitudinal data for larger populations followed for longer periods are needed to determine whether augmented stress-induced cardiovascular reactivity plays a causal role in the development of hyperten-

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Nontraditional Cardiovascular Risk Factors

sion and hypertension-induced cardiovascular disease in this high-risk group. Socioeconomic stress, blood pressure, and cardiovascular morbidity and mortality are clearly interrelated. Poverty, low occupational and educational status, and high levels of socioecologic stress are all related to the prevalence of cardiovascular disease. Cross-sectional and longitudinal studies support the hypothesis that increased environmental stress probably contributes to the higher prevalence of hypertension and its cardiovascular sequelae in the black population. For example, a study carried out in young men living in the Detroit area showed that living in a high-stress area was associated with significant increases in both systolic and diastolic blood pressure in blacks but not in whites. 93 Further, in the Charleston Heart Study, after 10 years of follow up, hypertension was 3.8 times more likely to occur in lower-social-class blacks than in uppersocial-class blacks. 94 Job stress is generally regarded as a contributor to the development of cardiovascular disease and atherothrombotic events. However, controlled studies have not consistently revealed a direct relationship between work stress and cardiovascular disorders, such as coronary artery disease and hypertension. 95 ,96 There were, however, significant independent relationships between adaptive or maladaptive coping mechanisms (such as healthy or unhealthy eating, excess alcohol consumption, lack of physical activity, use of denial and/or repression as a coping strategy to deal with underlying conflicts) and both hypertension and job stress. 96 Thus, although work stress per se had no direct effect on blood pressure, the ways that people reported coping with stress were significantly related to blood pressure, thus reinforcing the importance of personality traits as risk factors for cardiovascular disease. Insulin and Markers of Insulin Resistance

Insulin resistance and hyperinsulinemia are commonly observed in persons with hypertension and related cardiovascular disease. 97 Furthermore, hypertriglyceridemia and low HDL levels frequently coexist and are referred to as the insulin resistance syndrome or syndrome X.98 This subject has been the topic of many recent reviews and will not be discussed in detail here. It is thought that impaired insulin-mediated glucose uptake by skeletal muscle leads to compensatory hyperinsulinemia and, eventually, impaired glucose tolerance and type-2 diabetes. It has been suggested that elevated insulin levels per se may lead to hypertension and atherosclerotic vascular disease. Alternatively, other metabolic abnormalities characteristic of this syndrome, including hyperglycemia and dyslipidemia, may account for the increased risk of cardiovascular disease in patients with insulin resistance. Whether

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involved directly in the etiology of hypertension and accelerated atherosclerosis or only as a marker of these processes, hyperinsulinemia has come to be regarded as a risk factor for cardiovascular disease. The strength of this association was recently assessed in a meta-analysis of prospective populationbased cohort studies and nested case-control studies. 99 Activation of the Renin-Angiotensin System

Elevated plasma renin activity (PRA) has been put forward as an independent risk factor for cardiovascular disease events (both MI and stroke) based on a longitudinal study of 219 untreated patients with moderate to severe hypertension. 10o Over a 5-year period of observation, patients with normal or high PRA had an 11% and 14% incidence of MI or stroke, respectively, whereas patients with low PRA had no events. Subsequent studies showed that low renin patients had better preservation of renal function than those with normal or high PRA, despite comparable or greater severity and duration of hypertension.1 01 Interestingly, the young black patients in this group, who tended to have more severe hypertension with vascular sequelae, generally fell into the high/medium renin group, whereas older blacks tended to have milder disease and low renin levels. 101 A more recent study from the same group in which 1717 patients with mild hypertension were followed for 8 years confirmed that baseline PRA is highly predictive of MI.102 PRA was an independent predictor of MI in both sexes and both races: in patients with concomitant diabetes, hypercholesterolemia and/or smoking, the MI rate of highrenin patients was 3.2-fold higher than that of lowrenin patients; in those without other risk factors, the risk was increased 7 -fold. Although this strong positive relationship between PRA and cardiovascular risk has not been reproduced by other groups, the dramatic beneficial effects of the angiotensinconverting enzyme (ACE) inhibitors and angiotensin II receptor blockers in patients with MI accompanied by systolic dysfunction, congestive heart failure, and diabetes with proteinuria,103-106 provide powerful indirect evidence that angiotensin II has toxic effects on the heart and vasculature. The search for genetic causes of cardiovascular diseases and hypertension has implicated polymorphisms of the ACE and angiotensinogen genes in cardiovascular pathology. A deletion-insertion polymorphism of the human ACE gene that affects the level of serum ACE activity has been identified. The genotype (DD) with the highest ACE levels seems to be associated with left ventricular hypertrophylO7 and with increased risk of myocardial infarction and of dilated and hypertrophic cardiomyopathy.108 The mechanism by which the DD genotype of the ACE gene effects cardiac hypertrophy and accelerated March 1999 Volume 317 Number 3

Nontraditional Cardiovascular Risk Factors

38. 39. 40. 41. 42.

43.

44. 45.

46. 47.

48. 49. 50. 51.

52.

53.

54.

55. 56.

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between plasma homocysteine and extracranial carotid-artery stenosis. N Engl J Med 1995;332:286-91. Perry IJ, Refsum H, Morris RW, et al. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet 1995;346:1395-8. Graham 1M, Daly LE, Refsum HM, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA 1997;277:1775-81. Nygard 0, Nordrehaug JE, Refsum H, et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997;337:230-6. Ubbink JB, Vermaak WJ, van der Merwe A, et al. Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J Nutr 1994;124:1927-33. Robinson K, Arheart K, Refsum H, et al. Low circulating folate and vitamin Bs concentrations: risk factors for stroke, peripheral vascular disease, and coronary artery disease. Circulation 1998;97:437-43. Naurath HJ, Joosten E, Reizler R, et al. Effects of vitamin B 12 , folate, and vitamin Bs supplements in elderly people with normal serum vitamin concentrations. Lancet 1995;346:85-9. Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998; 279:359-64. Gimbrone MA, Bevilacqua MP, Cybulsky MI. Endothelial dependent mechanisms ofleukocyte adhesion in inflammation and atherosclerosis. Ann N Y Acad Sci 1990;598:7785. Belch JJF, Zoma A, Richards I, et al. Vascular damage and factor VIII related antigen in the rheumatic disease. Rheumatol Int 1987;7:107-11. Belch JJF, Shaw JW, Kirk G, et al. The white blood cell adhesion molecule E-selectin predicts restenosis in patients with intermittent claudication undergoing percutaneous transluminal angioplasty. Circulation 1997;95:2027-31. Phear D, Stirland R. The value of estimating fibrinogen and C-reactive protein levels in myocardial ischaemia. Lancet 1957;2:270-5. Ernst E, Resch, KL. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med 1993;118:956-63. Folsom AR, Wu KK, Davis CE, et al. Population correlates of plasma fibrinogen and factor VII, putative cardiovascular risk factors. Atherosclerosis 1991;91:191-205. Folsom AR, Wu KK, Shahar E, et al. Association of hemostatic variables with prevalent cardiovascular disease and asymptomatic carotid artery atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study Investigators. Arterioscler Thromb 1993;13:1829-36. Pankow JS, Folsom AR, Province MA, et al. Family history of coronary heart disease and hemostatic variables in middle-aged adults. Atherosclerosis Risk in Communities Investigators and Family Heart Study Research Group. Thromb Haemost 1997;77:87-93. Salomaa V, Stinson V, Kark JD, et al. Association of fibrinolytic parameters with early atherosclerosis. The ARIC Study. Atherosclerosis Risk in Communities Study. Circulation 1995;91:284-90. Anonymous. ECAT angina pectoris study: baseline associations of haemostatic factors with extent of coronary arteriosclerosis and other coronary risk factors in 3000 patients with angina pectoris undergoing coronary angiography. Eur Heart J 1993;14:8-17. Ghaddar HB, Cortes J, Salomaa V, et al. Correlation of specific platelet activation markers with carotid arterial wall thickness. Thromb Haemost 1995;74:943-8. Stein JR, Rosenson RS. Lipoprotein Lp(a) excess and coronary heart disease. Arch Intern Med 1997;157(11): 1170-6.

57. Bostom AG, Cupples LA, Jenner JL, et al. Elevated plasma lipoprotein(a) and coronary heart disease in men aged 55 years and younger. JAMA 1996;276:544-8. 58. Willeit J, Kiechi S, Santer P, et al. Lipoprotein{a) and asymptomatic carotid artery disease. Evidence of a prominent role in the evolution of advanced carotid plaques: the Bruneck Study. Stroke 1995;26:1582-7. 59. Cushing GL, Gaubatz JW, Nava ML, et al. Quantitation and localization of apolipoproteins(a) and B in coronary artery bypass vein grafts resected at re-operation. Arteriosclerosis 1989;9:593-603. 60. Desmarais RL, Sarembock IJ, Ayers CR, et al. Elevated serum lipoprotein(a) is a risk factor for clinical recurrence after coronary balloon angioplasty. Circulation 1995;91: 1403-9. 61. Harpel PC, Gordon BR, Parker TS. Plasmin catalyzes binding of lipoprotein(a) to immobilized fibrinogen and fibrin. Proc Natl Acad Sci USA 1989;86:3847-51. 62. Poon M, Zhang :x, Dunsky KG, et al. Apolipoprotein(a) induces monocyte chemotactic activity' in human vascular endothelial cells. Circulation 1997;96:2514-9. 63. Harpel PC, Chang VT, Borth W. Homocysteine and other sulfhydryl compounds enhance the binding of lipoprotein(a) to fibrin: a potential biochemical link between thrombosis, atherogenesis and sulfhydryl compound metabolism. Proc Natl Acad Sci USA 1992;89:10193-7. 64. Zioncheck TF, Powell LM, Rice GC, et al. Interaction of recombinant apolipoprotein(a) and lipoprotein(a) with macrophages. J Clin Invest 1991;87:767-71. 65. Cushing SD, Berliner JA, Valente AJ, et al. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc Natl Acad USA 1990;87:5134-8. 66. Hansen PR, Kharazmi A, Jauhianen M, et al. Induction of oxygen free radical generation in human monocytes by lipoprotein (a) level. J Clin Invest 1994;93:50-7. 67. Sorenson KE, Celermajer DS, Georgakopoulos D, et al. Impairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipoprotein(a) level. J Clin Invest 1994;93:50-7. 68. Genest JJ Jr, Martin-Munley SS, McNamara JR, et al. Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation 1992;85:2025-33. 69. Schaefer EJ, Lamon-Fava S, Jenner JL, et al. Lipoprotein(a) levels and risk of coronary heart disease in men. JAMA 1994;271:999-1003. 70. Wald NJ, Law M, Watt HC, et al. Apolipoproteins and ischaemic heart disease: implications for screening. Lancet 1994;343:75-9. 71. Cremer P, Nagel D, Labrot B, et al. Lipoprotein Lp(a) as predictor of myocardial infarction in comparison to fibrinogen, LDL cholesterol and other risk factors: results from the prospective Gottingen Risk Incidence and Prevalence Study (GRIPS). Eur J Clin Invest 1994;24:444-53. 72. Ridker PM, Hennekens CH, Meir MJ, et al. A prospective study oflipoprotein(a) and the risk of myocardial infarction. JAMA 1993;270:2195-9. 73. Schreiner PJ. Lipoprotein{a) as a risk factor for preclinical atherosclerotic disease in a biracial cohort: the Atherosclerosis Risk in Communities (ARIC) Study. Chern Phys Lipids 1994;67-68:405-10. 74. Schreiner PJ, Chambless LE, Brown SA, et al. Lipoprotein{a) as a correlate of stroke and transient ischemic attack prevalence in a biracial cohort: the ARIC Study. Atherosclerosis Risk in Communities. Ann Epidemiol 1994;4:351-9. 75. Schreiner PJ, Heiss G, Tyroler HA, et al. Race and gender differences in the association of Lp(a) with carotid artery wall thickness. The Atherosclerosis Risk in CommuMarch 1999 Volume 317 Number 3