Hypertension together with age are leading risk factors for silent or symptomatic cerebrovascular disease[15-17]. High blood pressure multiplies the risk for stroke as much as 4-fold. Both factors are also related to the probability of suffering some degree of cognitive impairment[4]. The risk of cerebral hemorrhage in hypertensive patients is 3.9 times higher than in non-hypertensive individuals. In aneurysmal subarachnoid hemorrhage the relative risk is 2.8 higher[18-22]. The diagnosis and control of hypertension one of the main strategies for primary and secondary prevention of stroke[22-24]. The effect of chronic hypertension on cerebral vessels and tissue (microhemorhages, silent infarctions, white matter lesions and atrophy) also supports a physiopathological mechanism for the association between hypertension and cognitive impairment[25-29]. As shown in Table 1, according to data of 2704 patients with first-ever ischemic stroke collected from the Sagrat Cor of Barcelona Stroke Registry, hypertension was the main risk factor in the different age groups[7].

Dyslipidemia, hypertension and obesity are atherogenic risk factors frequently found in type 2 diabetes patients[4,5]. Also, diabetes is an independent risk factor of ischemic stroke of atherothrombotic cause. The influence of diabetes upon increasing the stroke risk is higher in women than in men[30]. Diabetes is the main risk factor following hypertension of cerebral small vessel disease and has been identified as a significant independent variable of symptomatic recurrence in patients with first-ever cerebral infarction of the lacunar type[31,32]. The combination of hypercholesterolemia and hypertension increases the frequency of vascular complications in patients with diabetes.

Heart diseases are the second cause of acute cerebrovascular events and are diagnosed in one third of patients with stroke[33,34]. Atrial fibrillation (AF) and atrial flutter are the most important and modifiable risk factor, frequently associated with cardioembolic stroke. Cardioembolic infarction is the most severe stroke subtype due to the very low percentage of symptom-free patients at hospital discharge, the non-negligible risk of early recurrent embolic events and the high mortality in the acute stroke phase (27% in the Sagrat Cor of Barcelona Stroke Registry)[33-36]. The prevalence of AF increases with age. It has been shown that 5% of subjects older than 70 years have AF (the mean age of patients with AF is 75 years), and about one fourth of acute strokes in very old patients (> 80 years) are also caused by AF[37,38]. Future embolism is also more frequent in patients with underlying comorbid heart diseases, such as AF and stenosis of the mitral valve. The risk of stroke is 3 to 4 times higher in the absence of organic heart disease or risk factors (lone atrial fibrillation). On the other hand, AF associated to hypertensive heart disease is the most common cardiogenic source of cerebral embolization in industrialized countries[33]. Similar rates of cardioembolism for paroxysmal and chronic AF have been reported, so that preventive therapy should not be different for patients with paroxysmal AF and those with chronic AF[33]. In patients without history of transient ischemic attack (TIA) or stroke, AF carries a risk of stroke of 2%-4% per year. Cardiac emboli arising from cardiac chambers are often large and hence especially likely to cause severe stroke, disability and death[33].

A number of cardiac conditions are potential sources of embolism, such as dilated myocardiopathy, heart valve disease (mechanical prosthetic valve, mitral rheumatic stenosis, infectious endocarditis, marantic endocarditis), left ventricular hypertrophy, atrial myxoma and congenital heart diseases (such as patent foramen ovale, atrial septal aneurysm and ventricular septal defects). Acute coronary syndromes are minor causes of cardioembolism. There is an inverse correlation between ejection fraction of the left ventricle and the incidence of ischemic stroke[33-39].

Cigarette smoking is an independent predictor of cerebrovascular disease in both men and women[40]. Smokers have a relative risk of ischemic stroke of 1.92 times higher as compared to non-smokers. Smoking increases the risk of thrombus formation in narrow arterial vessels and contribute to enhance atherosclerotic plaque burden. Also, smoking increases blood viscosity, fibrinogen and platelet aggregation, and decreases high-density lipoprotein (HDL) cholesterol, which causes direct damage to endothelium and an increase in blood pressure[40-42]. A meta-analysis of 19 prospective studies has shown an association of smoking with dementia and cognitive decline[43]. Finally, there is growing acceptance that passive cigarette smoke increases the risk of stroke[44].

Plasma lipids and lipoproteins [total colesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, HDL cholesterol and lipoprotein (a)] have an influence on the risk of cerebral infarction, but the relationships between dyslipidemia and stroke have not been consistently elucidated[9]. Data from prospective studies in male patients have shown that in the presence of total serum cholesterol values > 240 to 270 mg/dL, there is an increase in the rates of ischemic stroke[45].

In general, the risk of ischemic stroke in both genders is clearly related with dyslipidemia. In men, low HDL levels is a risk factor for cerebral ischemia but data in women are inconclusive. Because high levels of LDL are clearly related with a higher cardiovascular risk, adequate control of LDL cholesterol is recommended (e.g., National Cholesterol Education Program III guidelines) in subjects without history of cerebrovascular accident[46].

High triglyceride levels are a component of the metabolic syndrome. In a study of 11117 patients with coronary heart disease, cerebral infarctions were significantly associated with high serum levels of triglycerides and low levels of HDL cholesterol[9].

Chronic heavy alcohol consumption (> 60 g/d) is associated with an increase in the relative risk of stroke [risk ratio (RR) of 1.69 in cerebral ischemia and RR = 2.18 in cerebral haemorrhage][44]. Ethanol is a direct neurotoxin and chronic ethanol abuse causes different neurodegenerative processes, including dementia[47,48]. However, light-to-moderate alcohol consumption (20-30 g/d, equivalent to 1 or 2 drinks per day) is associated with a lower risk of stroke, white matter disease and clinically silent cerebral infarcts[3,44].

Obesity is defined as an increase above 25% of the theoretical body weight according to age and sex. The term “adiposity” refers to the amount of adipose (fat) tissue in the body, and can be considered more precise than “obesity” which is mainly one of the ways to measure adiposity. Adiposity is an energy imbalance between energy intake (calories) and energy expenditure (physical activity and metabolic processes); however, the ideal or normal threshold for adiposity has not been established. Increase in fat tissue is associated with a higher risk of insulin resistance, diabetes, hypertension, dyslipidemia, vascular diseases and other conditions. Persons with a body mass index (BMI) of < 18.5 kg/m² are classified as being underweight, between 18.5 and 25.9 kg/m² as healthy weight range, between 26 and 29.9 kg/m² as overweight and ≥ 30 kg/m² as being obese[49]. Abdominal obesity is commonly measured by either the waist-to-hip ratio or waist circumference and appears to be a more sensitive measure of adiposity and vascular risk. Clinically, abdominal obesity is defined by a waist circumference > 102 cm in men and 88 in women[50]. Weight and abdominal fat reduction is associated with a lowering in blood pressure, and may thereby reduce the risk of stroke. Moreover, there is evidence linking the continuum of adiposity, hyperinsulinemia, and diabetes with dementia[51].

Metabolic syndrome is defined as te presence of three or more of the following: (1) abdominal obesity as determined by waist circumference > 102 cm and > 88 cm for women; (2) triglycerides ≥ 150 mg/dL; (3) HDL cholesterol < 40 mg/dL for men and < 50 mg/dL for women; (4) systolic blood pressure ≥ 130 mm Hg and diastolic blood pressure ≥ 85 mmHg; and (5) fasting glucose ≥ 110 mg/dL[52,53]. Hyperinsulinemia/insulin resistance is an important marker of the metabolic syndrome. The metabolic syndrome is a predictor of coronary heart disease, cardiovascular disease (which includes coronary heart disease and stroke) and all-cause mortality. Also, the risk of stroke is higher for patients presenting some of the diseases included in the metabolic syndrome[9].

Approximately between 5% and 10% of men and women over 65 years had > 50% and 1% > 80% asymptomatic carotid stenosis[3], which has been also identified as a risk for stroke[9] and an important clinical feature of underlying ischemic heart disease.

Epidemiological studies have shown that patients with intermittent claudication have a high risk of premature death due to ischemic heart disease and stroke. Also, individuals with peripheral vascular disease are at a higher stroke risk[9,54]. History of intermittent claudication, peripheral vascular disease or coronary heart disease in a patient with cerebral infarction indicates the presence of clinically generalized atherosclerosis, according to which the diagnosis of cerebral ischemia of atherothrombotic cause is highly probable.

Postmenopausal hormone therapy (estrogen with or without a progestin) should not be used for primary prevention of ischemic stroke because, paradoxically, the risk of stroke is increased.

The increased risk for vascular outcomes should be taken into account when hormone replacement therapy is used for other indications[9,45].

The risk of stroke associated with low-dose oral contraceptives (containing low doses of estrogens) in women without additional risk factors (e.g., cigarette smoking or history of thromboembolic episodes) appears low[45]. Women taking oral contraceptives older than 35 years, active smokers, with hypertension, diabetes, migraine headache or history of thromboembolism are at higher risk of stroke[9,45].

Drug abuse (mainly heroin, cocaine, amphetamins) has been also identified as a risk factor for stroke through different mechanisms, including blood pressure, hematologic, hemostatic and vasculitic-type changes, as well as increased platelet aggregation and blood viscosity[3,9,45].

Migraine has been marginally associated with stroke risk in young women but in persons over 60 years an association between stroke and migraine has not been documented[55]. The risk of stroke has been related to underlying pathophysiological mechanisms of migraine (with aura), such as reduced blood flow particularly in the posterior circulation[9]. In young adults, stroke and migraine may be linked by paradoxical embolism through a patent foramen ovale. Patients with migraine also show an increase in platelet–leukocyte aggregation and platelet activation, increasing the risk of emboli formation and suggesting a link at cellular level between stroke and migraine[55,56].

Plasma levels of apolipoprotein B (apoB) is an indicator of very-low density (VLDL) and LDL lipoproteins with proatherogenic properties because each VLDL and LDL particle contains a molecule of apoB. It seems that plasma concentration of apoB is the highest lipid predictor of ischemic heart disease. In patients with TIA, an increase in the apoB/apoA1 ratio would product stroke more strongly (HR = 2.9) than other lipid values, such as apoB (HR = 2.3), total cholesterol (HR = 1.8), LDL cholesterol (HR = 1.5), LDL/HDL ratio (HR = 1.3) and apoA1 (HR = 1.2)[9,45].

A sedentary lifestyle is associated with an increase in the risk of stroke. Regular physical activity has well-established benefits for reducing the risk of cardiovascular disease, premature death and stroke[9]. The excellent review of Hankey[45] of potential new risk factors for ischemic stroke includes data of a meta-analysis of 23 studies and shows that subjects with high physical activity as compared to those with low physical activity had a lower stroke risk (RR = 0.79). Also, in another study, a reduction in the risk of stroke was reported in relation to moderate physical activity at leisure time (RR = 0.87) and active daily activity ≥ 30 min daily (cycling/walking to work). The protective effect of physical activity may be partly mediated through its role in reducing blood pressure and controlling other risk factors for cardiovascular disease, diabetes and increased body weight. It has been also related to a reduction of plasma fibrinogen and platelet activity, with increases of both tissue plasminogen activator and HDL cholesterol[3,45].

A meta-analysis of 17 cohort studies showed that risk of stroke decreased by 11% for each additional portion per day of fruit, by 5% for fruit and vegetables, and by 3% for vegetables[3,45]. A higher sodium intake increases the risk of stroke, whereas a higher consumption of potassium was associated with a reduction in the risk of stroke, probably due to the blood pressure lowering effect and mitigation of sodium effects on pressor responsiveness[9,45]. In Asian populations, diets characterized by consumption of cholesterol and saturated fats, as well as low consumption of animal-related proteins have been associated with an increased stroke[9,45].

The risk of stroke is also increased in the presence of stressful live events, including depression[44].

The presence of sleep apnea is also a risk factor for stroke. Sleep apnea may increase the risk of stroke by leading to or worsening hypertension or ischemic heart disease. Sleep apnea causes reductions in cerebral blood flow, altered cerebral autoregulation, impaired endothelial function, accelerated atherogenesis, hypercoagulability, inflammation and paradoxical embolism in patients with patent foramen ovale. In patients with advanced sleep-disordered breathing, cardiac arrhythmias, atrioventricular block and atrial fibrillation appear when the oxyhemoglobin saturation falls to < 65%. Sleep apnea as a risk factor for cerebrovascular events is usually underdiagnosed[57-59].

There is increasing evidence of the relevance of inflammation as a physiopathological mechanism of atherothrombotic stroke.

Leukocyte and monocyte counts: In the CAPRIE trial (Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events) patients with a history of peripheral arterial disease, stroke, or myocardial infarction or who had a leukocyte count in the highest quartile at baseline showed a higher adjusted risk of recurrent ischemic events compared with those in the lowest quartile (RR = 1.42)[45]. Monocyte count has been shown to be an independent predictor of future atherosclerotic plaque formation in the carotid artery in subjects without preexisting carotid atherosclerosis[3,60].

C-reactive protein: In apparently healthy individuals, high-sensitive C-reactive protein, acute-phase reactant and biological marker of inflammation, has been shown to be an independent risk factor for death of vascular cause, stroke and myocardial infarction[45].

Other biomarkers: An increase in the levels of other inflammatory biomarkers, among which, tumor necrosis factor (TNF) and interleukin 2 (IL-2) are also related to subclinical carotid disease[45]. Inflammatory cells in the atherosclerotic plaque are involved in the release of substances (matrix metallopeptidases) causing rupture of the plaque by instability of the fibrotic layer[45]. An increase of inflammatory mediators have been shown in atherosclerotic plaques in symptomatic as compared to asymptomatic patients[3,45].

It has been shown that recent infection (within 1 wk) can be a risk factor for stroke and coronary-related complications[3]. This may be partly related to generalized activation of circulating leukocytes, enhancing the tendency for thrombosis at the site of atherosclerotic plaque. Moreover, Chlamydia pneumonia DNA or C. pneumonia antigen, have been identified in 40% of atherosclerotic plaques[3,45].

Periodontal disease related to seeding of the bloodstream with Gram-negative organisms has been associated with carotid atherosclerosis and the risk of stroke[45]. However, antibiotic treatment has been unsuccessful in the prevention of severe cardiovascular events, at least in patients with established coronary heart disease.

Cytomegalovirus, herpes virus and Mycoplasma pneumoniae infection increase the risk of stroke by various mechanisms, particularly by increasing inflammatory mediators, facilitating the coagulation cascade and enhancing expression of adhesion molecules on vascular endothelial cells[3,45].

Helicobacter pylori have also been identified in human atherosclerotic plaque.

These data support the concept of “infectious burden”, according to which prolonged exposure to multiple microorganisms during the life period may contribute to the development and activation of the atherosclerotic plaque[9,45].

In a meta-analysis of thres prospective studies, patient with fibrinogen concentrations above the median value showed an increased risk of stroke (HR = 1.34) in comparison with patients with serum fibrinogen values below the median, particularly in patients with non-lacunar syndromes (HR = 1.42)[45].

Hemocysteine: It has been consistently shown a positive and independent association between total plasma hemocysteine and atherosclerotic disease, risk of silent and symptomatic stroke and cognitive decline[45,61]. Also, MTHFR TT genotype confers a significantly greater mean hemocysteine levels and greater risk for stroke (OR = 1.26) than carriers of the MTHFR CC genotype. Although a standard definition of hyperhomocysteinemia is lacking, it seems that fasting plasma concentrations > 16 μmol/L may be considered indicative of hyperhomocysteinemia[3,55]. Ongoing randomized controlled clinical trials continue to assess the efficacy of homocysteine-lowering treatment for decreasing the risk of ischemic stroke.

Elevated lipoprotein (a): Lipoprotein (a) [Lp(a)] complex has proatherogenic and prothrombotic properties and has been shown to be a risk factor for coronary heart disease[45]. Lp(a) enhances arterial cholesterol deposition, thereby promoting atherogenesis[3,45]. There is an increasing evidence suggesting that high Lp(a) levels may induce cerebral ischemia but findings have not been completely consistent[45].

Lipoprotein-associated phospholipase A₂: High concentrations of Lp-PLA₂ are associated with an increased risk of cardiovascular events, independent of other risk factors, and potentially may increase the stroke risk[45].

Hypercoagulability: Venous thrombosis (but not cerebral infarction) is associated with thrombophilias (hereditary) or acquired hypercoagulable states[45]. Anti-phospholipid antibodies (aPL) is most frequently the cause of arterial thrombosis IgG and IgM anticardiolipin antibody and lupus anticoagulant are useful tests to detect aPL. Young women with cerebral infarction have a higher prevalence of aPL.

Therefore, primarily young women who have a history of thrombotic events and meet the laboratory criteria for antiphospholipid syndrome might benefit from the administration of moderate-intensity warfarin or other antithrombotic therapies as primary or secondary prevention strategies[3,45]. On the other hand, a relationship between stroke and other hereditary hypercoagulable states (protein S or antithrombin III, protein C deficiency, etc.) has not been reported in most case-control studies[45].

Albuminuria: An increased risk of stroke, death of vascular cause, myocardial infarction and renal dysfunction has been documented in patients with microalbuminuria or proteinuria (30-300 mg/d and > 1 g/d, respectively)[45].

Cystatin C: Cystatin C is a serum marker of renal function that has been shown to be a predictor of stroke, myocardial infarction and vascular death, even stronger in elderly subjects than is creatinine[3,45].

Asymptomatic vascular disease is the first consequence of the impact of uncontrolled progression of cardiovascular risk factors on systemic or cerebral arteria vessels of the organism. Asymptomatic vascular disorders may be viewed as subclinical arterial markers related to cardiovascular risk factors, and are predictors of stroke, myocardial infarction and vascular death in the mid- and long-term. Mild carotid stenosis, carotid intima-media thickness and atheroma of the aortic arch, as well as carotid artery distensibility and endothelial reactivity of the brachial artery have been reported as potential causes of asymptomatic vascular disease[3,44].

Complex atheromatosis of the aortic arch is a risk factor of embolism. There is a significant relationship between atheromatous plaques in the aortic arch and cerebral ischemia, particularly in the presence of protruding plaques ≥ 4 mm in thick. Morphologically complex plaques (aortic atherosclerotic debris) is considered a high risk embolic source (increased stroke risk by 1.7)[3,44,62-64].

Modern neuroimaging techniques allow the detection of clinically silent cerebral ischemia in the form of white matter hyperintensities, cerebral infarcts, cerebral atrophy or microbleeds, which may be considered stroke risk factors[45]. Most lacunar infarctions are asymptomatic and magnetic resonance imaging (MRI) studies reveal the presence of lacunes in approximately 20%-28% of individuals older than 65 years. Silent lacunar infarction is a risk factor of new infarctions of the lacunar type and cognitive impairment[65-69]. Also, symptomatic progression of lacunar disease has been demonstrated given that at 3 years, between 10% and 50% of patients will show new silent lacunar infarcts in MRI studies. Progression of leukoaraiosis is documented in 40% of patients with lacunar infarct. Therefore, clinically silent small vessel cerebral disease is a stroke risk factor that should be taken into account given the independent role as significant predictor of both symptomatic vascular recurrence and cognitive impairment[70,71].

Proteomic risk markers, history of TIA, previous cerebral infarction or primary intracerebral hemorrhage, chronic obstructive pulmonary disease (COPD), chronic liver disease and use of oral anticoagulants are other risk factor for stroke.