 |
|
CLINICIAN'S CORNER
Emerging Risk Factors for Atherosclerotic Vascular Disease
A Critical Review of the Evidence
Daniel G. Hackam, MD;
Sonia S. Anand, MD, PhD, FRCP
JAMA. 2003;290:932-940.
ABSTRACT
| |
Context Atherosclerotic vascular disease is an enormous public health problem. A number of emerging risk factors for atherosclerosis have recently been proposed to help identify high-risk individuals.
Objective To review the epidemiological, basic science, and clinical trial evidence concerning 4 emerging risk factors: C-reactive protein, lipoprotein(a), fibrinogen, and homocysteine.
Data Sources Using the terms atherosclerosis, cardiovascular disease, risk factors, prevention, screening, C-reactive protein, lipoprotein(a), fibrinogen, and homocysteine, we searched the MEDLINE database from January 1990 to January 2003. Conference proceedings, abstract booklets, bibliographies of pertinent articles and books, and personal files were hand searched to identify additional articles.
Study Selection Original investigations and reviews of the epidemiology of atherosclerosis and the association of conventional and novel risk factors with vascular risk were selected. On the basis of the search strategy, 373 relevant studies were identified.
Data Extraction A diverse array of studies were examined, including randomized controlled trials, prospective cohort studies, systematic overviews, case-control, cross-sectional, and mechanistic studies. Data extraction was performed by one of the authors.
Data Synthesis The available epidemiological and basic science evidence supports, to varying degrees, independent associations between these 4 candidate risk factors and atherosclerotic vascular disease. However, there is relatively little data regarding the additive yield of screening for these factors over that of validated global risk assessment strategies currently in use. Furthermore, controlled intervention studies targeting individuals with these factors for proven risk-reduction therapies, or specifically treating these factors with available therapies, are few. The explanatory power of the major, established cardiovascular risk factors has been systematically underestimated.
Conclusions Although C-reactive protein, lipoprotein(a), fibrinogen, and homocysteine are associated with vascular disease risk, their optimal use in routine screening and risk stratification remains to be determined.
INTRODUCTION
Cardiovascular disease (CVD) is the leading cause of death and disability in developed nations and is increasing rapidly in the developing world.1 By the year 2020, it is estimated that CVD will surpass infectious diseases as the world's leading cause of death and disability.2 Atherosclerotic vascular disease (ASVD), which encompasses coronary heart disease, cerebrovascular disease, and peripheral arterial disease, is responsible for the majority of cases of CVD in both developing and developed countries. Fortunately, major progress in the diagnosis, prevention, and treatment of atherosclerosis has been made in the past 3 decades.
One of the most important advances in medicine has been the identification of the major risk factors for CVD, which arose from large prospective cohort studies such as the Framingham Heart Study and the Seven Countries Study.3-4 The major modifiable risk factors include elevated blood pressure, dyslipidemia, smoking, and diabetes mellitus. A substantial body of evidence now supports reducing these factors to reduce morbidity and mortality associated with ASVD. Indeed, screening for and treating these conditions forms the basis of many published guidelines of risk assessment and reduction strategies.5-7
It is apparent, however, that a substantial proportion of cardiovascular events occurs in individuals without these established risk factors. The reasons for this are multifold; in particular, there is evidence that even modest elevations of blood pressure, cholesterol, and glucose levels combine to place individuals at risk for CVD.3, 8-9 Despite the fact that most cardiovascular events are explained by conventional risk factors, the search for additional etiologic agents continues. Moreover, while the population-attributable risk of the major vascular risk factors is substantial, it is often difficult to distinguish those individuals with a moderate baseline risk who might benefit from aggressive risk reduction strategies. Therefore, additional tests to assist in the prediction of risk in these individuals may be warranted.
In recent years, a number of new candidate risk factors or markers have been proposed as significant predictors of atherosclerosis and its complications (Box). This review will highlight 4 important emerging risk predictors: C-reactive protein (CRP), lipoprotein(a) [Lp(a)], fibrinogen, and homocysteine. These 4 risk predictors were selected because there is substantial evidence on their predictive abilities, there is a genetic basis for premature disease, modifying treatments are available, and/or these factors are the subject of ongoing or completed clinical trials (Table 1).
|
|
|
|
Table. Characteristics of 4 Emerging Risk Factors for Atherosclerotic Vascular Disease*
|
|
|
| Box. Novel Risk Factors for Atherosclerotic Vascular Disease
Inflammatory Markers
C-reactive protein
Interleukins (eg, IL-6)
Serum amyloid A
Vascular and cellular adhesion molecules
Soluble CD40 ligand
Leukocyte count
Hemostasis/Thrombosis Markers
Fibrinogen
von Willebrand factor antigen
Plasminogen activator inhibitor 1 (PAI-1)
Tissue-plasminogen activator
Factors V, VII, and VIII
D-dimer
Fibrinopeptide A
Prothrombin fragment 1 + 2
Platelet-Related Factors
Platelet aggregation
Platelet activity
Platelet size and volume
Lipid-Related Factors
Small dense low-density lipoprotein (LDL)
Lipoprotein(a)
Remnant lipoproteins
Apolipoproteins A1 and B
High-density lipoprotein subtypes
Oxidized LDL
Other Factors
Homocysteine
Lipoprotein-associated phospholipase A(2)
Microalbuminuria
Insulin resistance
PAI-1 genotype
Angiotensin-converting enzyme genotype
ApoE genotype
Infectious agents: Cytomegalovirus, Chlamydia pneumonia, Helicobacter pylori, Herpes simplex virus
Psychosocial factors
RETURN TO TEXT |
|
METHODS
Using the terms atherosclerosis, cardiovascular disease, risk factors, prevention, screening, C-reactive protein, lipoprotein(a), fibrinogen, and homocysteine, we searched the MEDLINE database from January 1990 to January 2003. Conference proceedings, abstract booklets, bibliographies of pertinent articles and books, and personal files were hand searched to identify additional articles. We selected original investigations and reviews of the epidemiology of atherosclerosis and the associations of conventional and novel risk factors with vascular risk. A diverse array of studies was examined, including controlled trials, prospective cohort studies, systematic overviews, case-control, cross-sectional, and mechanistic studies. Data extraction was performed by one of the authors (D. G. H.). For this narrative review, we focused our attention on assessing the clinical significance and additive predictive value of 4 candidate risk factors in comparison with established and validated risk prediction tools, such as the Framingham Risk Score (FRS).3
RESULTS
C-Reactive Protein
C-reactive protein (CRP) is a circulating acute-phase reactant that is increased many-fold during the inflammatory response to tissue injury or infection.10 C-reactive protein is synthesized primarily in the liver and its release is stimulated by interleukin 6 (IL-6) and other proinflammatory cytokines. This protein has received substantial attention in recent years as a promising biological predictor of atherosclerotic disease.11 This stems in part from a recent shift in thinking about the pathogenesis of ASVD, an entity once primarily considered to be a bland lipid storage disease. Inflammation is now widely accepted as central to every aspect of the atherosclerotic process, from its initiation to its progression to plaque rupture, the latter being the quintessential event underlying the acute coronary syndromes.12 In particular, local inflammatory processes may trigger the occurrence of vascular events by mediating plaque instability.13
An evolving body of work suggests that even small increases in CRP within the normal range are predictive of future vascular events in apparently healthy, asymptomatic individuals.14 Danesh et al15 recently reported a meta-analysis of 14 prospective long-term studies of CRP and the risk of nonfatal myocardial infarction or death from coronary heart disease. The analysis comprised 2557 cases with a mean age at entry of 58 years and a mean follow-up of 8 years. The combined adjusted risk ratio was 1.9 (95% confidence interval [CI], 1.5-2.3) for the development of coronary heart disease among individuals in the top tertile of baseline CRP concentrations compared with those in the bottom tertile. All component studies adjusted for age, sex, smoking, and other major vascular risk factors.
The predictive abilities of CRP seem to extend to patients with preexisting vascular disease as well. A number of prospective studies have demonstrated that CRP predicts recurrent events and/or increased mortality in patients with ischemic stroke,16-18 acute coronary syndromes,19-21 chronic stable angina,22-23 and peripheral vascular disease.24-25 An elevated CRP level before percutaneous coronary intervention also portends a worse prognosis,26-28 as it does among patients undergoing coronary artery bypass grafting.29 C-reactive protein is correlated with the presence of abdominal obesity and a raised level predicts the risk of developing type 2 diabetes.30-32 The predictive value of CRP is additive to that of several surrogate markers of atherosclerosis, including carotid intimal medial thickness, quantitative coronary calcium scoring, and the presence of the metabolic syndrome.33-35
Whether or not CRP is a marker or mediator of inflammation is unclear. There is evidence that CRP may play a direct role in the pathogenesis of atherosclerosis. The protein is markedly up-regulated in atheromatous plaques,36 where it may promote low-density lipoprotein (LDL) cholesterol uptake by macrophages, a key step in atherogenesis.37 C-reactive protein may also induce the expression of intercellular adhesion molecules by endothelial cells,38 thereby facilitating the recruitment of circulating monocytes to plaque sites, and can bind to and activate complement in serum.39 These effects appear to be mediated through CRP-induced secretion of endothelin 1 and IL-6.40
However, the utility of CRP as a tool in global risk assessment has some important limitations.41-42 These include CRP's poor specificity in the setting of coexisting inflammatory states43 (eg, rheumatoid arthritis, chronic pulmonary disease, and infections) and minimal data from nonwhite populations. In addition, CRP is strongly correlated with other cardiovascular risk factors such as fibrinogen; in studies examining CRP's incremental predictive value, its independence from fibrinogen has not been demonstrated.44 For example, in patients with established vascular disease, fibrinogen, but not CRP, was a significant independent predictor of recurrent cardiovascular events after adjustment for conventional risk factors.45 We are aware of only one study that formally compared the incremental predictive value of CRP added to that of an established risk prediction model (the FRS).14 In this latter analysis, the authors found that CRP remained a predictor of cardiovascular risk after adjustment for the FRS, although there was attenuation in the magnitude of risk after adjustment was performed. The incremental value of CRP in addition to the Framingham factors may have been overestimated given that the model was not adjusted for body mass index, abdominal fat, or physical activity levels—3 factors that are significant correlates of CRP. Furthermore, in this large prospective cohort study, covariates such as blood pressure, smoking, and diabetes were self-reported rather than measured, which may underestimate the impact of these factors on vascular risk.46
Retrospective subgroup analyses have raised the possibility that statins and aspirin (which lower CRP levels) may lead to reduced cardiovascular events even among patients without overt hyperlipidemia.47-48 In addition, some investigators advocate that a strategy of CRP screening to target statin therapy for the primary prevention of CVD among patients without overt hyperlipidemia could be cost-effective.49 However, to date, no clinical trials have prospectively demonstrated that targeting patients with elevated CRP lowers vascular event rates, or whether interventions aimed at lowering CRP translates into reduced vascular risk, although several are ongoing.50
Lipoprotein(a)
Lipoprotein(a) is an LDL-like particle in which an apolipoprotein(a) [apo(a)] moiety is linked via a disulfide bond to apoB-100.51 Concentrations of Lp(a) are largely under genetic control and vary substantially between individuals depending on the size of the apo(a) isoform present; conversely, Lp(a) levels vary little with diet or exercise, unlike other lipoproteins such as LDL and high-density lipoprotein (HDL).52 The wide range of Lp(a) in plasma within a population is due in large part to a variable number of plasminogen-like kringle IV repeats, and an inverse correlation between the number of kringle IV type 2 repeats in the apo(a) gene and Lp(a) plasma concentration exists.53 The biological function of Lp(a) is still unclear, but there is strong evidence that its phylogenetic role may have been to respond to tissue injury and vascular lesions, prevent infectious pathogens from invading cells, and promote wound healing.54
Lipoprotein(a) is an acute-phase reactant, more than doubling in concentration in response to the proinflammatory cytokine IL-6.55 Lipoprotein(a) binds avidly to endothelial cells, macrophages, fibroblasts, and platelets, as well as to the subendothelial matrix; there, it may promote proliferation of vascular smooth muscle cells and chemotaxis of human monocytes.56-58 However, its most important putative role in atherothrombosis may be to inhibit clot fibrinolysis at sites of tissue injury. By virtue of its unique structural homology to plasminogen, Lp(a) is thought to compete with plasminogen for binding to plasminogen receptors, fibrinogen, and fibrin.59 Lipoprotein(a) may also induce the production of plasminogen activator inhibitor 1 (the main inhibitor of the fibrinolytic system) and may inhibit the secretion of tissue-plasminogen activator by endothelial cells.60-61
By virtue of these properties, as well as its ability to deliver a rich source of cholesterol to sites of vascular injury (cholesterol represents almost 40% of its mass), Lp(a) has been postulated to be a highly atherothrombotic lipoprotein; the epidemiological evidence largely supports this hypothesis, albeit with several notable exceptions.62-63 A recent meta-analysis of 27 prospective studies with a mean follow-up of 10 years showed a combined risk ratio of 1.6 (95% CI, 1.4-1.8) for individuals in the top third of baseline Lp(a) concentrations compared with those in the bottom third.64 Adjustment for conventional risk factors did not diminish this association. Moreover, an elevated Lp(a) level may be particularly detrimental in the presence of high LDL levels, diabetes, low HDL levels, hypertension, hyperhomocysteinemia, or elevated fibrinogen concentrations.65-68
Nonetheless, the use of Lp(a) as a screening tool has some limitations. No universally accepted, standardized method of determination for Lp(a) exists, although recently, a working group of the International Federation of Clinical Chemistry demonstrated the inaccuracy of Lp(a) values determined by methods sensitive to apo(a) size and recommended the widespread implementation of a proposed reference material for those Lp(a) assays that are validated to be unaffected by apo(a) size heterogeneity.69 Lipoprotein(a) concentrations are unaffected by most available lipid-lowering therapies, with the exception of high-dose nicotinic acid, which is often poorly tolerated.70 This has made it difficult to demonstrate that Lp(a) plays a direct role in vascular disease, since large-scale controlled intervention studies examining the reduction of Lp(a) and hard cardiovascular end points have not been performed. Last, the incremental predictive value of Lp(a) measurement additive to that of traditional screening methods for global risk assessment has not been formally studied.
Fibrinogen
Fibrinogen is a circulating glycoprotein that acts at the final step in the coagulation response to vascular and tissue injury.71 Cleavage by thrombin produces soluble fibrin fragments, which are the most abundant component of blood clots.71 Aside from its role in thrombosis, fibrinogen has a number of other functions that lend it biological plausibility as a possible participant in vascular disease, including the following: (1) regulation of cell adhesion, chemotaxis, and proliferation72; (2) vasoconstriction at sites of vessel wall injury71; (3) stimulation of platelet aggregation73; and (4) determination of blood viscosity.74 Fibrinogen, like CRP, is an acute-phase reactant. Hepatic synthesis of fibrinogen can increase up to 4-fold in response to inflammatory or infectious triggers.75
Epidemiological data support an independent association between elevated levels of fibrinogen and cardiovascular morbidity and mortality. Two recent meta-analyses73, 76 involving 18 and 22 prospective, long-term studies demonstrated strong, statistically significant risk ratios for individuals in the upper tertile of baseline fibrinogen concentration compared with those in the lower tertile (risk ratio, 1.8; 95% CI, 1.6-2.0, and odds ratio [OR], 1.99; 95% CI, 1.85-2.13, respectively). Other studies have demonstrated associations between fibrinogen and ischemic stroke75, 77-78 and peripheral vascular disease,79-80 again largely independent of the classic risk factors.
Several factors other than inflammation have been shown to modulate fibrinogen levels. Smoking and smoking cessation are associated with an increase or decrease, respectively, of approximately 0.15 g/L in plasma fibrinogen.81 Furthermore, there is a dose-response relationship between number of cigarettes smoked and fibrinogen level.82 Fibrinogen levels tend to be higher in patients with diabetes, hypertension, obesity, and those with sedentary lifestyles.76 Fibrates and niacin lower fibrinogen levels (in addition to lipid parameters), whereas statins and aspirin do not.83 A recently completed, randomized controlled trial examined the effects of bezafibrate (400 mg/d) on cardiovascular event rates in 1568 patients with peripheral vascular disease.84 Despite a 13% reduction in fibrinogen (and a favorable effect on serum lipids, especially triglycerides), there was no reduction in the incidence of coronary heart disease events or stroke. Further clinical trials are necessary before it can be determined whether fibrinogen has a causal role in atherothrombosis or is merely a marker of the degree of vascular damage taking place. Finally, we found only one study that examined the additive yield of screening for fibrinogen in comparison with a validated scheme, such as the FRS.85 Although an elevated fibrinogen level remained independently predictive of cardiovascular events after adjustment for the FRS, the study entailed a high-risk secondary prevention cohort attending a vascular prevention clinic, and therefore, the possibility of selection bias and reverse causality cannot be excluded.
Homocysteine
Homocysteine is a highly reactive, sulfur-containing amino acid formed as a by-product of the metabolism of the essential amino acid methionine.86 Cells remetabolize homocysteine by a number of possible pathways involving several different enzymes; these enzymes variously use B vitamins as substrates or cofactors, namely folate, cobalamin (vitamin B12), and pyridoxine (vitamin B6).87
In the 1960s and 1970s, 3 different inborn errors of homocysteine metabolism involving these enzymes were described (termed "homozygous homocystinurias").88-89 Common to all 3 disorders are extremely high levels of homocysteine in the blood and urine of individuals homozygous for these mutations; half of affected individuals develop arterial or venous thrombosis by 30 years of age.87 This risk can be substantially ameliorated by the provision of high-dose B vitamins, which partially lower homocysteine levels back toward the normal range.90-91
It has been postulated that mild to moderate elevations of homocysteine in the general population predispose to atherosclerosis in a manner akin to the classic risk factors. This is important because of the availability of an inexpensive, safe, and effective therapy for lowering homocysteine (B vitamins).92 Mechanistic studies have demonstrated that homocysteine may induce vascular damage by promoting platelet activation, oxidative stress, endothelial dysfunction, hypercoagulability, vascular smooth muscle cell proliferation, and endoplasmic reticulum stress.86-87,93
A common gene mutation encoding one of the enzymes that metabolizes homocysteine (5,10-methylenetetrahydrofolate reductase [MTHFR]) leads to moderate increases in homocysteine levels on the order of 25%, particularly in the presence of low folate intake.94 Homozygosity for this MTHFR variant (677C T) is present in up to 15% of the Caucasian population, thus providing a natural experiment by which the relationships between the abnormal MTHFR genotype, higher homocysteine levels, and vascular disease can be discerned.87 Recently, 2 large meta-analyses95-96 of the MTHFR 677CT polymorphism confirmed modest but statistically significant increases in the risk of ischemic heart disease in homozygotes for the mutant allele (TT) compared with wild-type homozygotes (CC), with summary ORs of 1.21 (95% CI, 1.06-1.39) and 1.16 (95% CI, 1.05-1.28), respectively.
Numerous observational studies have also reported on the association between homocysteine levels and vascular risk in both the general population and in those with preexisting vascular disease. A number of meta-analyses have appeared in recent years in an attempt to summarize the evidence.95, 97-103 In general, prospective, longitudinal studies in healthy populations have offered substantially weaker support to the association between homocysteine and ASVD than retrospective case-control and cross-sectional studies. However, more recent meta-analyses that collected larger numbers of prospective studies and/or corrected for regression dilution bias (the intraindividual variability in homocysteine levels over follow-up) do show a significant association.95, 97-98,102-103 We found only one study of the risk prediction capabilities of homocysteine measurement with reference to the FRS (which also examined fibrinogen).85 As mentioned previously, this study specifically focused on a high-risk population with existing CVD; furthermore, only overall mortality (and not cause-specific death) was reported in longitudinal analyses.
Whether homocysteine is causative in the pathogenesis of atherosclerosis, is related to other confounding cardiovascular risk factors, or is a marker of existing vascular disease will have to await the completion of a number of large, randomized controlled trials studying the effect of homocysteine-lowering vitamins on cardiovascular end points.104-109 Although mandated cereal fortification with folic acid may affect the outcomes of clinical trials in North America, several studies are being conducted in regions of the world that have not mandated folate supplementation (eg, Australia and Europe).
One trial in patients undergoing coronary angioplasty has already been published.110 Schnyder et al randomized 205 patients following successful coronary angioplasty to a 6-month course of folic acid, vitamin B6, and vitamin B12 or matching placebos, in double-blind fashion.110 The risk of restenosis was reduced by 48% at 6 months in the group that received vitamins (relative risk, 0.52; 95% CI, 0.32-0.86), with a concomitant reduction in homocysteine of 35%. A 1-year follow-up of this study111 with a larger group of patients (n = 553) demonstrated these results were durable and persisted for a mean of 11 months (despite cessation of vitamins at 6 months). However, there was no reduction in myocardial infarction or death. It should also be noted that postangioplasty restenosis (which involves intimal hyperplasia) and atherosclerosis are different pathobiological processes, which therefore limits the generalizability of these results to other vascular patients.112 Furthermore, recent data from another randomized controlled study of 626 patients treated with B-vitamin therapy following percutaneous coronary intervention found increased rates of restenosis and major adverse cardiac events in the vitamin treatment group after 6 months of follow-up.113
COMMENT
A number of critical questions must be answered before any candidate risk factor can be recommended for routine screening.114 First, there must be an available, standardized, reproducible, and accurate laboratory test that has been prospectively validated in the population to which it will be applied. For some of the factors discussed in this review, including Lp(a), this goal has not yet been achieved; for other factors (eg, CRP and homocysteine), precise and valid laboratory tests are now available.115-116
Second, it must be demonstrated that measurement of the candidate factor adds to the information obtained from existing approaches to cardiovascular risk stratification. A number of global risk assessment schemes are available to clinicians today, with one of the most validated being the FRS.3, 117-118 As previously noted, we found only one study for each of CRP,14 homocysteine,85 and fibrinogen,85 and none for Lp(a), that directly assessed the additive yield of risk factor screening to the FRS or other commonly used methods of risk assessment.
Third, for each putative risk factor, there must be prospective controlled trials demonstrating that (1) targeting individuals with elevated levels of these risk factors for proven risk-reducing interventions offers advantages over current methods of targeting therapy (eg, by cholesterol, diabetes, and blood pressure screening); or (2) selectively and specifically reducing the risk factor reduces hard cardiovascular end points, such as mortality, nonfatal myocardial infarction, and stroke. For the risk markers reviewed here, we found only 2 clinical trials (both for homocysteine) meeting the latter criterion,110, 113 although we are aware that a number are in progress, particularly with respect to homocysteine and CRP.50, 119
Fourth, the diagnostic characteristics of any screening test are only applicable to the population from which they are derived. The sensitivity and specificity of a test may vary according to prevalence or spectrum of severity of disease in a given population.120 It is therefore critical that promising data on novel risk factor screening in a secondary prevention population, for instance, not be generalized to apparently healthy, asymptomatic individuals with vascular risk factors, or vice versa, in the case of CRP. Furthermore, as each population may be heterogeneous with respect to patient characteristics, it is likely that no single level of a candidate risk factor can be derived that is adequate for all subgroups.
One of the key motivating forces for searching for novel risk factors for ASVD has been the claim that only 50% of the risk of atherosclerosis can be explained by the classic, established risk factors.121-122 However, there appears to be no solid evidence on which this claim is based. Long-term follow-up from the Multiple Risk Factor Intervention Trial (MRFIT), a cohort of some 356 222 persons screened for primary prevention in the United States, showed that 92% of coronary heart disease deaths could be explained by suboptimal levels of cholesterol, blood pressure, cigarette smoking, and diabetes.8 Furthermore, the explanatory power of the most recent set of equations from the Framingham study, which in large part address the same variables, is approximately 75% to 77%.3 Even this figure is likely to be an underestimate of the true strength of the conventional risk factors, due to regression dilution bias, surrogate dilution effect, and misclassification error inherent in using arbitrary cutpoints for continuous risk factors.121, 123-124 Therefore, the explanatory power of the classic risk factors for ASVD is likely to be much higher than has been previously assumed.
There are other clear advantages to using a global risk assessment strategy, rather than relying on the measurement of single risk factors, whether conventional or novel. This has been reviewed in detail by Pasternak, who cites a number of important benefits.125 The use of global risk score (1) raises awareness that risk is continuous and graded and related to the overall burden of risk factors; (2) enables adjustment for the severity of individual component risk factors; (3) emphasizes that the clinician must approach the patient as a whole and not be excessively distracted by individual risk factors when multiple risk factors coexist; (4) promotes the use of risk-lowering strategies based on multiple components of an individual's risk; and (5) serves as a motivating, instructive force for both patients and clinicians. Furthermore, it should be noted that among many populations previously studied, levels of the classic vascular risk factors are suboptimally recognized and treated, and thus more emphasis should be placed on screening for and treating the conventional ASVD risk factors, given the proven value of targeting and lowering them.9, 126
There are, however, several situations for which we can envision measuring a panel of these 4 novel factors: (1) asymptomatic individuals with strong family histories of vascular disease in whom an excess of conventional risk factors is not apparent; (2) patients with premature vascular disease with no apparent explanatory factors; and (3) individuals with aggressive or recurrent vascular disease despite optimal management of all conventional risk factors (both by lifestyle and pharmacological means). However, it should be noted that evidence does not yet exist to support reducing these novel factors, yet the risk-benefit ratio could still be highly favorable (in some scenarios), given the innocuous nature of some therapies (eg, B vitamins) and the likelihood of further vascular events. With respect to CRP measurement, we agree with recent guidelines released by a joint panel of the American Heart Association and the Centers for Disease Control and Prevention that application of secondary prevention measures (either in the acute coronary syndrome setting or for long-term treatment of atherosclerosis) should not depend on CRP determination, since such patients are at heightened risk of future vascular events and should be targeted for aggressive treatment irrespective of CRP level.11
CONCLUSION
Despite support from epidemiological and basic science, more investigation is needed before measurement of CRP, Lp(a), fibrinogen, and homocysteine can be recommended for widespread use in primary or secondary prevention settings. The explanatory strength of the conventional risk factors has been underestimated, and perhaps in part because of this, detection and control of these important risks has been suboptimal across many populations. The focus of clinicians, policy makers, health care organizations, and patients must be on lowering the burden of proven, modifiable risk factors, including their upstream determinants (eg, obesity), if the burgeoning epidemic of CVD is to be altered.
AUTHOR INFORMATION
Corresponding Author and Reprints: Sonia S. Anand, MD, PhD, FRCP, Department of Medicine, Faculty of Health Sciences, McMaster University, 1200 Main St W, HSC—Rm 3X28, Hamilton, Ontario, Canada L8N 3Z5 (e-mail: anands{at}mcmaster.ca).
Author Contributions: Study concept and design: Hackam, Anand.
Acquisition of data: Hackam.
Analysis and interpretation of data: Hackam, Anand.
Drafting of the manuscript: Hackam, Anand.
Critical revision of the manuscript for important intellectual content: Hackam, Anand.
Statistical expertise: Hackam, Anand.
Administrative, technical, or material support: Hackam, Anand.
Study supervision: Anand.
Funding/Support: Dr Anand is a recipient of a Canadian Institutes of Health Research—Clinician-Scientist Award.
Author Affiliations: Population Health Research Institute and Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario.
REFERENCES
1. World Health Organization. The World Health Report 2002. Available at: http://www.who.int/whr/en. Accessibility verified July 16, 2003.
2. Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet. 1997;349:1269-1276.
FULL TEXT
|
ISI
| PUBMED
3. Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97:1837-1847.
FREE FULL TEXT
4. Keys A. Seven Countries: A Multivariate Analysis of Death and Coronary Heart Disease. Cambridge, Mass: Harvard University Press; 1980.
5. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.
FREE FULL TEXT
6. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med. 1997;157:2413-2446.
FREE FULL TEXT
7. Pearson TA, Blair SN, Daniels SR, et al. AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 Update: Consensus Panel Guide to Comprehensive Risk Reduction for Adult Patients Without Coronary or Other Atherosclerotic Vascular Diseases. American Heart Association Science Advisory and Coordinating Committee. Circulation. 2002;106:388-391.
FREE FULL TEXT
8. Stamler J, Stamler R, Neaton JD, et al. Low risk-factor profile and long-term cardiovascular and noncardiovascular mortality and life expectancy: findings for 5 large cohorts of young adult and middle-aged men and women. JAMA. 1999;282:2012-2018.
FREE FULL TEXT
9. Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization. Circulation. 2001;104:2746-2753.
FREE FULL TEXT
10. Pepys MB, Baltz ML. Acute phase proteins with special reference to C-reactive protein and related proteins (pentaxins) and serum amyloid A protein. Adv Immunol. 1983;34:141-212.
ISI
| PUBMED
11. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107:499-511.
FREE FULL TEXT
12. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med. 1999;340:115-126.
FREE FULL TEXT
13. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105:1135-1143.
FREE FULL TEXT
14. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347:1557-1565.
FREE FULL TEXT
15. Danesh J, Whincup P, Walker M, et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ. 2000;321:199-204.
FREE FULL TEXT
16. van Exel E, Gussekloo J, de Craen AJ, Bootsma-van der Wiel A, Frolich M, Westendorp RG. Inflammation and stroke: the Leiden 85-Plus Study. Stroke. 2002;33:1135-1138.
FREE FULL TEXT
17. Di Napoli M, Papa F, Bocola V. Prognostic influence of increased C-reactive protein and fibrinogen levels in ischemic stroke. Stroke. 2001;32:133-138.
FREE FULL TEXT
18. Muir KW, Weir CJ, Alwan W, Squire IB, Lees KR. C-reactive protein and outcome after ischemic stroke. Stroke. 1999;30:981-985.
FREE FULL TEXT
19. Biasucci LM, Liuzzo G, Grillo RL, et al. Elevated levels of C-reactive protein at discharge in patients with unstable angina predict recurrent instability. Circulation. 1999;99:855-860.
FREE FULL TEXT
20. Tommasi S, Carluccio E, Bentivoglio M, et al. C-reactive protein as a marker for cardiac ischemic events in the year after a first, uncomplicated myocardial infarction. Am J Cardiol. 1999;83:1595-1599.
FULL TEXT
|
ISI
| PUBMED
21. Heeschen C, Hamm CW, Bruemmer J, Simoons ML. Predictive value of C-reactive protein and troponin T in patients with unstable angina: a comparative analysis. CAPTURE Investigators. Chimeric c7E3 AntiPlatelet Therapy in Unstable angina REfractory to standard treatment trial. J Am Coll Cardiol. 2000;35:1535-1542.
FREE FULL TEXT
22. Zebrack JS, Muhlestein JB, Horne BD, Anderson JL. C-reactive protein and angiographic coronary artery disease: independent and additive predictors of risk in subjects with angina. J Am Coll Cardiol. 2002;39:632-637.
FREE FULL TEXT
23. Zebrack JS, Anderson JL, Maycock CA, Horne BD, Bair TL, Muhlestein JB. Usefulness of high-sensitivity C-reactive protein in predicting long-term risk of death or acute myocardial infarction in patients with unstable or stable angina pectoris or acute myocardial infarction. Am J Cardiol. 2002;89:145-149.
FULL TEXT
|
ISI
| PUBMED
24. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation. 1998;97:425-428.
FREE FULL TEXT
25. Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA. 2001;285:2481-2485.
FREE FULL TEXT
26. Walter DH, Fichtlscherer S, Britten MB, et al. Statin therapy, inflammation and recurrent coronary events in patients following coronary stent implantation. J Am Coll Cardiol. 2001;38:2006-2012.
FREE FULL TEXT
27. Chew DP, Bhatt DL, Robbins MA, et al. Incremental prognostic value of elevated baseline C-reactive protein among established markers of risk in percutaneous coronary intervention. Circulation. 2001;104:992-997.
FREE FULL TEXT
28. Walter DH, Fichtlscherer S, Sellwig M, Auch-Schwelk W, Schachinger V, Zeiher AM. Preprocedural C-reactive protein levels and cardiovascular events after coronary stent implantation. J Am Coll Cardiol. 2001;37:839-846.
FREE FULL TEXT
29. Milazzo D, Biasucci LM, Luciani N, et al. Elevated levels of C-reactive protein before coronary artery bypass grafting predict recurrence of ischemic events. Am J Cardiol. 1999;84:459-461, A9.
FULL TEXT
|
ISI
| PUBMED
30. Freeman DJ, Norrie J, Caslake MJ, et al. C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. Diabetes. 2002;51:1596-1600.
FREE FULL TEXT
31. Barzilay JI, Abraham L, Heckbert SR, et al. The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study. Diabetes. 2001;50:2384-2389.
FREE FULL TEXT
32. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001;286:327-334.
FREE FULL TEXT
33. Folsom AR, Aleksic N, Catellier D, Juneja HS, Wu KK. C-reactive protein and incident coronary heart disease in the Atherosclerosis Risk In Communities (ARIC) study. Am Heart J. 2002;144:233-238.
FULL TEXT
|
ISI
| PUBMED
34. Park R, Detrano R, Xiang M, et al. Combined use of computed tomography coronary calcium scores and C-reactive protein levels in predicting cardiovascular events in nondiabetic individuals. Circulation. 2002;106:2073-2077.
FREE FULL TEXT
35. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation. 2003;107:391-397.
FREE FULL TEXT
36. Torzewski M, Rist C, Mortensen RF, et al. C-reactive protein in the arterial intima: role of C-reactive protein receptor-dependent monocyte recruitment in atherogenesis. Arterioscler Thromb Vasc Biol. 2000;20:2094-2099.
FREE FULL TEXT
37. Zwaka TP, Hombach V, Torzewski J. C-reactive protein-mediated low density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation. 2001;103:1194-1197.
FREE FULL TEXT
38. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000;102:2165-2168.
FREE FULL TEXT
39. Torzewski J, Torzewski M, Bowyer DE, et al. C-reactive protein frequently colocalizes with the terminal complement complex in the intima of early atherosclerotic lesions of human coronary arteries. Arterioscler Thromb Vasc Biol. 1998;18:1386-1392.
FREE FULL TEXT
40. Verma S, Li SH, Badiwala MV, et al. Endothelin antagonism and interleukin-6 inhibition attenuate the proatherogenic effects of c-reactive protein. Circulation. 2002;105:1890-1896.
FREE FULL TEXT
41. Kushner I, Sehgal AR. Is high-sensitivity C-reactive protein an effective screening test for cardiovascular risk? Arch Intern Med. 2002;162:867-869.
FREE FULL TEXT
42. Weintraub WS, Harrison DG. C-reactive protein, inflammation and atherosclerosis: do we really understand it yet? Eur Heart J. 2000;21:958-960.
FREE FULL TEXT
43. Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation. 2001;103:1813-1818.
FREE FULL TEXT
44. Danesh J, Whincup P, Walker M, et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ. 2000;321:199-204.
FREE FULL TEXT
45. Smieja M, Yusuf S, Lonn E, et al. Inflammatory markers and risk of subsequent cardiovascular events in the HOPE trial [abstract]. American Heart Association Scientific Sessions; November 11-14, 2001; Anaheim, Calif.
46. Lloyd-Jones DM, Levy D. C-reactive protein in the prediction of cardiovascular events. N Engl J Med. 2003;348:1059-1061.
FREE FULL TEXT
47. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973-979.
FREE FULL TEXT
48. Ridker PM, Rifai N, Pfeffer MA, et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1998;98:839-844.
FREE FULL TEXT
49. Blake GJ, Ridker PM, Kuntz KM. Potential cost-effectiveness of C-reactive protein screening followed by targeted statin therapy for the primary prevention of cardiovascular disease among patients without overt hyperlipidemia. Am J Med. 2003;114:485-494.
FULL TEXT
|
ISI
| PUBMED
50. Bhatt DL, Topol EJ. Need to test the arterial inflammation hypothesis. Circulation. 2002;106:136-140.
FREE FULL TEXT
51. Milionis HJ, Winder AF, Mikhailidis DP. Lipoprotein (a) and stroke. J Clin Pathol. 2000;53:487-496.
FREE FULL TEXT
52. Gaw A, Boerwinkle E, Cohen JC, Hobbs HH. Comparative analysis of the apo(a) gene, apo(a) glycoprotein, and plasma concentrations of Lp(a) in three ethnic groups: evidence for no common "null" allele at the apo(a) locus. J Clin Invest. 1994;93:2526-2534.
ISI
| PUBMED
53. Kraft HG, Lingenhel A, Kochl S, et al. Apolipoprotein(a) kringle IV repeat number predicts risk for coronary heart disease. Arterioscler Thromb Vasc Biol. 1996;16:713-719.
FREE FULL TEXT
54. Lippi G, Guidi G. Lipoprotein(a): from ancestral benefit to modern pathogen? QJM. 2000;93:75-84.
FREE FULL TEXT
55. Craig WY, Ledue TB. Lipoprotein(a) and the acute phase response. Clin Chim Acta. 1992;210:231-232.
FULL TEXT
|
ISI
| PUBMED
56. Pillarisetti S, Paka L, Obunike JC, Berglund L, Goldberg IJ. Subendothelial retention of lipoprotein(a): evidence that reduced heparan sulfate promotes lipoprotein binding to subendothelial matrix. J Clin Invest. 1997;100:867-874.
ISI
| PUBMED
57. Grainger DJ, Kemp PR, Liu AC, Lawn RM, Metcalfe JC. Activation of transforming growth factor-beta is inhibited in transgenic apolipoprotein(a) mice. Nature. 1994;370:460-462.
FULL TEXT
| PUBMED
58. Poon M, Zhang X, Dunsky KG, Taubman MB, Harpel PC. Apolipoprotein(a) induces monocyte chemotactic activity in human vascular endothelial cells. Circulation. 1997;96:2514-2519.
FREE FULL TEXT
59. Loscalzo J. Lipoprotein(a): a unique risk factor for atherothrombotic disease. Arteriosclerosis. 1990;10:672-679.
FREE FULL TEXT
60. Li XN, Grenett HE, Benza RL, et al. Genotype-specific transcriptional regulation of PAI-1 expression by hypertriglyceridemic VLDL and Lp(a) in cultured human endothelial cells. Arterioscler Thromb Vasc Biol. 1997;17:3215-3223.
FREE FULL TEXT
61. Levin EG, Miles LA, Fless GM, et al. Lipoproteins inhibit the secretion of tissue plasminogen activator from human endothelial cells. Arterioscler Thromb. 1994;14:438-442.
FREE FULL TEXT
62. Ridker PM, Hennekens CH, Stampfer MJ. A prospective study of lipoprotein(a) and the risk of myocardial infarction. JAMA. 1993;270:2195-2199.
FREE FULL TEXT
63. Alfthan G, Pekkanen J, Jauhiainen M, et al. Relation of serum homocysteine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population based study. Atherosclerosis. 1994;106:9-19.
FULL TEXT
|
ISI
| PUBMED
64. Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease: meta-analysis of prospective studies. Circulation. 2000;102:1082-1085.
FREE FULL TEXT
65. Solfrizzi V, Panza F, Colacicco AM, et al. Relation of lipoprotein(a) as coronary risk factor to type 2 diabetes mellitus and low-density lipoprotein cholesterol in patients > or = 65 years of age (The Italian Longitudinal Study on Aging). Am J Cardiol. 2002;89:825-829.
FULL TEXT
|
ISI
| PUBMED
66. Cantin B, Despres JP, Lamarche B, et al. Association of fibrinogen and lipoprotein(a) as a coronary heart disease risk factor in men (The Quebec Cardiovascular Study). Am J Cardiol. 2002;89:662-666.
FULL TEXT
|
ISI
| PUBMED
67. von Eckardstein A, Schulte H, Cullen P, Assmann G. Lipoprotein(a) further increases the risk of coronary events in men with high global cardiovascular risk. J Am Coll Cardiol. 2001;37:434-439.
FREE FULL TEXT
68. Foody JM, Milberg JA, Robinson K, Pearce GL, Jacobsen DW, Sprecher DL. Homocysteine and lipoprotein(a) interact to increase CAD risk in young men and women. Arterioscler Thromb Vasc Biol. 2000;20:493-499.
FREE FULL TEXT
69. Marcovina SM, Albers JJ, Scanu AM, et al. Use of a reference material proposed by the International Federation of Clinical Chemistry and Laboratory Medicine to evaluate analytical methods for the determination of plasma lipoprotein(a). Clin Chem. 2000;46:1956-1967.
FREE FULL TEXT
70. Carlson LA, Hamsten A, Asplund A. Pronounced lowering of serum levels of lipoprotein Lp(a) in hyperlipidaemic subjects treated with nicotinic acid. J Intern Med. 1989;226:271-276.
ISI
| PUBMED
71. Herrick S, Blanc-Brude O, Gray A, Laurent G. Fibrinogen. Int J Biochem Cell Biol. 1999;31:741-746.
FULL TEXT
|
ISI
| PUBMED
72. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes (1). N Engl J Med. 1992;326:242-250.
ISI
| PUBMED
73. Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA. 1998;279:1477-1482.
FREE FULL TEXT
74. Di Minno G, Mancini M. Measuring plasma fibrinogen to predict stroke and myocardial infarction. Arteriosclerosis. 1990;10:1-7.
FREE FULL TEXT
75. Fey GH, Fuller GM. Regulation of acute phase gene expression by inflammatory mediators. Mol Biol Med. 1987;4:323-338.
ISI
| PUBMED
76. Maresca G, Di Blasio A, Marchioli R, Di Minno G. Measuring plasma fibrinogen to predict stroke and myocardial infarction: an update. Arterioscler Thromb Vasc Biol. 1999;19:1368-1377.
FREE FULL TEXT
77. Tanne D, Benderly M, Goldbourt U, et al. A prospective study of plasma fibrinogen levels and the risk of stroke among participants in the bezafibrate infarction prevention study. Am J Med. 2001;111:457-463.
FULL TEXT
|
ISI
| PUBMED
78. Folsom AR, Rosamond WD, Shahar E, et al. Prospective study of markers of hemostatic function with risk of ischemic stroke. The Atherosclerosis Risk in Communities (ARIC) Study Investigators. Circulation. 1999;100:736-742.
FREE FULL TEXT
79. Fowkes FG. Fibrinogen and peripheral arterial disease. Eur Heart J. 1995;16(suppl A):36-40.
80. Lee AJ, Fowkes FG, Lowe GD, Connor JM, Rumley A. Fibrinogen, factor VII and PAI-1 genotypes and the risk of coronary and peripheral atherosclerosis: Edinburgh Artery Study. Thromb Haemost. 1999;81:553-560.
ISI
| PUBMED
81. Meade TW, Imeson J, Stirling Y. Effects of changes in smoking and other characteristics on clotting factors and the risk of ischaemic heart disease. Lancet. 1987;2:986-988.
ISI
| PUBMED
82. Wilkes HC, Kelleher C, Meade TW. Smoking and plasma fibrinogen. Lancet. 1988;1:307-308.
ISI
| PUBMED
83. Ernst E, Resch KL. Therapeutic interventions to lower plasma fibrinogen concentration. Eur Heart J. 1995;16(suppl A):47-52.
84. Meade T, Zuhrie R, Cook C, Cooper J. Bezafibrate in men with lower extremity arterial disease: randomised controlled trial. BMJ. 2002;325:1139.
FREE FULL TEXT
85. Acevedo M, Pearce GL, Kottke-Marchant K, Sprecher DL. Elevated fibrinogen and homocysteine levels enhance the risk of mortality in patients from a high-risk preventive cardiology clinic. Arterioscler Thromb Vasc Biol. 2002;22:1042-1045.
FREE FULL TEXT
86. Mangoni AA, Jackson SH. Homocysteine and cardiovascular disease: current evidence and future prospects. Am J Med. 2002;112:556-565.
FULL TEXT
|
ISI
| PUBMED
87. De Bree A, Verschuren WM, Kromhout D, Kluijtmans LA, Blom HJ. Homocysteine determinants and the evidence to what extent homocysteine determines the risk of coronary heart disease. Pharmacol Rev. 2002;54:599-618.
FREE FULL TEXT
88. Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet. 1985;37:1-31.
ISI
| PUBMED
89. McCully KS. Homocystinuria, arteriosclerosis, methylmalonic aciduria, and methyltransferase deficiency: a key case revisited. Nutr Rev. 1992;50:7-12.
ISI
| PUBMED
90. Yap S, Naughten ER, Wilcken B, Wilcken DE, Boers GH. Vascular complications of severe hyperhomocysteinemia in patients with homocystinuria due to cystathionine beta-synthase deficiency: effects of homocysteine-lowering therapy. Semin Thromb Hemost. 2000;26:335-340.
FULL TEXT
|
ISI
| PUBMED
91. Kluijtmans LA, Boers GH, Kraus JP, et al. The molecular basis of cystathionine beta-synthase deficiency in Dutch patients with homocystinuria: effect of CBS genotype on biochemical and clinical phenotype and on response to treatment. Am J Hum Genet. 1999;65:59-67.
FULL TEXT
|
ISI
| PUBMED
92. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration. BMJ. 1998;316:894-898.
FREE FULL TEXT
93. Werstuck GH, Lentz SR, Dayal S, et al. Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. J Clin Invest. 2001;107:1263-1273.
ISI
| PUBMED
94. Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10:111-113.
FULL TEXT
|
ISI
| PUBMED
95. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002;325:1202.
FREE FULL TEXT
96. Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG. MTHFR 677CT polymorphism and risk of coronary heart disease: a meta-analysis. JAMA. 2002;288:2023-2031.
FREE FULL TEXT
97. Moller J, Nielsen GM, Tvedegaard KC, Andersen NT, Jorgensen PE. A meta-analysis of cerebrovascular disease and hyperhomocysteinaemia. Scand J Clin Lab Invest. 2000;60:491-499.
FULL TEXT
|
ISI
| PUBMED
98. Kelly PJ, Rosand J, Kistler JP, et al. Homocysteine, MTHFR 677CT polymorphism, and risk of ischemic stroke: results of a meta-analysis. Neurology. 2002;59:529-536.
FREE FULL TEXT
99. Ford ES, Smith SJ, Stroup DF, Steinberg KK, Mueller PW, Thacker SB. Homocyst(e)ine and cardiovascular disease: a systematic review of the evidence with special emphasis on case-control studies and nested case-control studies. Int J Epidemiol. 2002;31:59-70.
FREE FULL TEXT
100. Cleophas TJ, Hornstra N, van Hoogstraten B, van der MJ. Homocysteine, a risk factor for coronary artery disease or not? a meta-analysis. Am J Cardiol. 2000;86:1005-1009, A8.
FULL TEXT
|
ISI
| PUBMED
101. Christen WG, Ajani UA, Glynn RJ, Hennekens CH. Blood levels of homocysteine and increased risks of cardiovascular disease: causal or casual? Arch Intern Med. 2000;160:422-434.
FREE FULL TEXT
102. Bautista LE, Arenas IA, Penuela A, Martinez LX. Total plasma homocysteine level and risk of cardiovascular disease: a meta-analysis of prospective cohort studies. J Clin Epidemiol. 2002;55:882-887.
FULL TEXT
|
ISI
| PUBMED
103. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002;288:2015-2022.
FREE FULL TEXT
104. Spence JD, Howard VJ, Chambless LE, et al. Vitamin Intervention for Stroke Prevention (VISP) trial: rationale and design. Neuroepidemiology. 2001;20:16-25.
FULL TEXT
|
ISI
| PUBMED
105. The VITATOPS (Vitamins to Prevent Stroke) Trial: rationale and design of an international, large, simple, randomised trial of homocysteine-lowering multivitamin therapy in patients with recent transient ischaemic attack or stroke. Cerebrovasc Dis. 2002;13:120-126.
FULL TEXT
|
ISI
| PUBMED
106. MacMahon M, Kirkpatrick C, Cummings CE, et al. A pilot study with simvastatin and folic acid/vitamin B12 in preparation for the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH). Nutr Metab Cardiovasc Dis. 2000;10:195-203.
ISI
| PUBMED
107. Manson JE, Gaziano JM, Spelsberg A, et al. A secondary prevention trial of antioxidant vitamins and cardiovascular disease in women: rationale, design, and methods. The WACS Research Group. Ann Epidemiol. 1995;5:261-269.
FULL TEXT
| PUBMED
108. Bostom AG, Selhub J, Jacques PF, Rosenberg IH. Power shortage: clinical trials testing the "homocysteine hypothesis" against a background of folic acid-fortified cereal grain flour. Ann Intern Med. 2001;135:133-137.
FREE FULL TEXT
109. Genest J Jr, Audelin MC, Lonn E. Homocysteine: to screen and treat or to wait and see? CMAJ. 2000;163:37-38.
FREE FULL TEXT
110. Schnyder G, Roffi M, Pin R, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med. 2001;345:1593-1600.
FREE FULL TEXT
111. Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteine-lowering therapy with folic acid, vitamin B(12), and vitamin B(6) on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. JAMA. 2002;288:973-979.
FREE FULL TEXT
112. Lowe HC, Oesterle SN, Khachigian LM. Coronary in-stent restenosis: current status and future strategies. J Am Coll Cardiol. 2002;39:183-193.
FREE FULL TEXT
113. Lange HW, Dambrink J-H, Pasalary M, et al. Folate therapy increases in-stent restenosis: results from the Folate After Coronary Intervention Trial (FACIT). Presented at: American College of Cardiology 52nd Annual Scientific Meeting; Chicago, Ill; March 30, 2003.
114. Mosca L. C-reactive protein—to screen or not to screen? N Engl J Med. 2002;347:1615-1617.
FREE FULL TEXT
115. Lippi G, Guidi G. Standardization and clinical management of lipoprotein(a) measurements. Clin Chem Lab Med. 1998;36:5-16.
FULL TEXT
|
ISI
| PUBMED
116. Whicher JT. BCR/IFCC reference material for plasma proteins (CRM 470). Community Bureau of Reference. International Federation of Clinical Chemistry. Clin Biochem. 1998;31:459-465.
FULL TEXT
|
ISI
| PUBMED
117. D'Agostino RB Sr, Grundy S, Sullivan LM, Wilson P. Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation. JAMA. 2001;286:180-187.
FREE FULL TEXT
118. Wallis EJ, Ramsay LE, Haq IU, Ghahramani P, Jackson PR. Is coronary risk an accurate surrogate for cardiovascular risk for treatment decisions in mild hypertension? a population validation. J Hypertens. 2001;19:691-696.
FULL TEXT
|
ISI
| PUBMED
119. Doshi SN, Moat SJ, McDowell IF, Lewis MJ, Goodfellow J. Lowering plasma homocysteine with folic acid in cardiovascular disease: what will the trials tell us? Atherosclerosis. 2002;165:1-3.
FULL TEXT
|
ISI
| PUBMED
120. Moons KG, van Es GA, Deckers JW, Habbema JD, Grobbee DE. Limitations of sensitivity, specificity, likelihood ratio, and Bayes' theorem in assessing diagnostic probabilities: a clinical example. Epidemiology. 1997;8:12-17.
ISI
| PUBMED
121. Magnus P, Beaglehole R. The real contribution of the major risk factors to the coronary epidemics: time to end the "only-50%" myth. Arch Intern Med. 2001;161:2657-2660.
FREE FULL TEXT
122. Beaglehole R, Magnus P. The search for new risk factors for coronary heart disease: occupational therapy for epidemiologists? Int J Epidemiol. 2002;31:1117-1122.
FREE FULL TEXT
123. Clarke R, Shipley M, Lewington S, et al. Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies. Am J Epidemiol. 1999;150:341-353.
FREE FULL TEXT
124. Law MR, Wald NJ, Wu T, Hackshaw A, Bailey A. Systematic underestimation of association between serum cholesterol concentration and ischaemic heart disease in observational studies: data from the BUPA study. BMJ. 1994;308:363-366.
FREE FULL TEXT
125. Pasternak RC. Adjusting therapy to cardiovascular risk status. Am J Med. 1999;107(2A):31S-33S.
PUBMED
126. Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular diseases, part II: variations in cardiovascular disease by specific ethnic groups and geographic regions and prevention strategies. Circulation. 2001;104:2855-2864.
FREE FULL TEXT
Clinical Cardiology Section Editor: Michael S. Lauer, MD, Contributing Editor.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Differential effects of insulin deprivation and systemic insulin treatment on plasma protein synthesis in type 1 diabetic people
Jaleel et al.
Am. J. Physiol. Endocrinol. Metab. 2009;297:E889-E897.
ABSTRACT
| FULL TEXT
Relation between coronary atherosclerotic plaques and traditional risk factors in people with no history of cardiovascular disease undergoing multi-detector computed coronary angiography
Faletra et al.
Heart 2009;95:1265-1272.
ABSTRACT
| FULL TEXT
Criteria for Evaluation of Novel Markers of Cardiovascular Risk: A Scientific Statement From the American Heart Association
Hlatky et al.
Circulation 2009;119:2408-2416.
ABSTRACT
| FULL TEXT
Comparison of Gadofluorine-M and Gd-DTPA for Noninvasive Staging of Atherosclerotic Plaque Stability Using MRI
Ronald et al.
Circ Cardiovasc Imaging 2009;2:226-234.
ABSTRACT
| FULL TEXT
National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Emerging Biomarkers for Primary Prevention of Cardiovascular Disease
NACB LMPG Committee Members et al.
Clin. Chem. 2009;55:378-384.
ABSTRACT
| FULL TEXT
Evaluating cardiovascular risk assessment for asymptomatic people
Scott
BMJ 2009;338:a2844-a2844.
FULL TEXT
Ethnicity and peripheral artery disease
Bennett et al.
QJM 2009;102:3-16.
ABSTRACT
| FULL TEXT
Association Between Protein-Bound Sialic Acid and High-Sensitivity C-Reactive Protein in Essential Hypertension: A Possible Indication of Underlying Cardiovascular Risk
Sathiyapriya et al.
ANGIOLOGY 2009;59:721-726.
ABSTRACT
Heart rate and mortality from cardiovascular causes: a 12 year follow-up study of 379 843 men and women aged 40-45 years
Tverdal et al.
Eur Heart J 2008;29:2772-2781.
ABSTRACT
| FULL TEXT
Hyperhomocysteinemia and Lower Extremity Wounds
Schwartzfarb and Romanelli
INT J LOW EXTREM WOUNDS 2008;7:126-136.
ABSTRACT
Angiotensin-Converting Enzyme Insertion/Deletion Gene Polymorphic Variant as a Marker of Coronary Artery Disease: A Meta-analysis
Zintzaras et al.
Arch Intern Med 2008;168:1077-1089.
ABSTRACT
| FULL TEXT
Preventing Heart Disease in the 21st Century: Implications of the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Study
McGill et al.
Circulation 2008;117:1216-1227.
FULL TEXT
C-reactive Protein Level and Risk of Aging Macula Disorder: The Rotterdam Study
Boekhoorn et al.
Arch Ophthalmol 2007;125:1396-1401.
ABSTRACT
| FULL TEXT
Uraemic plasma decreases the expression of ABCA1, ABCG1 and cell-cycle genes in human coronary arterial endothelial cells
Cardinal et al.
Nephrol Dial Transplant 2007;22:409-416.
ABSTRACT
| FULL TEXT
Albuminuria as risk factor for initiation and progression of carotid atherosclerosis in non-diabetic persons: the Tromso Study
Jorgensen et al.
Eur Heart J 2007;28:363-369.
ABSTRACT
| FULL TEXT
The Relationship Between Circulating Fibrinogen and Lipoprotein (a) Levels in Patients With Primary Dyslipidemia
Ganotakis et al.
CLIN APPL THROMB HEMOST 2007;13:35-42.
ABSTRACT
Sleep Apnoea & Hypertension: Physiological bases for a causal relation: Intermittent hypoxia and vascular function: implications for obstructive sleep apnoea
Foster et al.
Exp Physiol 2007;92:51-65.
ABSTRACT
| FULL TEXT
Differential effects of oral conjugated equine estrogen and transdermal estrogen on atherosclerotic vascular disease risk markers and endothelial function in healthy postmenopausal women
Ho et al.
Hum Reprod 2006;21:2715-2720.
ABSTRACT
| FULL TEXT
Insight into the nature of the CRP-coronary event association using Mendelian randomization
Casas et al.
Int J Epidemiol 2006;35:922-931.
ABSTRACT
| FULL TEXT
Potential New Risk Factors for Ischemic Stroke: What Is Their Potential?
Hankey
Stroke 2006;37:2181-2188.
ABSTRACT
| FULL TEXT
Additive Value of Immunoassay-Measured Fibrinogen and High-Sensitivity C-Reactive Protein Levels for Predicting Incident Cardiovascular Events
Mora et al.
Circulation 2006;114:381-387.
ABSTRACT
| FULL TEXT
Biomarkers of Cardiovascular Disease: Molecular Basis and Practical Considerations
Vasan
Circulation 2006;113:2335-2362.
FULL TEXT
Confounding of the Relation between Homocysteine and Peripheral Arterial Disease by Lead, Cadmium, and Renal Function
Guallar et al.
Am J Epidemiol 2006;163:700-708.
ABSTRACT
| FULL TEXT
Dietary choline and betaine assessed by food-frequency questionnaire in relation to plasma total homocysteine concentration in the Framingham Offspring Study.
Cho et al.
Am. J. Clin. Nutr. 2006;83:905-911.
ABSTRACT
| FULL TEXT
Periodontal Infections and Coronary Heart Disease: Role of Periodontal Bacteria and Importance of Total Pathogen Burden in the Coronary Event and Periodontal Disease (CORODONT) Study.
Spahr et al.
Arch Intern Med 2006;166:554-559.
ABSTRACT
| FULL TEXT
Serum C-reactive protein as a marker for wellness assessment.
Kao et al.
Annals of Clinical & Laboratory Science 2006;36:163-169.
ABSTRACT
| FULL TEXT
Non-High-Density Lipoprotein Cholesterol and Apolipoprotein B in the Prediction of Coronary Heart Disease in Men
Pischon et al.
Circulation 2005;112:3375-3383.
ABSTRACT
| FULL TEXT
When Is a New Prediction Marker Useful?: A Consideration of Lipoprotein-Associated Phospholipase A2 and C-Reactive Protein for Stroke Risk
Greenland and O'Malley
Arch Intern Med 2005;165:2454-2456.
FULL TEXT
Does Elevated Plasma Fibrinogen Increase the Risk of Coronary Heart Disease?: Evidence from a Meta-Analysis of Genetic Association Studies
Smith et al.
Arterioscler. Thromb. Vasc. Bio. 2005;25:2228-2233.
ABSTRACT
| FULL TEXT
Role of C-Reactive Protein in Atherogenesis: Can the Apolipoprotein E Knockout Mouse Provide the Answer?
Reifenberg et al.
Arterioscler. Thromb. Vasc. Bio. 2005;25:1641-1646.
ABSTRACT
| FULL TEXT
Integrating Complementary Medicine Into Cardiovascular Medicine: A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents (Writing Committee to Develop an Expert Consensus Document on Complementary and Integrative Medicine)
Vogel et al.
J Am Coll Cardiol 2005;46:184-221.
FULL TEXT
Effect of Lowering of Homocysteine Levels on Inflammatory Markers: A Randomized Controlled Trial
Durga et al.
Arch Intern Med 2005;165:1388-1394.
ABSTRACT
| FULL TEXT
Supplementation with Conjugated Linoleic Acid for 24 Months Is Well Tolerated by and Reduces Body Fat Mass in Healthy, Overweight Humans
Gaullier et al.
J. Nutr. 2005;135:778-784.
ABSTRACT
| FULL TEXT
Monocyte Count Is a Predictor of Novel Plaque Formation: A 7-Year Follow-up Study of 2610 Persons Without Carotid Plaque at Baseline The Tromso Study
Johnsen et al.
Stroke 2005;36:715-719.
ABSTRACT
| FULL TEXT
Risk reduction studies in schizophrenia * Author's reply:
Chaturvedi and Niemi
Br. J. Psychiatry 2005;186:355-356.
FULL TEXT
Biochemical risk markers: a novel area for better prediction of renal risk?
Stuveling et al.
Nephrol Dial Transplant 2005;20:497-508.
FULL TEXT
Conditional Risk Factors for Atherosclerosis
Kullo and Ballantyne
Mayo Clin Proc. 2005;80:219-230.
ABSTRACT
Postprandial dysmetabolism and cardiovascular disease in type 2 diabetes
Tushuizen et al.
Postgrad. Med. J. 2005;81:1-6.
ABSTRACT
| FULL TEXT
CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: Ability of Inflammatory Markers to Predict Disease in Asymptomatic Patients: A Background Paper
Wilson
Circulation 2004;110:e568-e571.
ABSTRACT
| FULL TEXT
Inflammatory Markers and the Risk of Coronary Heart Disease in Men and Women
Pai et al.
NEJM 2004;351:2599-2610.
ABSTRACT
| FULL TEXT
Low-Grade Inflammation and Microalbuminuria in Hypertension
Pedrinelli et al.
Arterioscler. Thromb. Vasc. Bio. 2004;24:2414-2419.
ABSTRACT
| FULL TEXT
History of Emerging Vascular Disease Risk Factors
Pilgeram
JAMA 2004;292:2086-2086.
FULL TEXT
Braving New Worlds: To Conquer, to Endure
Moffat
ptjournal 2004;84:1056-1086.
ABSTRACT
| FULL TEXT
Poor Predictive Value of High-Sensitivity C-Reactive Protein Indicates Need for Reassessment
Levinson et al.
Clin. Chem. 2004;50:1733-1735.
FULL TEXT
Uteroplacental insufficiency alters DNA methylation, one-carbon metabolism, and histone acetylation in IUGR rats
MacLennan et al.
Physiol. Genomics 2004;18:43-50.
ABSTRACT
| FULL TEXT
Conjugated linoleic acid supplementation for 1 y reduces body fat mass in healthy overweight humans
Gaullier et al.
Am. J. Clin. Nutr. 2004;79:1118-1125.
ABSTRACT
| FULL TEXT
C-reactive protein for the prediction of cardiovascular risk: Ready for prime-time?
Hackam and Shumak
CMAJ 2004;170:1563-1565.
FULL TEXT
Is there a need for novel cardiovascular risk factors?
von Eckardstein
Nephrol Dial Transplant 2004;19:761-765.
FULL TEXT
Novel Risk Factors for Atherosclerosis
von Eckardstein
JAMA 2004;291:301-301.
FULL TEXT
Novel Risk Factors for Atherosclerosis
Davidson
JAMA 2004;291
:301-301.
FULL TEXT
Beyond (or Back to) Traditional Risk Factors: Preventing Cardiovascular Disease in Patients with Chronic Kidney Disease
Appel
ANN INTERN MED 2004;140:60-61.
FULL TEXT
Traditional CHD Risk Factors: Still the Ones to Watch
Journal Watch Cardiology 2003;2003:4-4.
FULL TEXT
New Risk Factors for Vascular Disease Not Ready to Be Used for Screening
JWatch Emergency Med. 2003;2003:5-5.
FULL TEXT
Major Risk Factors for Cardiovascular Disease: Debunking the "Only 50%" Myth
Canto and Iskandrian
JAMA 2003;290:947-949.
FULL TEXT
|
