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(Stroke. 2006;37:2181.)
© 2006 American Heart Association, Inc.

Comments, Opinions, and Reviews

Potential New Risk Factors for Ischemic Stroke

What Is Their Potential?

From the Stroke Unit, Royal Perth Hospital, Perth, and the School of Medicine and Pharmacology, University of Western Australia, Perth, Australia.

Correspondence to Clinical Professor Graeme J. Hankey, Stroke Unit, Department of Neurology, Royal Perth Hospital, 197 Wellington St, Perth, Australia, 6001. E-mail gjhankey{at}cyllene.uwa.edu.au

	Abstract

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Background and Purpose— About 60% to 80% of all ischemic strokes can be attributed to increasing blood pressure, blood cholesterol, cigarette smoking, carotid stenosis, and diabetes mellitus (atherosclerotic ischemic stroke), and atrial fibrillation and valvular heart disease (cardiogenic ischemic stroke). The aim of this review was to examine the potential role of other risk factors in the etiology of ischemic stroke.

Summary of Review— About 10% to 20% of atherosclerotic ischemic strokes can probably be attributed to recently established, causal risk factors for ischemic heart disease: raised apoB/apoA 1 ratio, obesity, physical inactivity, pyschosocial stress and low fruit and vegetable intake. However, their causal role remains to be proven. The direct genetic contribution of any single gene towards ischemic stroke is likely to be modest and apply in selected patients only and in combination with environmental factors or via other epistatic (gene-gene or gene-environmental) effects.

Conclusions— Research resources should not be allocated disproportionately to emerging novel risk factors that may account for up to only 20% of all strokes at the expense of researching the determinants of the relatively few established causal factors that account for up to 80% of all strokes.

Key Words: cerebral infarct • risk factors

	Introduction

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A risk factor for ischemic stroke is a characteristic in an individual that indicates that the individual has an increased risk of ischemic stroke compared with an individual without that characteristic. It does not necessarily imply that the risk factor causes ischemic stroke; it may simply be a marker of a causal risk factor (eg, having a cigarette lighter is a risk factor for stroke but only as a marker of current smoking). The causal significance of any risk factor depends on the factors listed in Table 1.

	Causal Risk Factors for Ischemic Stroke

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Increasing blood pressure, increasing blood cholesterol, carotid stenosis, and atrial fibrillation are definite causal risk factors for ischemic stroke because randomized controlled trials (RCTs) have shown that treating them reduces the incidence of ischemic stroke.^1–5

Cigarette smoking, diabetes mellitus, ischemic heart disease, and valvular heart disease are probably also causal risk factors for ischemic stroke because epidemiological case-control and cohort studies have shown that these characteristics are significantly associated with an increased risk of stroke; moreover, the association is strong, consistent among studies, biologically plausible, and independent of other factors that were measured and analyzed (Table 1).^6–11 However, it is possible that these associations are confounded by other factors that have not been measured and analyzed in epidemiological studies—uncontrolled confounding—as highlighted by recent unequivocal evidence from RCTs that hormone replacement therapy and antioxidant vitamins do not reduce the risk of stroke,^12,13 despite strong previous evidence from epidemiological studies suggesting the contrary.^14–16

	Population-Attributable Risk of Causal Risk Factors

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Population-based studies in Rochester, Minn, in which the prevalence of risk factors for stroke in the population and the relative risk of stroke for each risk factor were analyzed by means of multiple logistic-regression techniques, estimate that the population-attributable risk (PAR) of ischemic stroke due to all 7 of the major risk factors combined is 57% (95% CI, 48% to 67%; Table 2).¹⁷ The PAR is the risk of ischemic stroke in a total population that can be attributed to exposure to a specific risk factor or constellation of risk factors: the difference between the risk in the total population and the risk in the unexposed group. This means that 57% of all cases of ischemic stroke in the population of Rochester, Minn (at the time of the study) could be attributable to the 7 causal risk factors listed in Table 2. If serum cholesterol and carotid stenosis^2–4 had also been included in this analysis, it is likely that up to 80% of all ischemic strokes could be attributed to these risk factors. If this is correct, potential new risk factors for ischemic stroke are unlikely to account for more than 20% of all ischemic strokes. It may therefore be more cost-effective to apply the "80/20 rule" to stroke prevention and redistribute some of the substantial resources that are being assigned to the quest for discovering new risk factors (which are unlikely to add much more to risk prediction and modification) to the quest to better understand the determinants of established causal risk factors and implement effective strategies of minimizing long-term exposure to these causal risk factors. But are these estimates correct?

	Validation

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The estimates derived from the Rochester data are likely to be internally valid because the bootstrap method, which is a multiple resampling procedure, was used to validate the model, the coefficient estimates, and their standard errors.^17,18

The external validity (ie, generalizability to other populations and to the year 2006) of the estimates are supported by a comprehensive review of published work and other sources (eg, government reports and international databases), which have reported that 70% to 76% of the disease burden associated with stroke and 65% to 73% of mortality due to stroke could be attributed to 7 major risk factors, 3 of which are established causal risk factors for stroke (high blood pressure, tobacco use, high cholesterol) and 4 of which are "newer" risk factors (low fruit and vegetable intake, physical inactivity, obesity as measured by a high body mass index [BMI], and alcohol use) for stroke and myocardial infarction (see following section and Table 3).^19,20

Another way of assessing whether the estimates are externally valid is to explore whether the established causal risk factors for ischemic stroke also account for a similar proportion of ischemic heart disease (IHD) events. One caveat of this approach is that the etiology of ischemic stroke is more heterogeneous than that for IHD (50% of ischemic stroke is caused by large-artery atherosclerosis; 25%, small-vessel disease; 20%, cardiac embolism; and 5%, a miscellany of causes such as arterial dissection²¹). Moreover, risk factors may be different for different etiological subtypes of ischemic stroke (eg, atrial fibrillation and mitral valve disease are risk factors for cardioembolic ischemic stroke only but not for atherosclerotic ischemic stroke or IHD).²² Hence, the PAR of all causal risk factors for atherosclerotic ischemic stroke can be only 50% to 75% for all ischemic stroke (as high as 75% if large-artery atherosclerosis and intracranial small-vessel disease share the same causal risk factors and as low as 50% if they do not²³).

Nevertheless, 3 studies of patients with IHD suggest that the aforementioned causal risk factors for atherosclerotic ischemic stroke (Table 2) are also causal risk factors for atherosclerotic IHD. The Framingham Study and the Third National Health and Nutrition Examination Survey reported that raised levels of at least 1 of 5 causal risk factors (blood pressure, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels, glucose intolerance, and smoking) accounted for 90% of the PAR of IHD events.²⁴ The INTERHEART study of 15 152 cases of acute myocardial infarction (MI) and of 14 820 controls found that 9 risk factors (Table 4) accounted for 90% of the PAR of acute MI.²⁵ Although a substantial proportion of cases of MI could be attributed to known causal risk factors for stroke (smoking, hypertension, diabetes), a substantial proportion could be attributable to other, newer risk factors for MI, such as a raised apolipoprotein (apo) B–apo A1 ratio, abdominal obesity, psychosocial stress, lack of daily fruit and vegetable intake, lack of exercise for 4 hours or more per week, and lack of regular alcohol consumption 3 or more times per week (Table 4).²⁵

	Are the Newer Risk Factors for MI Also New Risk Factors for Atherosclerotic Ischemic Stroke?

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Raised Apo B–Apo A1 Ratio
Apo B plasma levels reflect the concentration of the proatherogenic lipoproteins very low-density lipoprotein (VLDL) and LDL because each VLDL and LDL particle has 1 molecule of apo B.²⁶ The plasma concentration of apo B has recently been reported to be the best lipid predictor of coronary heart disease.^26,27 Among 286 patients with transient ischemic attack who were assessed at baseline and followed up for 10 years, a raised apo B–apo A1 ratio was also a stronger risk factor to subsequent stroke, after adjusting for other vascular risk factors (hazard ratio [HR], 2.9; 95% CI, 1.4 to 5.9) than other lipid measurements (apo B [HR, 2.3; 95% CI, 1.1 to 4.5], total cholesterol [HR, 1.8; 95% CI, 0.9 to 3.3], LDL cholesterol [HR, 1.5; 95% CI, 0.8 to 2.8]; LDL/HDL [HR, 1.3; 95% CI, 0.7 to 2.4], apo A1 [HR, 1.2; 95% CI, 0.6 to 2.2], and HDL [HR, 1.0; 95% CI, 0.5 to 1.9]).²⁸ These results await confirmation in other studies.

Abdominal Obesity
General obesity, as measured by a raised BMI, and abdominal obesity, as measured by a raised waist-to-hip ratio, have been reported as independent risk factors for stroke.^29–33 A prospective, observational, cohort study of 21 414 US male physicians followed up for 12.5 years (mean) for the occurrence of 631 ischemic strokes found that a BMI 30 kg/m² was associated with an adjusted relative risk (RR) of ischemic stroke of 2.0 (95% CI, 1.5 to 2.7) compared with men with a BMI <30 kg/m².³⁰ Furthermore, each unit increase in BMI was associated with a 6% (95% CI, 3% to 8%) increase in the RR of ischemic stroke.³⁰ Almost identical results were reported subsequently in an observational study of 7402 healthy Swedish men aged 47 to 55 years who were followed up for 28 years for the occurrence of 495 ischemic strokes.³² Although hypertension, diabetes, and cholesterol levels are mediators in the link between obesity and stroke (as evidenced by attenuation of the magnitude of the RR of stroke after adjusting for these factors), the significant association between obesity and stroke risk persists, independent of these factors.

Lack of Exercise for 4 Hours or More per Week
A meta-analysis of 23 studies from 1966 to 2002 reported that compared with low physical activity, individuals with high physical activity have a significantly lower risk of stroke (RR, 0.79; 95% CI, 0.69 to 0.91).³⁴ A more recent observational study of 47 721 Finnish people aged 25 to 64 years followed up for 19 years (mean) for the occurrence of 2264 ischemic strokes found that, compared with low leisure time physical activity (sedentary), self-reported moderate leisure time physical activity (>4 hours per week of walking, cycling, or light gardening) was associated with an adjusted RR of ischemic stroke of 0.87 (95% CI, 0.79 to 0.95).³⁵ High leisure time physical activity (>3 hours per week of jogging, swimming, heavy gardening, or regular sports several times per week) was associated with an adjusted RR of ischemic stroke of 0.80 (95% CI, 0.63 to 0.93; P for trend=0.001).³⁵ Active commuting (walking/cycling) to work for 30 or more minutes daily was also associated with a significant reduction in risk of ischemic stroke (RR, 0.86; 95% CI, 0.76 to 0.96).³⁵

Lack of Daily Fruit and Vegetable Intake
A meta-analysis of 7 cohort studies involving a total of 242 049 men and women followed up for 3 to 20 years for the occurrence of 2955 strokes reported that the risk of stroke decreased by 11% (RR, 0.89; 95% CI, 0.85 to 0.93) for each additional portion per day of fruit, by 5% (RR, 0.95; 95% CI, 0.92 to 0.97) for fruit and vegetables, and by 3% (RR, 0.97; 95% CI, 0.92 to 1.02) for vegetables, after adjusting for factors known to be more common among fruit consumers such as (less) smoking, (more) exercise, and (higher) education.³⁶

Lack of Regular Alcohol Consumption 3 or More Times per Week
A meta-analysis of 35 studies from 1966 to 2002 reported that, compared with abstainers of alcohol, individuals who consumed <12 g daily (1 standard drink) of alcohol had a significantly lower adjusted RR of ischemic stroke (RR, 0.80; 95% CI, 0.67 to 0.96), as did individuals who consumed 12 to 24 g daily (1 to 2 standard drinks) of alcohol (RR, 0.72; 95% CI, 0.57 to 0.91).³⁷ However, individuals who consumed >60 g daily of alcohol had a significantly higher adjusted RR of ischemic stroke (RR, 1.69; 95% CI, 1.3 to 2.1).³⁷ A recent observational study of 38 156 US male health professionals followed up for 14 years (mean) for the occurrence of 412 ischemic strokes found that, compared with abstainers of alcohol, the adjusted RR of ischemic stroke was 0.99 (95% CI, 9.72 to 1.37) for light drinkers who consumed 0.1 to 9.9 g daily (1 standard drink), 1.26 (95% CI, 0.90 to 1.76) for moderate drinkers of 10 to 29.9 g daily (1 to 2 standard drinks), and 1.42 (95% CI, 0.97 to 2.09) for heavy drinkers of 30 g daily (3 standard drinks).³⁸ Moderate consumption of alcohol (10.0 to 29.9 g per day on 3 or 4 days per week) was associated with the lowest RR of ischemic stroke (RR, 0.68; 95% CI, 0.44 to 1.05).³⁸ These results are consistent with those for MI in the INTERHEART study,²⁵ but they could also reflect uncontrolled confounding (eg, people who drink alcohol in moderation may also be likely to do other unmeasured but stroke-protective behaviors in moderation, in contrast to people who do not drink at all who may be more likely to not do other unmeasured but stroke-protective behaviors at all).³⁹

Psychosocial Stress
Major life events and depression have been associated with an increased risk of stroke, but the data are limited.^40,41 A prospective, observational, cohort study of 2805 Australians >60 years of age followed up for 5 years (median) for the occurrence of 306 incident ischemic strokes found that, compared with the lowest tertile of depression, the adjusted RR of ischemic stroke was 1.2 (95% CI, 0.8 to 1.6) for the second tertile and 1.4 (95% CI, 1.0 to 2.0) for the third tertile.⁴¹

Interpretation
The aforementioned studies indicate that the newer risk factors for MI reported in the INTERHEART study are also newer risk factors for atherosclerotic ischemic stroke. However, proof of a causal relationship remains elusive in the absence of evidence from RCTs. And if a causal relationship is proven, the incremental PAR of any of these risk factors, over and above that contributed by established causal risk factors, remains to be quantified.

	Potential New Risk Factors for Ischemic Stroke

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Numerous potential novel risk factors for ischemic stroke have been proposed (Table 5),^42–45 but the quality and volume of the published data are inconclusive,⁴⁶ and there is no evidence (yet) that reducing exposure to any of them reduces the risk of stroke. The evidence for (arguably) the most promising of these factors is discussed next.

Inherited Susceptibility
A family history of stroke is a risk factor for ischemic stroke, but the mechanisms remain uncertain. Inherited susceptibility to ischemic stroke may result from the direct effect of a single gene on the risk of stroke at a young age (before environmental and behavioral factors have had time to modify the phenotype), interactions of a gene with environmental or behavioral factors, an additive effect of several genes (a gene-dose effect), or synergistic coeffects of several genes.⁴⁷ A classical mendelian pattern of inheritance of single-gene disorders is rare, accounting for <1% of cases of ischemic stroke.⁴⁷

At least part of any heritability of ischemic stroke is a genetic susceptibility to hypertension (as manifested by a strong association between family history of stroke and hypertension).^48–51 Another part of any heritability of ischemic stroke may be contributed by common variants in several genes, each exerting a modest effect.⁴³ A meta-analysis of 120 case-control studies of 32 genes involving 18 000 cases of stroke and 58 000 controls identified statistically significant associations with ischemic stroke for the 4 most heavily investigated candidate genes: angiotensin-converting enzyme insertion/deletion (odds ratio [OR], 1.21; 95% CI, 1.08 to 1.35), factor V Leiden Arg 506 Gln (OR, 1.33; 95% CI, 1.12 to 1.58), prothrombin G20210A (OR, 1.44; 95% CI, 1.11 to 1.86), and methylenetetrahydrofolate reductase (MTHFR) C677T (OR, 1.24; 95% CI, 1.08 to 1.42).^51–53 No statistically significant association with ischemic stroke was detected for the 3 next most investigated genes: human platelet antigen type 1 (OR, 1.11; 95% CI, 0.95 to 1.28), factor XIII (OR, 0.97; 95% CI, 0.75 to 1.25), and apo E (OR, 0.96; 95% CI, 0.84 to 1.11).⁵¹ The PARs for the 4 significant polymorphisms ranged from 1.3% for prothrombin G20210A to 4.5% for angiotensin-converting enzyme insertion/deletion, values that are far lower than those reported for established causal risk factors for ischemic stroke (Tables 2 and 3).⁵¹

A subsequent meta-analysis of 7 case-control studies involving 3243 stroke cases and 3804 controls reported a significant association between stroke and the gene encoding phosphodiesterase 4D, single-nucleotide polymorphism (SNP) 87 (pooled P=0.001), SNP 83 (0.003), SNP 56 (0.03), and SNP 41 (0.02).⁵⁴ However, there was statistical heterogeneity (P<0.1) among the studies in the direction of association for each of the individual SNPs tested. Preliminary reports suggest that the 5-lipoxygenase–activating protein gene may also be associated with an increased risk of ischemic stroke, but the results are inconsistent, reflecting underpowered case-control studies.^55,56

Inflammatory Markers
Leukocyte and Monocyte Counts
A meta-analysis of 19 prospective studies involving 7229 patients followed up for 8 years (mean) revealed that, compared with individuals with a leukocyte count in the lowest tertile, the highest tertile yielded an increased risk of IHD (RR, 1.5; 95% CI, 1.4 to 1.6).⁵⁷ In the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, patients with a history of stroke, MI, or peripheral arterial disease who had a baseline leukocyte count in the highest quartile had a higher adjusted risk of recurrent ischemic events compared with those in the lowest quartile (RR, 1.42; 95% CI, 1.25 to 1.63 overall; RR, 1.30; 95% CI, 1.56, and 1.51 for stroke, MI, and vascular death).⁵⁸ Monocyte count has been reported to be an independent predictor of future carotid artery atherosclerotic plaque formation in subjects without preexisting carotid atherosclerosis.⁵⁹

High-Sensitivity C-Reactive Protein
More than 20 prospective epidemiological studies demonstrate that high-sensitivity C-reactive protein is an independent predictor of stroke, MI, and vascular death in apparently healthy individuals.^44,60 Among 1462 individuals registered in the Framingham study, each quartile increase in plasma concentration of C-reactive protein at baseline was associated with an increased adjusted RR of ischemic stroke and transient ischemic attack by 1.25 (95% CI, 1.0 to 1.54) in men and by 1.29 (95% CI, 1.07 to 1.55) in women after 12 to 14 years of follow-up.⁶¹

Infection
Observational studies suggest that infection may be a risk factor for stroke and coronary events.⁶² Furthermore, Chlamydia pneumoniae DNA and/or antigen have been detected in at least 40% of atherosclerotic plaques of patients in various parts of the world,⁶³ and rabbits inoculated with C pneumoniae have developed inflammatory lesions in arteries.⁶³ However, a meta-analysis of RCTs⁶⁴ and 2 subsequent RCTs^65,66 suggest that antibiotic therapy fails to prevent the occurrence of serious cardiovascular events, at least in patients with established coronary artery disease. Prospective epidemiological studies based on serology may help to better distinguish cause from consequence.⁶⁷

Hemostatic Factors: Fibrinogen
A meta-analysis of 3 prospective studies of 5113 patients with transient ischemic attack and minor ischemic stroke who were followed up for 5 years revealed that fibrinogen concentrations above the median were associated with an increased risk of ischemic stroke, compared with those below the median (HR, 1.34; 95% CI, 1.13 to 1.60).⁶⁸ The association was stronger in patients with nonlacunar (HR, 1.42; 95% CI, 1.13 to 1.78) than lacunar (HR, 1.09; 95% CI, 0.80 to 1.49) syndromes but not significantly so (P=0.018).⁶⁸ The relation between increasing fibrinogen levels and risk of ischemic stroke (and also acute coronary events) was linear.⁶⁸

Other Factors
Homocysteine
Systematic reviews of observational studies have consistently shown a strong, positive, independent and dose-related association between total plasma homocysteine (tHcy) and the risk of stroke, and laboratory studies have shown that the association is biologically plausible.⁶⁹ Furthermore, a meta-analysis of genetic association studies shows that natural (mendelian) randomization to the MTHFR TT genotype confers a significantly greater mean tHcy (1.93 µmol/L; 95% CI, 1.38 to 2.47) and greater risk of stroke (OR, 1.26; 95% CI, 1.14 to 1.40) than does random assignment of the MTHFR CC genotype.⁵³ However, there is no evidence from RCTs that lowering tHcy reduces the incidence of stroke and other major vascular events.^69,70 Ongoing RCTs continue to explore the efficacy of homocysteine-lowering treatment in reducing the risk of ischemic stroke.⁷¹

Microalbuminuria
The appearance of trace amounts of albumin (microalbuminuria, 30 to 300 mg/d) and larger amounts (frank proteinuria, >1 g/d) are associated with an increased risk of stroke, MI, vascular death, and renal failure.^45,72,73

Cystatin C
Cystatin C is a serum measure of renal function that appears to be independent of age, sex, and lean muscle mass and has been shown to be a stronger predictor of risk of stroke, MI, and death from vascular causes in elderly persons than is creatinine.⁷⁴

Patent Foramen Ovale
A meta-analysis of case-control studies reported an increased prevalence of patient foramen ovale (PFO) among patients with cryptogenic stroke who were 55 years of age or younger, compared with stroke-free controls (OR, 5.0; 95% CI; 3.2 to 7.7) but not among persons 55 years of age or older (OR, 1.2; 95% CI; 0.6 to 2.6).⁷⁵ However, many of these studies were prone to biases associated with hospital referral of cases and controls, referral of patients for echocardiography for various indications (with variable thoroughness of assessment of PFO), and nonblinded interpretation of the echocardiograms. A more recent community-based, case–control study found a PFO in 20.8% of 519 randomly selected, asymptomatic, community-based controls and in only 16.5% of 133 patients referred for evaluation of cryptogenic stroke, suggesting that there is no increase in the prevalence of PFO among patients with cryptogenic stroke compared with a random, nonhospitalized, reference population.⁷⁶ Ongoing trials are evaluating whether closing a PFO reduces the risk of cardioembolic ischemic stroke.^77–79

Conclusion
Stroke has many causes.²¹ Although increasing blood pressure is a causal risk factor for all major pathological subtypes of stroke and etiological subtypes of ischemic stroke, most other causal risk factors for stroke are causal only for specific pathological types of stroke and etiological subtypes of ischemic stroke.²²

There is reasonably reliable evidence to suggest that 60% to 80% of all ischemic strokes can be attributed to increasing blood pressure, blood cholesterol, cigarette smoking and carotid stenosis, and diabetes mellitus (atherosclerotic ischemic stroke), and to atrial fibrillation and valvular heart disease (cardiogenic ischemic stroke; Tables 2 and 3).^1–11 Another 10% to 20% of atherosclerotic ischemic strokes can probably be attributed to additional, recently established, causal risk factors for MI: raised apo B–apo A1 ratio, obesity, physical inactivity, psychosocial stress, and low fruit and vegetable intake (Tables 3 and 4). However, their causal role remains to be proven, because studies in stroke patients have been limited to small populations with differences in stroke subtype, stroke severity, and lifestyle, and it has not been shown in RCTs that reducing exposure to these risk factors reduces the risk of stroke.^19,20,25 It also remains uncertain whether any of the newer emerging risk factors for stroke (Table 5) are causal, and if so, by how much they may also contribute to the burden of stroke. Evidence to date suggests that the direct genetic contribution of any single gene toward ischemic stroke is likely to be modest and to apply in selected patients only, in combination with environmental factors or by other epistatic (gene-gene or gene-environmental) effects. Proteomics, the analysis of the entire protein content of a cell or tissue, promises to identify new biomarkers for stroke.⁸⁰ Despite the potential for genomics and proteomics to refine stroke risk and personalize stroke medicine,^80,81 research resources should not be allocated disproportionately to emerging novel risk factors that may account for up to only 20% of all strokes at the expense of researching the determinants of the few established causal factors that account for up to 80% of all strokes. For example, the yield from future genetic research may be greater from studying the genetics of the established causal risk factors (eg, the genetic determinants of behaviors and other factors that increase blood pressure) than searching for new genes for stroke.⁸² In addition, strategies to reduce the burden of ischemic stroke should continue to target risk, as defined by established causal risk factors, and aim to reduce risk among individuals and the population by reducing exposure to causal risk factors for stroke.

	Footnotes

 
Presented as an invited plenary lecture at the World Congress of Neurology, Sydney, Australia, November 2005.

Received January 9, 2006; revision received March 16, 2006; accepted April 10, 2006.

	References

Top Abstract Introduction Causal Risk Factors for... Population-Attributable Risk of... Validation Are the Newer Risk... Potential New Risk Factors... References

 
1. Lawes CMM, Bennett DA, Feigin VL, Rodgers A. Blood pressure and stroke: an overview of published reviews. Stroke. 2004; 35: 776–785.[Abstract/Free Full Text]

2. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90|056 participants in 14 randomised trials of statins. Lancet. 2005; 366: 1267–1278.[CrossRef][Medline] [Order article via Infotrieve]

3. Rothwell PM, Eliasziw M, Gutnikov SA, Fox AJ, Taylor W, Mayberg MR, Warlow CP, Barnett HJ, for the Carotid Endarterectomy Trialists’ Collaboration. Pooled analysis of individual patient data from randomised controlled trials of endarterectomy for symptomatic carotid stenosis. Lancet. 2003; 361: 107–116.[CrossRef][Medline] [Order article via Infotrieve]

4. MRC Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial. Lancet. 2004; 363: 1491–1502.[CrossRef][Medline] [Order article via Infotrieve]

5. Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med. 1999; 131: 492–501.[Abstract/Free Full Text]

6. Bonita R, Duncan J, Truelson T, Jackson R, Beaglehole R. Passive smoking as well as active smoking increases the risk of stroke. Tobacco Control. 1999; 8: 156–160.[Abstract/Free Full Text]

7. Asia Pacific Cohort Studies Collaboration. Blood glucose and risk of cardiovascular disease in the Asia Pacific region. Diabetes Care. 2004; 27: 2836–2842.[Abstract/Free Full Text]

8. Loh E, Sutton MS, Wun CC, Rouleau JL, Flaker GC, Gottlieb SS, Lamas GA, Moye LA, Goldhaber SZ, Pfeffer MA. Ventricular dysfunction and the risk of stroke after myocardial infarction. N Engl J Med. 1997; 336: 251–257.[Abstract/Free Full Text]

9. Coulshed N, Epstein EJ, McKendrick CS, Galloway RW, Walker E. Systemic embolism in mitral valve disease. BMJ. 1970; 32: 26–34.

10. Kizer JR, Wiebers DO, Whisnant JP, Welty TK, Lee ET, Best LG, Resnick HE, Roman MJ, Devereaux RB. Mitral annular calcification, aortic valve sclerosis, and incident stroke in adults free of clinical cardiovascular disease: the Strong Heart Study. Stroke. 2005; 36: 2533–2537.[Abstract/Free Full Text]

11. Rodgers H, Greenaway J, Davies T, Wood R, Steen N, Thomson R. Risk factors for first-ever stroke in older people in the north east of England: a population-based study. Stroke. 2004; 35: 7–11.[Abstract/Free Full Text]

12. Bath PMW, Gray LJ. Association between hormone replacement therapy and subsequent stroke. BMJ. 2005; 330: 342–345.[Abstract/Free Full Text]

13. Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet. 2003; 361: 2017–2023.[CrossRef][Medline] [Order article via Infotrieve]

14. Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen therapy and cardiovascular disease: ten-year follow-up from the Nurses’ Health Study. N Engl J Med. 1991; 325: 756–762.[Abstract]

15. Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD. Postmenopausal hormone replacement therapy: scientific review. JAMA. 2002; 266: 872–881.

16. Lawlor DA, Davey Smith G, Bruckdorfer R, Kundu D, Ebrahim S. Those confounded vitamins: what can we learn from the differences between observational versus randomised trial evidence? Lancet. 2004; 363: 1724–1727.[CrossRef][Medline] [Order article via Infotrieve]

17. Whisnant JP. Modelling of risk factors for ischemic stroke: the Willis Lecture. Stroke. 1997; 28: 1840–1844.[Free Full Text]

18. Urban Hjorth JS. Computer Intensive Statistical Methods Validation Model Selection and Bootstrap. London, UK: Chapman and Hall; 1994.

19. Ezzati M, Lopez AD, Rodgers A, Vander Hoorn S, Murrary CJL, and the Comparative Risk Assessment Collaborating Group. Selected major risk factors and global and regional burden of disease. Lancet. 2002; 360: 1347–1360.[CrossRef][Medline] [Order article via Infotrieve]

20. Ezzati M, Vander Hoorn S, Rodgers A, Lopez AD, Mathers CD, Murrary CJL, and the Comparative Risk Assessment Collaborating Group. Estimates of global and regional health gains from reducing multiple major risk factors. Lancet. 2003; 362: 271–280.[CrossRef][Medline] [Order article via Infotrieve]

21. Warlow C, Sudlow C, Dennis M, Wardlaw J, Sandercock P. Stroke. Lancet. 2003; 362: 1211–1224.[CrossRef][Medline] [Order article via Infotrieve]

22. Schulz UGR, Rothwell PM. Differences in vascular risk factors between etiological subtypes of ischemic stroke: importance of population-based studies. Stroke. 2003; 34: 2050–2059.[Abstract/Free Full Text]

23. Jackson C, Sudlow C. Are lacunar strokes really different? A systematic review of differences in risk factor profiles between lacunar and nonlacunar infarcts. Stroke. 2005; 36: 891–904.[Abstract/Free Full Text]

24. Vasan RS, Sullivan LM, Wilson PWF, Sempos CT, Sundstrom J, Kannel WB, Levy D, D’Agostino RB. Relative importance of borderline and elevated levels of coronary heart disease risk factors. Ann Intern Med. 2005; 142: 393–402.[Abstract/Free Full Text]

25. Yusuf S, Hawken S, Ôunpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L; INTERHEART Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004; 364: 937–952.[CrossRef][Medline] [Order article via Infotrieve]

26. Sniderman AD, Furberg CD, Keech A, Roeters van Lennep JE, Frohlich J, Jungner I, Walldius G. Apolipoproteins versus lipids as indices of coronary risk and as targets for statin treatment. Lancet. 2003; 361: 777–780.[CrossRef][Medline] [Order article via Infotrieve]

27. Pischon T, Girman CJ, Sacks FM, Rifai N, Stampfer MJ, Rimm EB. Non-high-density lipoprotein cholesterol and apolipoprotein B in the prediction of coronary heart disease in men. Circulation. 2005; 112: 3375–3383.[Abstract/Free Full Text]

28. Bhatia M, Howard SC, Clarke TG, Neale R, Qizilbash N, Murphy MFG, Rothwell PM. Apolipoproteins as predictors of ischemic stroke in patients with a previous transient ischemic attack. Cerebrovasc Dis. 2006; 21: 323–328.[CrossRef][Medline] [Order article via Infotrieve]

29. Rexrode KM, Hennekens CH, Willett WC, Colditz GA, Stampfer MJ, Rich-Edwards JW, Speizer FE, Manson JE. A prospective study of body mass index, weight change, and risk of stroke in women. JAMA. 1997; 277: 1539–1545.[Abstract/Free Full Text]

30. Kurth T, Gaziano JM, Berger K, Case CS, Rexrode KM, Cook NR, Buring JE, Manson JE. Body mass index and the risk of stroke in men. Arch Intern Med. 2002; 162: 2557–2562.[Abstract/Free Full Text]

31. Suk SH, Sacco RL, Boden-Albala B, Cheun JF, Elkind MS, Paik MC. Abdominal obesity and risk of ischemic stroke: the Northern Manhattan Stroke Study. Stroke. 2003; 34: 1586–1592.[Abstract/Free Full Text]

32. Jood K, Jern C, Wilhelmsen L, Rosengren A. Body mass index in mid-life is associated with a first stroke in men: a prospective population study over 28 years. Stroke. 2004; 35: 2764–2769.[Abstract/Free Full Text]

33. Song YM, Sung J, Smith GD, Ebrahim S. Body mass index and ischemic and hemorrhagic stroke: a prospective study in Korean men. Stroke. 2004; 35: 831–836.[Abstract/Free Full Text]

34. Lee CD, Folsom AR, Blair SN. Physical activity and stroke risk: a meta-analysis. Stroke. 2003; 34: 2475–2481.[Abstract/Free Full Text]

35. Hu G, Sarti C, Jousilahti P, Silventoinen K, Barengo NC, Tuomilehto J. Leisure time, occupational, and commuting physical activity and the risk of stroke. Stroke. 2005; 36: 1994–1999.[Abstract/Free Full Text]

36. Dauchet L, Amouyel P, Dallongeville J. Fruit and vegetable consumption and risk of stroke: a meta-analysis of cohort studies. Neurology. 2005; 65: 1193–1197.[Abstract/Free Full Text]

37. Reynolds K, Lewis B, Nolen JD, Kinney GL, Sathya B, He J. Alcohol consumption and risk of stroke: a meta-analysis. JAMA. 2003; 289: 579–588.[Abstract/Free Full Text]

38. Mukamal KJ, Ascherio A, Mittleman MA, Conigrave KM, Camargo CA Jr, Kawachi I, Stampfer MJ, Willett WC, Rimm EB. Alcohol and risk of ischemic stroke in men: the role of drinking patterns and usual beverage. Ann Intern Med. 2005; 142: 11–19.[Abstract/Free Full Text]

39. Naimi TS, Brown DW, Brewer RD, Giles WH, Mensah G, Serdula MK, Mokdad AH, Hungerford DW, Lando J, Naimi S, Stroup DF. Cardiovascular risk factors and confounders among non-drinking and moderate-drinking U.S. adults. Am J Prev Med. 2005; 28: 369–373.[CrossRef][Medline] [Order article via Infotrieve]

40. House A, Dennis M, Mogridge L, Hawton K, Warlow C. Life events and difficulties preceding stroke. J Neurol Neurosurg Psychiatry. 1990; 53: 1024–1028.[Abstract/Free Full Text]

41. Simons LA, McCallum J, Friedlander Y, Simons J. Risk factors for stroke: Dubbo Study of the Elderly. Stroke. 1998; 29: 1341–1346.[Abstract/Free Full Text]

42. Hackam DG, Anand SS. Emerging risk factors for atherosclerotic vascular disease: a critical review of the evidence. JAMA. 2003; 290: 932–940.[Abstract/Free Full Text]

43. Voetsch B, Loscalzo J. Genetic determinants of arterial thrombosis. Arterioscler Thromb Vasc Biol. 2004; 24: 216–229.[Abstract/Free Full Text]

44. Ridker PM, Brown NJ, Vaughan DE, Harrison DG, Mehta JL. Established and emerging plasma biomarkers in the prediction of first atherothrombotic events. Circulation. 2004; 109 [suppl IV]: IV-6–IV-19.[Medline] [Order article via Infotrieve]

45. Cohn JN, Quyyumi AA, Hollenberg NK, Jamerson KA. Surrogate markers for cardiovascular disease: functional markers. Circulation. 2004; 109 [suppl IV]: IV-31–IV-46.[Medline] [Order article via Infotrieve]

46. Bhatia M, Rothwell PM. A systematic comparison of the quality and volume of published data available on novel risk factors for stroke versus coronary heart disease. Cerebrovasc Dis. 2005; 20: 180–186.[Medline] [Order article via Infotrieve]

47. Hassan A, Markus HS. Genetics and ischaemic stroke. Brain. 2000; 123: 1784–1812.[Abstract/Free Full Text]

48. Schulz UGR, Flossmann E, Rothwell PM. Heritability of ischemic stroke in relation to age, vascular risk factors, and subtypes of incident stroke in population-based studies. Stroke. 2004; 35: 819–825.[Abstract/Free Full Text]

49. Flossmann E, Rothwell PM. Family history of stroke in patients with transient ischemic attack in relation to hypertension and other intermediate phenotypes. Stroke. 2005; 36: 830–835.[Abstract/Free Full Text]

50. Flossmann E, Schulz UGR, Rothwell PM. Potential confounding by intermediate phenotypes in studies of the genetics of ischaemic stroke. Cerebrovasc Dis. 2005; 19: 1–10.[Medline] [Order article via Infotrieve]

51. Casas JP, Hingorani AD, Bautista LE, Sharma P. Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18000 cases and 58000 controls. Arch Neurol. 2004; 61: 1652–1662.[Abstract/Free Full Text]

52. Lalouschek W, Schillinger M, Hsieh K, Endler G, Tentschert S, Lang W, Cheng S, Mannhalter C. Matched case-control study on Factor V Leiden and the prothrombin G20210A mutation in patients with ischemic stroke/transient ischemic attack up to the age of 60 years. Stroke. 2005; 36: 1405–1409.[Abstract/Free Full Text]

53. Casas JP, Bautista LE, Smeeth L, Sharma P, Hingorani AD. Homocysteine and stroke: evidence on a causal link from mendelian randomisation. Lancet. 2005; 365: 224–232.[Medline] [Order article via Infotrieve]

54. Staton JM, Sayer MS, Hankey GJ, Attia J, Thakkinstian A, Yi Q, Cole VJ, Baker R, Eikelboom JW. Association between phosphodiesterase 4D gene and ischemic stroke. J Neurol Neurosurg Psych. 2006; In press.

55. Helgadottir A, Gretarsdottir S, St. Clair D, Manolescu A, Cheung J, Thorleifsson G, Pasdar A, Grant SF, Whalley LJ, Hakonarson H, Thorsteindottir U, Kong A, Gulcher J, Stefansson K, MacLeod MJ. Association between the gene encoding 5-lipoxygenase-activating protein and stroke replicated in a Scottish population. Am J Hum Genet. 2005; 76: 505–509.[CrossRef][Medline] [Order article via Infotrieve]

56. Meschia JF, Brott TG, Brown RD Jr, Crook R, Worrall BB, Kissela B, Brown WM, Rich SS, Case LD, Evans EW, Hague S, Singleton A, Hardy J; SWISS Study Group; ISGS Study Group; MSGD Study Group. Phosphodiesterase 4D and 5-lipoxygenase-activating protein in ischemic stroke. Ann Neurol. 2005; 58: 351–361.[CrossRef][Medline] [Order article via Infotrieve]

57. Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin and leukocyte count with coronary heart disease: meta-analysis of prospective studies. JAMA. 1998; 279: 1477–1482.[Abstract/Free Full Text]

58. Grau AJ, Boddy AW, Dukovic DA, Buggle F, Lichy C, Brandt T, Hacke W. Leukocyte count as an independent predictor of recurrent ischemic events. Stroke. 2004; 35: 1147–1152.[Abstract/Free Full Text]

59. Johnsen SH, Fosse E, Joakimsen O, Mathiesen EB, Arnesen E, Njolstad I. Monocyte count is a predictor of novel plaque formation: a 7-year follow-up study of 2610 persons without carotid plaque at baseline: the Tromsø study. Stroke. 2005; 36: 715–719.[Abstract/Free Full Text]

60. Torres JL, Ridker PM. Clinical use of high-sensitivity C-reactive protein for the prediction of adverse cardiovascular events. Curr Opin Cardiol. 2003; 18: 471–478.[CrossRef][Medline] [Order article via Infotrieve]

61. Rost NS, Wolf PA, Kase CS, Kelly-Hayes M, Silbershatz H, Massaro JM, D’Agostino RB, Franzblau C, Wilson PW. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham Study. Stroke. 2001; 32: 2575–2579.[Abstract/Free Full Text]

62. Lindsberg P, Grau AJ. Inflammation and infections as risk factors for ischemic stroke. Stroke. 2003; 34: 2518–2532.[Abstract/Free Full Text]

63. Taylor-Robinson D, Thomas BJ. Chlamydia pneumoniae in arteries: the facts, their interpretation, and future studies. J Clin Pathol. 1998; 51: 793–797.[Medline] [Order article via Infotrieve]

64. Wells BJ, Mainous AG, Dickerson LM. Antibiotics for the secondary prevention of ischemic heart disease. Arch Intern Med. 2004; 164: 2156–2161.[Abstract/Free Full Text]

65. Grayston JT, Kronmal RA, Jackson LA, Parisi AF, Muhlestein JB, Cohen JD, Rogers WJ, Crouse JR, Borrowdale SL, Schron E, Knirsch C; ACES Investigators. Azithromycin for the secondary prevention of coronary events. N Engl J Med. 2005; 352: 1637–1645.[Abstract/Free Full Text]

66. Cannon CP, Braunwald E, McCabe CH, Grayston JT, Muhlestein B, Giugliano RP, Cairns R, Skene AM; Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 Investigators. Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. N Engl J Med. 2005; 352: 1646–1654.[Abstract/Free Full Text]

67. Danesh J. Antibiotics in the prevention of heart attacks. Lancet. 2005; 365: 365–367.[Medline] [Order article via Infotrieve]

68. Rothwell PM, Howard SC, Power DA, Gutnikov SA, Algra A, van Gijn J, Clark TG, Murphy MF, Warlow CP. Fibrinogen concentration and risk of ischemic stroke and acute coronary events in 5113 patients with transient ischemic attack and minor ischemic stroke. Stroke. 2004; 35: 2300–2305.[Abstract/Free Full Text]

69. Hankey GJ. Is homocysteine a modifiable risk factor for stroke? Nat Clin Pract Neurol. 2006; 2: 26–33.[CrossRef][Medline] [Order article via Infotrieve]

70. Davey Smith G, Ebrahim S. Folate supplementation and cardiovascular disease. Lancet. 2005; 366: 1679–1681.[CrossRef][Medline] [Order article via Infotrieve]

71. B-vitamin Treatment Trialists’ Collaboration. Homocysteine-lowering trials for prevention of cardiovascular events: a review of the design and power of the large randomized trials. Am Heart J. 2006; 151: 282–287.[CrossRef][Medline] [Order article via Infotrieve]

72. Miettinen J, Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Proteinuria predicts stroke and other atherosclerotic vascular disease events in nondiabetic and non-insulin-dependent diabetic subjects. Stroke. 1996; 27: 2033–2039.[Abstract/Free Full Text]

73. Ibsen H, Olsen MH, Wachtell K, Borch-Johnsen K, Lindholm LH, Mogensen CE, Dahlof B, Devereux RB, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Lederballe-Pedersen O, Nieminen MS, Omvik P, Oparil S. Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients; Losaran Intervention for Endpoint Reduction in Hypertension Study. Hypertension. 2005; 45: 198–202.[Abstract/Free Full Text]

74. Shlipak MG, Sarnak MJ, Katz R, Fried LF, Seliger SL, Newman AB, Siscovick D, Stehman-Breen C. Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med. 2005; 352: 2049–2060.[Abstract/Free Full Text]

75. Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology. 2000; 55: 1172–1179.[Abstract/Free Full Text]

76. Petty GW, Khanderia BK, Meissner I, Whisnant JP, Rocca WA, Christianson TJ, Sicks JD, O’Fallon WM, McClelland RL, Wiebers DO. A population-based study of the relationship between patent foramen ovale and cerebrovascular ischaemic events. Mayo Clin Proc. 2006; 81: 602–608.[Abstract/Free Full Text]

77. Saver JL, Carroll JD, Hijazi ZM, et al. Randomised evaluation of Recurrent Stroke comparing PFO closure to Established Current standard of care Treatment (RESPECT): ongoing clinical trial abstracts. International Stroke Conference, 2005, American Stroke Association, CTP42. February 2–4, 2005; New Orleans, Louisiana, USA.

78. Mattle HP, Meier B, Windecker S. PC-trial-Patent foramen ovale and Cryptogenic embolism: ongoing clinical trial abstracts. International Stroke Conference, 2005, New Orleans, La, CTP55.

79. Maisel WH, Laskey WK. Patent foramen ovale closure devices: moving beyond equipoise. JAMA. 2005; 294: 366–369.[Free Full Text]

80. Vivanco F, Martin-Ventura JL, Duran MC, Barderas MG, Blanco-Colio L, Darde VM, Mas S, Meilhac O, Michel JB, Tunon J, Egido J. Quest for novel cardiovascular biomarkers by proteomic analysis. J Proteome Res. 2005; 4: 1181–1191.[CrossRef][Medline] [Order article via Infotrieve]

81. Ginsgurg GS, Donahue MP, Newby PK. Prospects of personalized cardiovascular medicine: the impact of genomics. J Am Coll Cardiol. 2005; 46: 1615–1627.[Abstract/Free Full Text]

82. Hubner N, Yagil C, Yagil Y. Novel integrative approaches to the identification of candidate genes in hypertension. Hypertension. 2006; 47: 1–5.[Abstract/Free Full Text]

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