- Email: [email protected]
Extended Risk Factors for Stroke Prevention
Extended Risk Factors for Stroke Prevention Shuai Zhang, M.D., Ph.D.,1 Wei Zhang, M.S.,1 Guangqian Zhou, M.D., Ph.D.
Conflict of interest: None. Acknowledgements: This study is supported by grants from the National Natural Science Foundation of China (grant number 81701195), National Key R&D Program of China (2017FA105202) and the China Postdoctoral Science Foundation (2018M633112). Abstract: Stroke causes disability and high mortality, while it can be prevented by increasing public awareness of risk factors. The common known risk factors are hypertension, atrial fibrillation, heart failure, smoking, alcohol consumption, low physical activity, overweight and hypercholesterolemia. However, the deep understanding of risk factors is limited. Moreover, more risk factor emerges in recent years. To further increase the awareness of risk factors for stroke prevention, this review indicates the reasonable application of antihypertensive agents according to the age-dependent changes of hypertension, and some new risk factors including chronic kidney disease, obstructive sleep apnea, migraine with aura, working environment, genetic factors and air pollution. Therefore, internal risk factors (e.g. heredity, hypertension, hyperglycemia) and external risk factors (e.g. working environment, air pollution) are both important for stroke prevention. All of these are reviewed to provide more information for the pre-hospital prevention and management, and the future clinical studies. Keywords: Risk factors-Stroke-Prevention
Author affiliations: Shuai Zhang, Shenzhen Key Laboratory for Anti-aging and Regenerative Medicine, Health Science Center, Shenzhen University, Shenzhen, 518060, China; Wei Zhang, College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, Guangdong 518060, China; Guangqian Zhou, Shenzhen Key Laboratory for Anti-aging and Regenerative Medicine, Health Science Center, Shenzhen University, Shenzhen, 518060, China 1
These authors contributed same work to this paper and they are the co-first authors.
Correspondence: Guangqian Zhou, M.D., Ph.D., Guangzhou, China., email: gqzhou@szu. edu.cn ª 2019 by the National Medical Association. Published by Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jnma.2019.02.004
INTRODUCTION
S
troke and its complications are a leading cause of disability and death worldwide. In all neurological diseases, stroke imposes the greatest burden of disability-adjusted life-years.1e3 Due to the ageing society, stroke will be the leading cause of healthy life year lost by 2020.4 Furthermore, stroke consumes about 2e4% of total health-care costs and ranks third in the Global Burden of Disease Study 2010.1,5 In clinical practice, thrombolytic therapy is most effective, but has a narrow time window (4.5 h).6 Therefore, effort to shorten delay in initiation of treatment can elevate the thrombolytic effects. Recognition of stroke risk factors is essential for decreasing stroke incidence, pre-hospital stroke care and saves time from the onset of stroke symptoms to hospital arrival.4,7,8 However, many studies show that fewer than half of people know the signs, symptoms, or risk factors of stroke.9,10 The most common sources of stroke information were general life experiences and personal acquaintances rather than
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professionals.11 Consequently, improving public knowledge regarding stroke risk factors is essential for a stroke prevention and management.
Risk factors of stroke Recognition of risk factors (Figure 1) is crucial for making preventive strategies to reduce stroke incidence.12e16 According to the native and external environment of the body, the risk factors in Figure 1 can be classified in two categories including internal risk factors (e.g. hypertension, hypercholesterolemia, genetic factors) and external risk factors (e.g. smoking, alcohol consumption, air pollution). The common risk factors of stroke are hypertension, smoking, alcohol consumption, low physical activity, overweight and hypercholesterolemia.17 While, air pollution, genetic factors and working environment are gradually found to promote stroke occurrence.18 So risk factors of stroke become more variable and complex. Complexity of risk factors. The risk factors have age, gender, racial and region differences. In young patients (18e55 years) with cerebrovascular events, the most frequent risk factors are smoking, physical inactivity, arterial hypertension, dyslipidemia, obesity and diabetes mellitus.19 Some risk factors, such as high-risk alcohol consumption and short sleep duration, are more frequent in men, and migraine is more frequent in women.19 Hypertension and diabetes mellitus are more prevalent in the black stroke population, but with less atrial fibrillation, alcohol and smoking sufferings compared with the white.20 Furthermore, some symptoms also promote stroke occurrence in patients with other diseases. For example, proteinuria is associated with an increased risk of ischaemic stroke in primary aldosteronism patients.21 Exposure to multiple risk factors increases the incidence of stroke. Patients with hypertension and other risk factors are at the greater risk for stroke.22 Patients with valvular heart disease, infective endocarditis, vasculitis or peripheral vascular disease significantly increase the morbidity and mortality of stroke through prothrombolic effects and cerebral hypoperfusion.23,24 Therefore, the risk factors are various and complex. The studies about the risk factors of stroke should be classified and make these factors more targeted. Risk factors in haemorrhagic stroke. Ischemia and hemorrhage are the two major subtypes of stroke. Hemorrhagic stroke including intracerebral hemorrhage and subarachnoid hemorrhage accounts less than 15% of all stroke cases, but it can cause about 40% of all stroke
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Figure 1. Risk factors of stroke.12e16 SBP: systolic blood pressure; BMI: body-mass index; PM2.5: particulate matter (2.5 mm); GFR: glomerular filtration rate
deaths.25 Multiple risk factors (Table 1), such as hypertension, smoking, high alcohol intake and renal dysfunction, increase the incidence of haemorrhagic stroke.26e31 Intracerebral hemorrhage is the major type of hemorrhagic stroke and heavy alcohol intake, hypertension and, anticoagulant treatment are the independent risk factors for intracerebral hemorrhage.32 While hypertension, smoking and cocaine use are responsible for increasing the incidence of subarachnoid hemorrhage.33,34 A systematic meta-analysis indicates that reducing blood pressure and smoking prevalence can obviously decrease worldwide incidence of subarachnoid hemorrhage.33 So risk factors identification, avoidance, or destruction are important for stroke prevention. Risk factors in ischaemic stroke. Ischaemic stroke is the most common type of stroke and can be classified into large-vessel occlusion, cardioembolism, small-vessel occlusion, stroke of other determined cause and stroke of undetermined cause.5 Numerous risk factors (Table 1), such as hypertension, smoking, high alcohol intake, atrial fibrillation and diabetes, increase the incidence of ischaemic stroke.26e31 Distinction between haemorrhagic stroke and ischaemic stroke is clinically valuable to determine the preventive interventions. In the results from many countries, multiple factors contribute to the ischaemic stroke, while, smoking, hypertension and alcohol intake seem to be more related with hemorrhagic stroke (Table 1). In three population-based cohort studies, high total cholesterol/ high-density lipoprotein cholesterol ratio decreases the intracerebral hemorrhage rates but increases ischaemic
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incidence.26 Moreover, aging and previous cerebrovascular disease are independently associated with ischemia rather than hemorrhage.20 Older age, male sex, hypertension, and high alcohol intake are found to be the risk factors of intracerebral hemorrhage through 14 casecontrol and 11 cohort studies, while, high cholesterol is related with a lower risk of intracerebral hemorrhage.35 So stroke subtypes related risk factors are significant for the decision of preventive strategies. Atrial fibrillation. Atrial fibrillation (AF), a disorder of heart rhythm, is an important risk factor of ischaemic stroke resulting from cardioembolism of a large cerebral artery.36 So stroke-related atrial fibrillation are largely preventable by using oral anticoagulants, such as warfarin (vitamin K antagonists)37,38 Moreover, AF frequently coexists with atrial abnormalities and might be a marker of other atrial abnormalities, such as endothelial dysfunction, fibrosis, chamber dilatation and mechanical dysfunction in the left atrial appendage.39 These atrial abnormalities are associated with stroke risk.40 Therefore, the AF management becomes more complex for stroke prevention and further studies are needed to diagnose pre-fibrillators patients at risk of developing stroke-associated AF. Heart failure. Heart failure (HF) is a complex clinical syndrome with structural or functional impairment of the ventricle to eject blood. HF patients without AF are at high risk of stroke, with an incidence rate of 1.2% per year, as great as in HF patients with AF (1.6% per year), despite anticoagulant treatment in 62% of the patients.41 Several pathophysiologic factors including increased thrombus
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31
Sweden (539287) renal dysfunction (female) renal dysfunction (male, female)
30
22 countries (3000) hypertension, smoking, diet, alcohol intake, waist-to-hip ratio hypertension (history of hypertension or blood pressure >160/ 90 mm Hg), alcohol intake (more than 30 drinks per month or binge drinking), current smoking, waist-to-hip ratio, diet risk score, regular physical activity, diabetes, psychosocial stress, depression, cardiac causes, ratio of apolipoproteins B to A1
29
Nigeria (282) systolic BP 140 mmHg age 62 years, systolic BP < 140 mmHg, previous TIA
28
high alcohol intake hypertension, diabetes
Australia (536)
Denmark (39484) smoking alcohol consumption diabetes, atrial fibrillation, previous myocardial infarction, previous stroke, intermittent arterial claudication
27
United States, Ommoord, Rotterdam, Netherlands (27493) high total cholesterol/high-density lipoprotein cholesterol ratio
Reference Ischemia
Table 1. Risk factors of ischaemic stroke and hemorrhagic stroke.
Hemorrhage
Country (number of patients)
26
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formation, coagulation, thrombocyte aggregation, endothelial dysfunction and reduced fibrinolysis are involved in HF-mediated elevation of stroke incidence.42 HF majorly promotes thrombus formation and causes cardioembolic stroke by increasing cerebral hypoperfusion, cerebral blood flow abnormalities and hypercoagulable state.43,44 Up to now, anticoagulant therapy is effective for stroke prevention in patients with HF. Besides the traditional anticoagulants, such as aspirin and warfarin, NOACs, including dabigatran, rivaroxaban, apixaban, and edoxaban, are also potential drugs to prevent stroke in patients with HF due to their anticoagulant effects.45,46 Moreover, the CHADS2 score could stratify the risk of ischemic stroke in HF patients without AF and has a great prognostic significance with the CHADS2 score [low (¼1), 0 per 100 person-years; intermediate (¼2), 1.6 per 100 person-years; high (3), 4.7 per 100 person-years; p ¼ 0.04].47 Among patients with HF with or without AF, the CHA2DS2-VASc score was associated with risk of ischemic stroke and applied to stratify the stroke risk of patients with HF.48 More strategies and methods are needed to prevent stroke in patients with HF based on the stroke risk prediction model. Hypertension trajectories. Most studies have indicated that the risk of stroke increases with increasing blood pressure levels by using a single measurement or the average of blood pressure levels assessed over time.49,50 It has been known that hypertension is a major risk factor for stroke and many antihypertensive drugs are used for stroke prevention.51 However, long-term patterns of blood pressure may further influence stroke risk.52 Recently, in a population-based study of people aged 55 years (Figure 2), high blood pressure (average 160 mm Hg) and rapidly increasing blood pressure (120e200 mm Hg) in 5 decades are associated with a high risk of stroke and death, whereas moderately high blood pressure (average 140 mm Hg) is only related to an increased risk of stroke.53 Therefore, the traditional methods by detecting single values of blood pressure are not fully effective for stroke prevention. It is very important to make new preventive strategies according to the four trajectories of blood pressure. Moreover, it is essential to have antihypertensive agents according to the age-dependent changes of hypertension.54 Genetic factors. In recent years, clinical gene testing has been markedly increased as gene sequencing technologies penetrate the market. Cardiovascular disease is at the forefront of gene testing in the clinical studies.55 The incidence of ischaemic stroke is about 80%, as opposed to haemorrhagic.56 In prospective studies, a combined genetic risk scores for cardiovascular risk factors including atrial fibrillation, coronary artery disease, hypertension,
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Figure 2. Trajectories of blood pressure and risk of stroke. Class 1: gradually increasing blood pressure from z120 to 160 mm Hg (on average) over 5 decades; Class 2: more steep increase from an average of z120e200 mm Hg; Class 3: moderate blood pressure (z140 mm Hg) at midlife and throughout; Class 4: high blood pressure (z160 mm Hg) at midlife that decreased.53
and systolic blood pressure are significantly associated with ischaemic stroke.56 Thus, stroke is a multifactorial disorder and epidemiological evidences indicate the genetic component to the disease.57,58 Nowadays, genetic testing is increasingly available and marketed to the public. However, no single nucleotide polymorphisms (SNPs) for stroke risk are used for clinical application. Recognition of the genetic factors is important for a stroke prevention and diagnosis. So more studies are recently struggling to find the stroke-related genes and specific SNPs (Table 2),57e79 which are significant for stroke prediction. Genetic variability contribute to stroke risk via several potential mechanisms.80 The direct cause of stroke is the specific single gene disorders causing vascular abnormality, such as mutations Notch3 gene mutation causing cerebral autosomal dominant arteriopathy with subcortical infarcts.65,66 Furthermore, the gene disorders causing conventional stroke risk factors, such as atrial fibrillation, diabetes mellitus, and hypertension, are the indirect factors associated with risk of stroke.80 Generally, genetic predisposition differs depending on stroke subtype.81,82 According to the pathophysiological mechanisms, ischaemic stroke has several subtypes including large-vessel disease stroke, small-vessel disease stroke, and cardioembolic stroke.69 The genetic studies could help to distinguish stroke subtypes (Table 2) and genetic tests could help to make the diagnosis of strokes and patient management. Therefore, stroke subtypes with their specific genes have different pathophysiological mechanisms, which implies the target treatment for stroke according to the stroke subtypes.59 Although the previous studies82 have been made in the identification of genes for stroke, comparatively little is known about the specific genes and the improvement in
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clinical risk prediction is still limited.56,57 More progress from multiple centers and large sample size is needed to elucidate the genetic basis of multifactorial stroke and find the related phenotypes performed in multiple population and region samples.57,58 Moreover, another subsequent challenge is to move from these associated SNPs to a deeper understanding of the biology of risk for stroke, and provides new therapeutic targets and strategies.58,83 Consequently, great efforts are required to identify the specific genes of stroke for risk prediction. Chronic kidney disease (CKD). CKD is defined as the deterioration of renal function with a glomerular filtration rate less than 60 mL/min/1.73 m2 or the presence of protein in the urine.84,85 Renal dysfunction increases the incidence of ischaemic and hemorrhagic stroke with gender differences.31 CKD can cause hypertension and vascular lesion (arteriosclerosis), endothelial dysfunction, accumulation of indoxyl sulfate and sleep-disordered breathing, which facilitate stroke occurrence.84,85 Consequently, CKD, as a new risk factor, can be used as a predictor of ischaemic and haemorrhagic strokes, and standard for the awareness assessment of stroke risk factors. Obstructive sleep apnea. Obstructive sleep apnea (OSA), the most common form of sleep-disordered breathing, is associated with an increased incidence of new-onset stroke as an independent risk factor of stroke and is present in more than 50% of patients with stroke.86,87 OSA can cause intermittent hypoxemia and consequently lead to hypertension due to sympathetic activation and vasoconstrictive substances release.88 Moreover, OSA increases the levels of inflammatory cytokines (plasminogen activator inhibitor-1, interleukin-6, TNF-a) of patients with acute ischemic stroke.89 The
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Table 2. Stroke-related genes according to stroke subtypes.
Stroke subtypes All ischaemic stroke
Large-vessel disease stroke
Small-vessel disease stroke
Embolic stroke
Female-only stroke Young stroke
Chromosome
SNP
Candidate gene
reference
1
rs225132
ERRFI1
59
12
rs17696736
NAA25 (C12orf30)
59
3
rs16851055
SPSB4
59
22
rs6007897
CELSR1
60
12p13
rs12425791
NINJ2
59,61
13
e
ALOX5AP
57,58
19
e
MCEMP1
62
11
rs7937106
ALKBH8
59
6
rs556621
-
59
7
rs2107595
HDAC9
59,63
9
rs2383207
9p21
59,64
18
rs7407640
AFG3L2
59
2
rs13407662
-
59
19
e
NOTCH3
65,66
10
e
HTRA1
67
13
e
COL4A1
68
3
e
TREX1
69
4q25
rs2200733
PITX2
59,70
4q25
rs10033464
-
70
14q22-q23
rs2230500
PRKCH
59,71,72
1
e
MTHFR C677T
73
3
rs6763538
OXNAD1
59
16q22
rs7193343-T
ZFHX3
59,74
5q12
e
PDE4D
75,76
1
e
FXIIIB
77
3
rs7432308
-
59
12
rs2238151
ALDH2
59
7
rs12703165
PRKAG2
59
10q25
e
HABP2
78
11
e
G20210A
79
deleterious effects of OSA including arrhythmias, reactive oxidative stress, endothelial dysfunction, atherosclerosis, altered cerebral blood flow, hypertension, autonomic dysfunction and hypercoagulability might contribute to stroke.90 OSA is highly prevalent in patients with stroke. Some studies show that the continuous positive airway pressure treatment improves the functional recovery after stroke.91,92 Therefore, exploring more systematic approaches for the diagnosis and treatment of OSA are significant and should be implemented in the management of stroke.
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Migraine with aura. Migraine with aura indicates that migraineurs experience transient neurological symptoms, and is considered as a risk factor for silent brain infarcts and white matter hyperintensities.93e95 While a population-based study with female twins shows no association between silent brain infarcts, white matter hyperintensities, and migraine with aura.96 Another within-pair analyses also suggest no increased stroke risk related to migraine but modestly increased risk for stroke related to migraine with aura.97 So familial factors might contribute to the association of stroke risk and migraine
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with aura. Further research finds that older migraineurs with visual aura in late middle age have increased risk of cardioembolic stroke, while migraine without visual aura was not, over the period of 20 years.98 The underlying mechanisms of migraine increasing stroke risk are involved in cortical spreading depression, endovascular dysfunction, vasoconstriction, neurogenic inflammation, hypercoagulability, increased prevalence of vascular risk factors, shared genetic defects, cervical artery dissection, and patent foramen ovale.99 Nowadays, no preventive therapy in migraineurs can decrease stroke risk. Migraine prevalence is high in women of reproductive age and hormonal contraceptive is used in clinical practice, but the hormonal contraceptive can increase the risk of ischemic stroke in those who have migraine, specifically migraine with aura.100 Therefore, a woman with migraine with aura should be encouraged to cease smoking and avoid taking oral contraceptives with high estrogen doses.99 More investigation is needed to better understand the complexity of migraine-stroke association and find preventive strategies. Working environment. Recent studies focus on the relationship between working environment and stroke, and find bad working environment is also a risk factor of stroke. Wherein, working time is one important aspect of work environment.18 In a cumulative meta-analysis, Miki Kivimäki and colleagues found that individuals who work 55 h or more per week had a higher risk of incident stroke than those working standard hours (35e40 h per week).101 Long working hours can cause sustained stress and also indirectly increase the exposure to risk factors of stroke. Working long hours increase smoking propensities among workers who are going to quit cigarette consumption when they work more than 50 h a week.102 Moreover, long working hours are associated with physical inactivity and increased alcohol consumption.103,104 So those factors, such as smoking, physical inactivity and alcohol consumption, can alleviates work stress caused by long working hours but increase the risk of stroke. Although the association between long working hours and stroke is involved with many factors, such as the work environment and individual characteristics, long working hours, an important factor increasing stroke incidence, should be avoided. Moreover, a cohort study found no significant associations between psychosocial work environment, as measured by the job demand-control model, and ischaemic stroke.105,106 However, some studies show that job strain is associated with an almost 20% increased risk of acute ischaemic stroke.107,108 However, it is not enough to define risk with the standard thresholds due to the population variability across countries and regions.12 Up to now, some researches find the risk factors of stroke are
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related with working environment, but further systemic studies about working time, job strain, and gender/region differences are needed to determine whether interventions targeting these factors would reduce stroke risk beyond existing preventive strategies. Additionally, pathological mechanism about work-environment mediated stroke is also important for making preventive strategies. Some studies find that stroke caused by working environment may be mediated by a series of factors, such as the repetitive triggering of the stress response through activation of the hypothalamicepituitaryeadrenal and sympathoadrenomedullary axis, physical inactivity and the metabolic syndrome.109e111 These findings suggest that enhancing management of these risk factors is essential for individuals who have long working hours or strong job strain. Air pollution. The impact of air pollution on human health is currently of international concern.112,113 In the Global Burden of Disease study from 1990 to 2013, air pollution contributes to 29.2% of the burden of stroke and is being a significant risk factor.12 The main air pollutants related to stroke are particulate matter, NO2, SO2, CO and O3 produced by industry, traffic emissions and combustion of fossil or solid fuel.114 Particulate matter less than 10 mm in diameter (PM10) can reach the nasal cavities and PM2.5 perhaps pass into the bloodstream when inhaled. long-term exposure of PM10 or PM2.5 is strongly associated with stroke incidence.115 So living near a main road, traffic sources, point sources of emissions, or higher modeled exposure to PM10, CO, and NO2 increase the risk of stroke.
CONCLUSION Internal and external risk factors are both important for stroke prevention. More importantly, deep understanding about each risk factor would provide specific guidance in practice. However, the risk factors are not fully recognized and understood nowadays, which need to be further researched to make them more systematic and precise.
ETHICAL CONSIDERATIONS Ethical issues (Including plagiarism, informed consent, misconduct, data fabrication and/or fal-sification, double publication and/or submission, redundancy, etc.) have been completely observed by the authors.
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Stroke, 47, 895e900. 40. Stollberger, C., Chnupa, P., Kronik, G., et al. (1998). Transesophageal echocardiography to assess embolic risk in patients with atrial fibrillation. Elat study group. Embolism in left atrial thrombi. Ann Intern Med, 128, 630e638. 41. Abdul-Rahim, A. H., Perez, A. C., Fulton, R. L., et al. (2015). Risk of stroke in chronic heart failure patients without atrial fibrillation: analysis of the controlled rosuvastatin in multinational trial heart failure (corona) and the gruppo italiano per lo studio della sopravvivenza nell’insufficienza cardiacaheart failure (gissi-hf) trials. Circulation, 131, 1486e1494. discussion 1494. 42. Haeusler, K. G., Laufs, U., & Endres, M. (2011). Chronic heart failure and ischemic stroke. Stroke, 42, 2977e2982. 43. de Peuter, O. R., Kok, W. E., Torp-Pedersen, C., Buller, H. R., & Kamphuisen, P. W. (2009). Systolic heart failure: a prothrombotic state. Semin Thromb Hemost, 35, 497e504.
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39. Kamel, H., Okin, P. M., Elkind, M. S., & Iadecola, C. (2016). Atrial fibrillation and mechanisms of stroke: time for a new model.
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Journal of the American Heart Association, 4. 53. Portegies, M. L., Mirza, S. S., Verlinden, V. J., et al. (2016). Midto late-life trajectories of blood pressure and the risk of stroke: the rotterdam study. Hypertension, 67, 1126e1132. 54. James, P. A., Oparil, S., Carter, B. L., et al. (2014). 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the eighth joint national committee (jnc 8). Jama, 311, 507e520. 55. Arndt, A. K., & MacRae, C. A. (2014). Genetic testing in cardiovascular diseases. Curr Opin Cardiol, 29, 235e240. 56. Malik, R., Bevan, S., Nalls, M. A., et al. (2014). Multilocus genetic risk score associates with ischemic stroke in case-control and prospective cohort studies. Stroke, 45, 394e402. 57. Dichgans, M. (2007). Genetics of ischaemic stroke. Lancet Neurol, 6, 149e161. 58. Matarin, M., Singleton, A., Hardy, J., & Meschia, J. (2010). The genetics of ischaemic stroke. J Intern Med, 267, 139e155.
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75. Gretarsdottir, S., Thorleifsson, G., Reynisdottir, S. T., et al. (2003).
60. Yamada, Y., Fuku, N., Tanaka, M., et al. (2009). Identification of celsr1 as a susceptibility gene for ischemic stroke in Japanese individuals by a genome-wide association study. Atherosclerosis, 207, 144e149.
The gene encoding phosphodiesterase 4d confers risk of ischemic stroke. Nat Genet, 35, 131e138. 76. Jorgensen, C., Yasmeen, S., Iversen, H. K., & Kruuse, C. (2015). Phosphodiesterase4d (pde4d)–a risk factor for atrial fibrillation
61. Ikram, M. A., Seshadri, S., Bis, J. C., et al. (2009). Genomewide association studies of stroke. N Engl J Med, 360, 1718e1728. 62. Raman, K., O’Donnell, M. J., Czlonkowska, A., et al. (2016). Peripheral blood mcemp1 gene expression as a biomarker for stroke prognosis. Stroke, 47, 652e658.
and stroke? J Neurol Sci, 359, 266e274. 77. Hanscombe, K. B., Traylor, M., Hysi, P. G., et al. (2015). Genetic factors influencing coagulation factor xiii b-subunit contribute to risk of ischemic stroke. Stroke, 46, 2069e2074. 78. Cheng, Y. C., Stanne, T. M., Giese, A. K., et al. (2016).
63. Bellenguez, C., Bevan, S., Gschwendtner, A., et al. (2012).
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65. Joutel, A., Corpechot, C., Ducros, A., et al. (1996). Notch3 mutations in cadasil, a hereditary adult-onset condition causing stroke and dementia. Nature, 383, 707e710. 66. Lacombe, P., Oligo, C., Domenga, V., Tournier-Lasserve, E., & Joutel, A. (2005). Impaired cerebral vasoreactivity in a transgenic mouse model of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy arteriopathy. Stroke, 36, 1053e1058. 67. Hara, K., Shiga, A., Fukutake, T., et al. (2009). Association of htra1 mutations and familial ischemic cerebral small-vessel disease. N Engl J Med, 360, 1729e1739. 68. Lanfranconi, S., & Markus, H. S. (2010). Col4a1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Stroke, 41, e513ee518. 69. Markus, H. S. (2011). Stroke genetics. Hum Mol Genet, 20, R124eR131.
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factors, genetics, and prevention. Circ Res, 120, 472e495. 81. Huang, H. D., Yang, C. M., Shu, H. F., et al. (2015). Genetic predisposition of stroke: understanding the evolving landscape through meta-analysis. Int J Clin Exp Med, 8, 1315e1323. 82. Markus, H. S., & Bevan, S. (2014). Mechanisms and treatment of ischaemic stroke–insights from genetic associations. Nat Rev Neurol, 10, 723e730. 83. Markus, H. S. (2012). Stroke genetics: prospects for personalized medicine. BMC Med, 10, 113. 84. Toyoda, K., & Ninomiya, T. (2014). Stroke and cerebrovascular diseases in patients with chronic kidney disease. Lancet Neurol, 13, 823e833. 85. Kusano, E. (2011). Mechanism by which chronic kidney disease causes cardiovascular disease and the measures to manage this phenomenon. Clin Exp Nephrol, 15, 627e633.
70. Gretarsdottir, S., Thorleifsson, G., Manolescu, A., et al. (2008). Risk variants for atrial fibrillation on chromosome 4q25 asso-
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87. Yaggi, H. K., Concato, J., Kernan, W. N., Lichtman, J. H., Brass, L. M., & Mohsenin, V. (2005). Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med, 353, 2034e2041. 88. Somers, V. K., White, D. P., Amin, R., et al. (2008). Sleep apnea and cardiovascular disease: an american heart association/ american college of cardiology foundation scientific state-
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Conflict of interest: None. Acknowledgements: This study is supported by grants from the National Natural Science Foundation of China (grant number 81701195), National Key R&D Program of China (2017FA105202) and the China Postdoctoral Science Foundation (2018M633112). Abstract: Stroke causes disability and high mortality, while it can be prevented by increasing public awareness of risk factors. The common known risk factors are hypertension, atrial fibrillation, heart failure, smoking, alcohol consumption, low physical activity, overweight and hypercholesterolemia. However, the deep understanding of risk factors is limited. Moreover, more risk factor emerges in recent years. To further increase the awareness of risk factors for stroke prevention, this review indicates the reasonable application of antihypertensive agents according to the age-dependent changes of hypertension, and some new risk factors including chronic kidney disease, obstructive sleep apnea, migraine with aura, working environment, genetic factors and air pollution. Therefore, internal risk factors (e.g. heredity, hypertension, hyperglycemia) and external risk factors (e.g. working environment, air pollution) are both important for stroke prevention. All of these are reviewed to provide more information for the pre-hospital prevention and management, and the future clinical studies. Keywords: Risk factors-Stroke-Prevention
Author affiliations: Shuai Zhang, Shenzhen Key Laboratory for Anti-aging and Regenerative Medicine, Health Science Center, Shenzhen University, Shenzhen, 518060, China; Wei Zhang, College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, Guangdong 518060, China; Guangqian Zhou, Shenzhen Key Laboratory for Anti-aging and Regenerative Medicine, Health Science Center, Shenzhen University, Shenzhen, 518060, China 1
These authors contributed same work to this paper and they are the co-first authors.
Correspondence: Guangqian Zhou, M.D., Ph.D., Guangzhou, China., email: gqzhou@szu. edu.cn ª 2019 by the National Medical Association. Published by Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jnma.2019.02.004
INTRODUCTION
S
troke and its complications are a leading cause of disability and death worldwide. In all neurological diseases, stroke imposes the greatest burden of disability-adjusted life-years.1e3 Due to the ageing society, stroke will be the leading cause of healthy life year lost by 2020.4 Furthermore, stroke consumes about 2e4% of total health-care costs and ranks third in the Global Burden of Disease Study 2010.1,5 In clinical practice, thrombolytic therapy is most effective, but has a narrow time window (4.5 h).6 Therefore, effort to shorten delay in initiation of treatment can elevate the thrombolytic effects. Recognition of stroke risk factors is essential for decreasing stroke incidence, pre-hospital stroke care and saves time from the onset of stroke symptoms to hospital arrival.4,7,8 However, many studies show that fewer than half of people know the signs, symptoms, or risk factors of stroke.9,10 The most common sources of stroke information were general life experiences and personal acquaintances rather than
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professionals.11 Consequently, improving public knowledge regarding stroke risk factors is essential for a stroke prevention and management.
Risk factors of stroke Recognition of risk factors (Figure 1) is crucial for making preventive strategies to reduce stroke incidence.12e16 According to the native and external environment of the body, the risk factors in Figure 1 can be classified in two categories including internal risk factors (e.g. hypertension, hypercholesterolemia, genetic factors) and external risk factors (e.g. smoking, alcohol consumption, air pollution). The common risk factors of stroke are hypertension, smoking, alcohol consumption, low physical activity, overweight and hypercholesterolemia.17 While, air pollution, genetic factors and working environment are gradually found to promote stroke occurrence.18 So risk factors of stroke become more variable and complex. Complexity of risk factors. The risk factors have age, gender, racial and region differences. In young patients (18e55 years) with cerebrovascular events, the most frequent risk factors are smoking, physical inactivity, arterial hypertension, dyslipidemia, obesity and diabetes mellitus.19 Some risk factors, such as high-risk alcohol consumption and short sleep duration, are more frequent in men, and migraine is more frequent in women.19 Hypertension and diabetes mellitus are more prevalent in the black stroke population, but with less atrial fibrillation, alcohol and smoking sufferings compared with the white.20 Furthermore, some symptoms also promote stroke occurrence in patients with other diseases. For example, proteinuria is associated with an increased risk of ischaemic stroke in primary aldosteronism patients.21 Exposure to multiple risk factors increases the incidence of stroke. Patients with hypertension and other risk factors are at the greater risk for stroke.22 Patients with valvular heart disease, infective endocarditis, vasculitis or peripheral vascular disease significantly increase the morbidity and mortality of stroke through prothrombolic effects and cerebral hypoperfusion.23,24 Therefore, the risk factors are various and complex. The studies about the risk factors of stroke should be classified and make these factors more targeted. Risk factors in haemorrhagic stroke. Ischemia and hemorrhage are the two major subtypes of stroke. Hemorrhagic stroke including intracerebral hemorrhage and subarachnoid hemorrhage accounts less than 15% of all stroke cases, but it can cause about 40% of all stroke
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Figure 1. Risk factors of stroke.12e16 SBP: systolic blood pressure; BMI: body-mass index; PM2.5: particulate matter (2.5 mm); GFR: glomerular filtration rate
deaths.25 Multiple risk factors (Table 1), such as hypertension, smoking, high alcohol intake and renal dysfunction, increase the incidence of haemorrhagic stroke.26e31 Intracerebral hemorrhage is the major type of hemorrhagic stroke and heavy alcohol intake, hypertension and, anticoagulant treatment are the independent risk factors for intracerebral hemorrhage.32 While hypertension, smoking and cocaine use are responsible for increasing the incidence of subarachnoid hemorrhage.33,34 A systematic meta-analysis indicates that reducing blood pressure and smoking prevalence can obviously decrease worldwide incidence of subarachnoid hemorrhage.33 So risk factors identification, avoidance, or destruction are important for stroke prevention. Risk factors in ischaemic stroke. Ischaemic stroke is the most common type of stroke and can be classified into large-vessel occlusion, cardioembolism, small-vessel occlusion, stroke of other determined cause and stroke of undetermined cause.5 Numerous risk factors (Table 1), such as hypertension, smoking, high alcohol intake, atrial fibrillation and diabetes, increase the incidence of ischaemic stroke.26e31 Distinction between haemorrhagic stroke and ischaemic stroke is clinically valuable to determine the preventive interventions. In the results from many countries, multiple factors contribute to the ischaemic stroke, while, smoking, hypertension and alcohol intake seem to be more related with hemorrhagic stroke (Table 1). In three population-based cohort studies, high total cholesterol/ high-density lipoprotein cholesterol ratio decreases the intracerebral hemorrhage rates but increases ischaemic
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incidence.26 Moreover, aging and previous cerebrovascular disease are independently associated with ischemia rather than hemorrhage.20 Older age, male sex, hypertension, and high alcohol intake are found to be the risk factors of intracerebral hemorrhage through 14 casecontrol and 11 cohort studies, while, high cholesterol is related with a lower risk of intracerebral hemorrhage.35 So stroke subtypes related risk factors are significant for the decision of preventive strategies. Atrial fibrillation. Atrial fibrillation (AF), a disorder of heart rhythm, is an important risk factor of ischaemic stroke resulting from cardioembolism of a large cerebral artery.36 So stroke-related atrial fibrillation are largely preventable by using oral anticoagulants, such as warfarin (vitamin K antagonists)37,38 Moreover, AF frequently coexists with atrial abnormalities and might be a marker of other atrial abnormalities, such as endothelial dysfunction, fibrosis, chamber dilatation and mechanical dysfunction in the left atrial appendage.39 These atrial abnormalities are associated with stroke risk.40 Therefore, the AF management becomes more complex for stroke prevention and further studies are needed to diagnose pre-fibrillators patients at risk of developing stroke-associated AF. Heart failure. Heart failure (HF) is a complex clinical syndrome with structural or functional impairment of the ventricle to eject blood. HF patients without AF are at high risk of stroke, with an incidence rate of 1.2% per year, as great as in HF patients with AF (1.6% per year), despite anticoagulant treatment in 62% of the patients.41 Several pathophysiologic factors including increased thrombus
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31
Sweden (539287) renal dysfunction (female) renal dysfunction (male, female)
30
22 countries (3000) hypertension, smoking, diet, alcohol intake, waist-to-hip ratio hypertension (history of hypertension or blood pressure >160/ 90 mm Hg), alcohol intake (more than 30 drinks per month or binge drinking), current smoking, waist-to-hip ratio, diet risk score, regular physical activity, diabetes, psychosocial stress, depression, cardiac causes, ratio of apolipoproteins B to A1
29
Nigeria (282) systolic BP 140 mmHg age 62 years, systolic BP < 140 mmHg, previous TIA
28
high alcohol intake hypertension, diabetes
Australia (536)
Denmark (39484) smoking alcohol consumption diabetes, atrial fibrillation, previous myocardial infarction, previous stroke, intermittent arterial claudication
27
United States, Ommoord, Rotterdam, Netherlands (27493) high total cholesterol/high-density lipoprotein cholesterol ratio
Reference Ischemia
Table 1. Risk factors of ischaemic stroke and hemorrhagic stroke.
Hemorrhage
Country (number of patients)
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formation, coagulation, thrombocyte aggregation, endothelial dysfunction and reduced fibrinolysis are involved in HF-mediated elevation of stroke incidence.42 HF majorly promotes thrombus formation and causes cardioembolic stroke by increasing cerebral hypoperfusion, cerebral blood flow abnormalities and hypercoagulable state.43,44 Up to now, anticoagulant therapy is effective for stroke prevention in patients with HF. Besides the traditional anticoagulants, such as aspirin and warfarin, NOACs, including dabigatran, rivaroxaban, apixaban, and edoxaban, are also potential drugs to prevent stroke in patients with HF due to their anticoagulant effects.45,46 Moreover, the CHADS2 score could stratify the risk of ischemic stroke in HF patients without AF and has a great prognostic significance with the CHADS2 score [low (¼1), 0 per 100 person-years; intermediate (¼2), 1.6 per 100 person-years; high (3), 4.7 per 100 person-years; p ¼ 0.04].47 Among patients with HF with or without AF, the CHA2DS2-VASc score was associated with risk of ischemic stroke and applied to stratify the stroke risk of patients with HF.48 More strategies and methods are needed to prevent stroke in patients with HF based on the stroke risk prediction model. Hypertension trajectories. Most studies have indicated that the risk of stroke increases with increasing blood pressure levels by using a single measurement or the average of blood pressure levels assessed over time.49,50 It has been known that hypertension is a major risk factor for stroke and many antihypertensive drugs are used for stroke prevention.51 However, long-term patterns of blood pressure may further influence stroke risk.52 Recently, in a population-based study of people aged 55 years (Figure 2), high blood pressure (average 160 mm Hg) and rapidly increasing blood pressure (120e200 mm Hg) in 5 decades are associated with a high risk of stroke and death, whereas moderately high blood pressure (average 140 mm Hg) is only related to an increased risk of stroke.53 Therefore, the traditional methods by detecting single values of blood pressure are not fully effective for stroke prevention. It is very important to make new preventive strategies according to the four trajectories of blood pressure. Moreover, it is essential to have antihypertensive agents according to the age-dependent changes of hypertension.54 Genetic factors. In recent years, clinical gene testing has been markedly increased as gene sequencing technologies penetrate the market. Cardiovascular disease is at the forefront of gene testing in the clinical studies.55 The incidence of ischaemic stroke is about 80%, as opposed to haemorrhagic.56 In prospective studies, a combined genetic risk scores for cardiovascular risk factors including atrial fibrillation, coronary artery disease, hypertension,
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Figure 2. Trajectories of blood pressure and risk of stroke. Class 1: gradually increasing blood pressure from z120 to 160 mm Hg (on average) over 5 decades; Class 2: more steep increase from an average of z120e200 mm Hg; Class 3: moderate blood pressure (z140 mm Hg) at midlife and throughout; Class 4: high blood pressure (z160 mm Hg) at midlife that decreased.53
and systolic blood pressure are significantly associated with ischaemic stroke.56 Thus, stroke is a multifactorial disorder and epidemiological evidences indicate the genetic component to the disease.57,58 Nowadays, genetic testing is increasingly available and marketed to the public. However, no single nucleotide polymorphisms (SNPs) for stroke risk are used for clinical application. Recognition of the genetic factors is important for a stroke prevention and diagnosis. So more studies are recently struggling to find the stroke-related genes and specific SNPs (Table 2),57e79 which are significant for stroke prediction. Genetic variability contribute to stroke risk via several potential mechanisms.80 The direct cause of stroke is the specific single gene disorders causing vascular abnormality, such as mutations Notch3 gene mutation causing cerebral autosomal dominant arteriopathy with subcortical infarcts.65,66 Furthermore, the gene disorders causing conventional stroke risk factors, such as atrial fibrillation, diabetes mellitus, and hypertension, are the indirect factors associated with risk of stroke.80 Generally, genetic predisposition differs depending on stroke subtype.81,82 According to the pathophysiological mechanisms, ischaemic stroke has several subtypes including large-vessel disease stroke, small-vessel disease stroke, and cardioembolic stroke.69 The genetic studies could help to distinguish stroke subtypes (Table 2) and genetic tests could help to make the diagnosis of strokes and patient management. Therefore, stroke subtypes with their specific genes have different pathophysiological mechanisms, which implies the target treatment for stroke according to the stroke subtypes.59 Although the previous studies82 have been made in the identification of genes for stroke, comparatively little is known about the specific genes and the improvement in
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clinical risk prediction is still limited.56,57 More progress from multiple centers and large sample size is needed to elucidate the genetic basis of multifactorial stroke and find the related phenotypes performed in multiple population and region samples.57,58 Moreover, another subsequent challenge is to move from these associated SNPs to a deeper understanding of the biology of risk for stroke, and provides new therapeutic targets and strategies.58,83 Consequently, great efforts are required to identify the specific genes of stroke for risk prediction. Chronic kidney disease (CKD). CKD is defined as the deterioration of renal function with a glomerular filtration rate less than 60 mL/min/1.73 m2 or the presence of protein in the urine.84,85 Renal dysfunction increases the incidence of ischaemic and hemorrhagic stroke with gender differences.31 CKD can cause hypertension and vascular lesion (arteriosclerosis), endothelial dysfunction, accumulation of indoxyl sulfate and sleep-disordered breathing, which facilitate stroke occurrence.84,85 Consequently, CKD, as a new risk factor, can be used as a predictor of ischaemic and haemorrhagic strokes, and standard for the awareness assessment of stroke risk factors. Obstructive sleep apnea. Obstructive sleep apnea (OSA), the most common form of sleep-disordered breathing, is associated with an increased incidence of new-onset stroke as an independent risk factor of stroke and is present in more than 50% of patients with stroke.86,87 OSA can cause intermittent hypoxemia and consequently lead to hypertension due to sympathetic activation and vasoconstrictive substances release.88 Moreover, OSA increases the levels of inflammatory cytokines (plasminogen activator inhibitor-1, interleukin-6, TNF-a) of patients with acute ischemic stroke.89 The
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Table 2. Stroke-related genes according to stroke subtypes.
Stroke subtypes All ischaemic stroke
Large-vessel disease stroke
Small-vessel disease stroke
Embolic stroke
Female-only stroke Young stroke
Chromosome
SNP
Candidate gene
reference
1
rs225132
ERRFI1
59
12
rs17696736
NAA25 (C12orf30)
59
3
rs16851055
SPSB4
59
22
rs6007897
CELSR1
60
12p13
rs12425791
NINJ2
59,61
13
e
ALOX5AP
57,58
19
e
MCEMP1
62
11
rs7937106
ALKBH8
59
6
rs556621
-
59
7
rs2107595
HDAC9
59,63
9
rs2383207
9p21
59,64
18
rs7407640
AFG3L2
59
2
rs13407662
-
59
19
e
NOTCH3
65,66
10
e
HTRA1
67
13
e
COL4A1
68
3
e
TREX1
69
4q25
rs2200733
PITX2
59,70
4q25
rs10033464
-
70
14q22-q23
rs2230500
PRKCH
59,71,72
1
e
MTHFR C677T
73
3
rs6763538
OXNAD1
59
16q22
rs7193343-T
ZFHX3
59,74
5q12
e
PDE4D
75,76
1
e
FXIIIB
77
3
rs7432308
-
59
12
rs2238151
ALDH2
59
7
rs12703165
PRKAG2
59
10q25
e
HABP2
78
11
e
G20210A
79
deleterious effects of OSA including arrhythmias, reactive oxidative stress, endothelial dysfunction, atherosclerosis, altered cerebral blood flow, hypertension, autonomic dysfunction and hypercoagulability might contribute to stroke.90 OSA is highly prevalent in patients with stroke. Some studies show that the continuous positive airway pressure treatment improves the functional recovery after stroke.91,92 Therefore, exploring more systematic approaches for the diagnosis and treatment of OSA are significant and should be implemented in the management of stroke.
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Migraine with aura. Migraine with aura indicates that migraineurs experience transient neurological symptoms, and is considered as a risk factor for silent brain infarcts and white matter hyperintensities.93e95 While a population-based study with female twins shows no association between silent brain infarcts, white matter hyperintensities, and migraine with aura.96 Another within-pair analyses also suggest no increased stroke risk related to migraine but modestly increased risk for stroke related to migraine with aura.97 So familial factors might contribute to the association of stroke risk and migraine
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with aura. Further research finds that older migraineurs with visual aura in late middle age have increased risk of cardioembolic stroke, while migraine without visual aura was not, over the period of 20 years.98 The underlying mechanisms of migraine increasing stroke risk are involved in cortical spreading depression, endovascular dysfunction, vasoconstriction, neurogenic inflammation, hypercoagulability, increased prevalence of vascular risk factors, shared genetic defects, cervical artery dissection, and patent foramen ovale.99 Nowadays, no preventive therapy in migraineurs can decrease stroke risk. Migraine prevalence is high in women of reproductive age and hormonal contraceptive is used in clinical practice, but the hormonal contraceptive can increase the risk of ischemic stroke in those who have migraine, specifically migraine with aura.100 Therefore, a woman with migraine with aura should be encouraged to cease smoking and avoid taking oral contraceptives with high estrogen doses.99 More investigation is needed to better understand the complexity of migraine-stroke association and find preventive strategies. Working environment. Recent studies focus on the relationship between working environment and stroke, and find bad working environment is also a risk factor of stroke. Wherein, working time is one important aspect of work environment.18 In a cumulative meta-analysis, Miki Kivimäki and colleagues found that individuals who work 55 h or more per week had a higher risk of incident stroke than those working standard hours (35e40 h per week).101 Long working hours can cause sustained stress and also indirectly increase the exposure to risk factors of stroke. Working long hours increase smoking propensities among workers who are going to quit cigarette consumption when they work more than 50 h a week.102 Moreover, long working hours are associated with physical inactivity and increased alcohol consumption.103,104 So those factors, such as smoking, physical inactivity and alcohol consumption, can alleviates work stress caused by long working hours but increase the risk of stroke. Although the association between long working hours and stroke is involved with many factors, such as the work environment and individual characteristics, long working hours, an important factor increasing stroke incidence, should be avoided. Moreover, a cohort study found no significant associations between psychosocial work environment, as measured by the job demand-control model, and ischaemic stroke.105,106 However, some studies show that job strain is associated with an almost 20% increased risk of acute ischaemic stroke.107,108 However, it is not enough to define risk with the standard thresholds due to the population variability across countries and regions.12 Up to now, some researches find the risk factors of stroke are
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related with working environment, but further systemic studies about working time, job strain, and gender/region differences are needed to determine whether interventions targeting these factors would reduce stroke risk beyond existing preventive strategies. Additionally, pathological mechanism about work-environment mediated stroke is also important for making preventive strategies. Some studies find that stroke caused by working environment may be mediated by a series of factors, such as the repetitive triggering of the stress response through activation of the hypothalamicepituitaryeadrenal and sympathoadrenomedullary axis, physical inactivity and the metabolic syndrome.109e111 These findings suggest that enhancing management of these risk factors is essential for individuals who have long working hours or strong job strain. Air pollution. The impact of air pollution on human health is currently of international concern.112,113 In the Global Burden of Disease study from 1990 to 2013, air pollution contributes to 29.2% of the burden of stroke and is being a significant risk factor.12 The main air pollutants related to stroke are particulate matter, NO2, SO2, CO and O3 produced by industry, traffic emissions and combustion of fossil or solid fuel.114 Particulate matter less than 10 mm in diameter (PM10) can reach the nasal cavities and PM2.5 perhaps pass into the bloodstream when inhaled. long-term exposure of PM10 or PM2.5 is strongly associated with stroke incidence.115 So living near a main road, traffic sources, point sources of emissions, or higher modeled exposure to PM10, CO, and NO2 increase the risk of stroke.
CONCLUSION Internal and external risk factors are both important for stroke prevention. More importantly, deep understanding about each risk factor would provide specific guidance in practice. However, the risk factors are not fully recognized and understood nowadays, which need to be further researched to make them more systematic and precise.
ETHICAL CONSIDERATIONS Ethical issues (Including plagiarism, informed consent, misconduct, data fabrication and/or fal-sification, double publication and/or submission, redundancy, etc.) have been completely observed by the authors.
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