Title:

Level of physical activity in chronic stroke patients at tertiary care

hospitals in Peshawar: A cross-sectional study

Introduction:
Stroke is a neurological disorder characterized by blockage of blood vessels. Clots form in the
brain and interrupt blood flow, clogging arteries and causing blood vessels to break, leading
to bleeding. Rupture of the arteries leading to the brain during stroke results in the sudden
death of brain cells owing to a lack of oxygen. Stroke can also lead to depression and
dementia.
Until the publication of the International Classification of Diseases 11 (icd-11) in 2018, stroke
was classed as a blood vessel illness. Clinical data obtained from stroke patients were
formerly included as part of the cardiovascular disorders chapter, significantly distorting the
severity and particular disease burden of stroke. As a result of this icd misclassification,
stroke sufferers and researchers did not receive government assistance or grant funding for
neurological disorders. The actual nature and impact of stroke were recognized in the icd-11
after years of advocacy by a group of physicians; stroke was re-categorized into the
neurological chapter [1]. The categorization of stroke as a neurological condition has resulted
in more precise data documentation and statistical analysis, which supports improvements in
acute healthcare and acquisition of research funds for stroke.
Epidemiology of stroke
Stroke is the world's second biggest cause of mortality. It affects around 13.7 million people
and kills around 5.5 million people each year. Approximately 87% of strokes are ischemic
infarctions, with the prevalence increasing significantly between 1990 and 2016, leading to
lower mortality and improved therapeutic interventions. The majority of strokes are caused by
primary (first-time) hemorrhages, with secondary (second-time) hemorrhages accounting for
10-25% [2,3]. Stroke incidence exceeded doubled in low- and middle-income countries
during 1990 and 2016, but decreased by 42% in high-income countries during the same time
period. Although the occurrence of stroke has reduced, the age of those affected, their gender,
and their geographic location indicate that the socioeconomic burden of stroke has increased
over time [3].
Types of stroke
There are three main types of stroke:
Ischemic stroke: This is the most common type of stroke, making up 87% of all cases. A
blood clot prevents blood and oxygen from reaching an area of the brain.
Hemorrhagic stroke: This occurs when a blood vessel ruptures. These are usually the result
of aneurysms or arteriovenous malformations (avms)trusted source.
Transient ischemic attack (tia): This occurs when blood flow to a part of the brain is
inadequate for a brief period of time. Normal blood flow resumes after a short amount of
time, and the symptoms resolve without treatment. Some people call this a ministroke.

Pathophysiology of stroke:
Stroke is described as an abrupt neurological outburst caused by inadequate blood vessel
perfusion to the brain. Understanding the neurovascular anatomy is crucial for studying the
clinical manifestations of stroke. Two internal carotid arteries anteriorly and two vertebral
arteries posteriorly (the circle of willis) control blood flow to the brain. Ischemic stroke is
caused by a lack of blood and oxygen to the brain, whereas hemorrhagic stroke is caused by
bleeding or leaky blood vessels.
Ischemic occlusions account for around 85% of stroke fatalities, with the balance caused by
intracerebral hemorrhage. Ischemic occlusion in the brain causes thrombotic and embolic
situations [4]. Blood flow is restricted in thrombosis due to blood vessel constriction caused
by atherosclerosis. Plaque buildup will eventually narrow the vascular chamber and lead to
clots, which causes thrombotic stroke. An embolism is caused by decreased blood flow to the
brain region in an embolic stroke; the blood supply to the brain decreases, producing extreme
stress and premature cell death (necrosis). Necrosis is followed by plasma membrane
breakdown, organelle enlargement and leakage of cellular contents into extracellular space,
and neuronal function loss[5]. Inflammation, energy failure, loss of homeostasis, acidosis,
elevated intracellular calcium levels, excitotoxicity, free radical-mediated toxicity, cytokine-
mediated cytotoxicity, complement activation, disruption of the blood–brain barrier, glial cell
activation, oxidative stress, and leukocyte infiltration are additional major events that
contribute to stroke pathology [6].
About 10% to 15% of all strokes are hemorrhagic strokes, which have a high mortality rate.
Blood vessels rupture in this condition as a result of internal injuries and stress on the brain
tissue. It causes the vascular system to become toxic, which leads to infarction [7]. There are
two types of hemorrhages: subarachnoid and intracerebral. When ich occurs, blood vessels
burst, resulting in an abnormal buildup of blood in the brain. Hypertension, abnormalities in
the vasculature, overuse of anticoagulants, and thrombolytic agents are the primary causes of
ich. When there is a head injury or cerebral aneurysm, blood builds up in the brain's
subarachnoid space, resulting in subarachnoid hemorrhage. [8].

Risk factors for stroke

As was previously mentioned, the risk of stroke rises with age and doubles for both men and
women over the age of 55. A person's pre-existing medical conditions, such as hypertension,
coronary artery disease, or hyperlipidemia, increase their risk. Patients with a history of
transient ischemic attacks (tia) account for nearly 60% of stroke cases. Certain stroke risk
factors can be modify, while others cannot .
Non-Modifiable risk factors
These include age, gender, ethnicity, tia, and hereditary traits. In the United States in 2005,
the average age of stroke occurrence was 69.2 years [2,9]. According to recent research,
people aged 20-54 years are at an increased risk of stroke, most likely due to pre-existing
secondary factors [10]. Women, regardless of age, are at equal or greater risk of stroke than
men [11]. Hispanic and black populations are at higher risk of stroke than white populations,
according to research from the United States; specifically, the incidence of hemorrhagic
stroke is significantly higher in black people than in age-matched white populations [12].
A transient ischemic attack is categorized as a mini stroke because it shares the same
underlying mechanism as a full-blown stroke. In tia, a portion of the brain's blood supply is
momentarily cut off. It serves as a warning indicator prior to the incident, giving time to
modify lifestyle choices and start taking medicine to decrease the risk of stroke [13]
Genetics influences both modifiable and non-modifiable stroke risk factors. Although genetic
risk is proportional to an individual's age, gender, and race [14], a variety of genetic
mechanisms can increase the risk of stroke. For starters, having a parent or family member
who has had a stroke increases the likelihood of developing this neurological disorder.
Second, a rare single gene mutation, such as in cerebral autosomal dominant arteriopathy, can
contribute to pathophysiology in which stroke is the primary clinical manifestation. Third,
stroke can be one of many side effects of a variety of syndromes caused by genetic mutations,
such as sickle cell anemia. Fourth, some common genetic variants, such as the 9p21 genetic
polymorphism, are linked to an increased risk of stroke [15].A genome-wide association
study of stroke found that large blood vessel disease has a high heritability (around 40%) and
small vessel disorders have a low heritability (16.7%). According to recent evidence, studying
heritability will improve understanding of stroke subtypes, improve patient management, and
allow for earlier and more efficient prognosis [5,16].
Modifiable risk factors:
These are critical because prompt and appropriate medical intervention can reduce the risk of
stroke in vulnerable individuals. Hypertension, diabetes, a lack of physical activity, alcohol
and drug abuse, cholesterol, diet management, and genetics are the major modifiable risk
factors for stroke.
One of the most important risk factors for stroke is hypertension. A blood pressure (bp) of at
least 160/90 mmhg and a history of hypertension were considered equally important stroke
risk factors in one study, with 54% of the stroke-affected population having these
characteristics [17]. Bp and the risk of stroke are linked in both hypertensive and non-
hypertensive people. According to one study, lowering blood pressure by 5-6 mm Hg reduced
the relative risk of stroke by 42%. Randomized trials of hypertension-lowering interventions
in people aged 60 and up yielded similar results, lowering the incidences of stroke symptoms
by 36% and 42%, respectively[18].
Diabetes doubles the risk of an ischemic stroke and increases mortality by about 20%.
Furthermore, diabetic patients face a worse prognosis after a stroke than non-diabetic patients,
with higher rates of severe disability and slower recovery [47,48]. Tight glycemic control
alone is ineffective; medical intervention combined with behavioral changes could help
diabetics reduce the severity of stroke.
Atrial fibrillation (AF): Depending on the patient's age, AF can increase stroke risk by two to
five times [18]. It is a significant risk factor for stroke. In comparison to strokes unrelated to
afebrile cerebropathy, it accounts for 15% of all strokes and results in greater mortality and
severe disability [19]. Previous studies have demonstrated that in patients with af, reduced left
ventricular blood flow results in thrombolysis and embolism in the brain. However, more
recent research has refuted this finding, pointing to weak evidence of a sequential timing of
incidence of af and stroke, and pointing out that in certain patients, af is only diagnosed after
a stroke; in other cases, people with af-specific genetic mutations can experience stroke long
before af manifests itself [20]. As such, improved techniques for monitoring the heart rhythms
linked to the vascular risk factors of af and thromboembolism are required.
Although hyperlipidemia plays a significant role in coronary heart disease, its connection to
stroke is not clear-cut. While high-density lipoprotein (hdl) lowers the incidence of stroke,
total cholesterol is linked to an increased risk of stroke. As a result, assessing lipid profile
allows for the estimation of stroke risk. Low hemoglobin (<0.90 mmol/l), high total
triglyceride (>2.30 mmol/l), and hypertension were linked in one study to a two-fold increase
in the population's risk of stroke-related death [21].
Alcohol and drug abuse: There is a curvilinear pattern in the relationship between the risk of
stroke and alcohol intake, with the risk increasing with daily alcohol consumption. Alcohol
consumption that is low to moderate (≤2 standard drinks per day for men and ≤1 for women)
lowers the risk of stroke, while high intake raises it. On the other hand, even moderate alcohol
use increases the risk of hemorrhagic stroke[18].Frequent use of illegal substances, such as
amphetamines, cannabis/marijuana, cocaine, heroin, phencyclidine (pcp), lysergic acid
diethylamide (lsd), or cocaine, is linked to an increased risk of strokes in all subtypes[22].
Use of illicit drugs is a common risk factor for stroke in people under the age of 35.
According to US research, the percentage of illicit drug users among stroke patients between
the ages of 15 and 44 was six times higher than that of patients who were admitted with
similar age ranges but other serious conditions. The link between these medications and
stroke is anecdotal, and there isn't enough evidence to support these conclusions [23].
Smoking: There is a direct correlation between tobacco use and a higher risk of stroke. The
risk of having a stroke is doubled for average smokers compared to non-smokers. Fifteen
percent of stroke-related deaths are caused by smoking. According to research, quitting
smoking lowers one's relative risk of stroke, but prolonged exposure to secondhand smoke
increases one's risk of stroke by 30%[24].
A poor diet and insufficient physical activity are linked to an increased risk of stroke. A
person is more likely to have a stroke attack if they do not exercise. Low levels of physical
activity are also associated with high blood pressure, obesity, and diabetes, all of which are
conditions that are associated with a higher risk of stroke [25]. A poor diet increases the risk
of stroke by causing obesity, diabetes, hypertension, and hyperlipidemia. It is commonly
recognized that some dietary components increase risk; for instance, consuming too much salt
is associated with high blood pressure and stroke. On the other hand, research has
demonstrated that a diet rich in fruits and vegetables, such as the Mediterranean diet, lowers
the risk of stroke [26].

Phases of stoke
Stroke management is typically categorized into three primary phases .
Acute phase
The first is the acute phase which refers to the initial period immediately after a stroke occurs.
It typically lasts for the first few hours or days. During this phase, the focus is on urgent
medical intervention to minimize brain damage and restore blood flow to the affected area.
Subacute phase
The subacute phase is the period that follows the acute phase, typically starting a few days
after the stroke and lasting up to several weeks or months. It is believed that this is a time
when the brain is most primed for recovery, where the brain restructures its functions,
adjusting to the damage from the stroke.
Chronic phase
The chronic phase begins after the subacute phase and represents the long-term phase of
stroke recovery. It encompasses the period of months to years after the stroke. In the chronic
phase, the focus is on continued rehabilitation, management of residual symptoms, and long-
term support for the individual's physical, cognitive, and emotional well-being.

Figure 1 - timeline of stroke recovery:

Prevention and treatment strategies for stroke:

Stroke prevention involves modifying risk factors within a population or individuals, while
stroke management depends on treating its pathophysiology. Despite an enormous amount of
research into stroke over the last two decades, no simple means of treating or preventing all
the clinical causes of stroke has been established.
Excitotoxicity:One of the main signs of a stroke is neuronal death. Neuronal depolarization
and the cell's incapacity to sustain membrane potential are major causes of this phenomenon.
The glutamate receptors α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (ampa) and
n-methyl-d-aspartate (nmda), which were among the first neuroprotective drugs tested in
stroke prevention, mediate this process. Uninhibited calcium inflow and protein damage result
from the premature release of glutamate, which overwhelms the system that keeps glutamate
out of the cell and causes aberrant release of nmda and ampa molecules. Consequently, there
is no evidence that these agents lessen neuronal death in human subjects. Rather than focusing
solely on glutamatergic signaling, targeting the molecular pathways that follow excitotoxicity
signaling may help lessen the process's negative effects [27].
Gamma aminobutyric acid (gaba) agonists:Tests on the gaba agonist clomethiazole showed
that it could lessen stroke patients' symptoms, but it was unable to lessen the toxicity brought
on by the glutamate receptor.
Sodium (na+) channel blockers:In a number of animal stroke models, Na+ channel blockers
have been employed as neuroprotective treatments. They lessen white matter damage and stop
neuronal death. Clinical trials have tested a number of voltage-gated NA+ channel blockers,
but the majority have shown to be ineffective[18]. Mexiletine is a neuroprotectant and na+
channel blocker that worked well for ischemic stroke in the grey and white matter, though
more research is needed to confirm its function [28]. Initial clinical trials with umbeluzole
demonstrated a reduction in stroke mortality; however, subsequent trials were unable to
replicate these results. Similarly, a phase II clinical trial involving stroke patients revealed
that sipatrigine, a na+ and ca2+ channel blocker, was ineffective. It has been demonstrated
that amiodarone exacerbates brain damage brought on by poor na+ ion transport and
accumulation in the brain following a stroke [29].
Calcium (ca2+) channel blockers: In animal models of brain injury, voltage-dependent ca2+
ion channel blockers have been demonstrated to lessen the ischemic insult. When given to
stroke patients in phase I and II clinical trials, the ca2+ ion chelator dp-b99 demonstrated
effectiveness and safety. Similar improvements in clinical symptoms were seen in phase II
trials for stroke patients treated within 12 hours of onset [30]. In a different study, ca2+
channel blockers, as opposed to diuretics and β-blockers, decreased the risk of stroke by
13.5%.
Antioxidants: Antioxidants produced by a responsive mechanism balance the reactive oxygen
species produced in a normal brain. Redox disequilibrium is brought about in the ischemic
stroke model, nevertheless, by an overabundance of free radical production and the
inactivation of detoxifying agents. This phenomenon results in neuronal injury and oxidative
stress. Antioxidants are therefore used in the treatment of acute stroke in order to scavenge or
inhibit the production of free radicals and break down existing free radicals within the body.
Using antioxidant aeol 10,150 (manganese (iii) meso-tetrakis (di-n-ethylimidazole)
porphyrin), researchers were able to reduce ischemic damage and reperfusion in stroke
patients by effectively regulating the gene expression profiles related to inflammation and
stress response[31].In another, deferoxamine was demonstrated to control the expression of
hypoxia-inducible factor-1, a transcriptional factor that is activated by oxygen levels and that,
in turn, activates other genes such as erythropoietin and vascular endothelial growth factor.
This mechanism has been shown to be helpful in decreasing lesion size and enhancing
sensorimotor capabilities in an animal stroke model [32]. In a similar vein, the compound
nxy-059 functions as a scavenger to get rid of free radicals and lessen neurological
impairments. The efficacy and safety of nxy-059 were demonstrated in the stroke-acute-
ischemic-nxy-treatment-i (saint) clinical trial; however, saint ii was unable to replicate the
beneficial effects of this medication in stroke patients[33]. In an additional investigation,
scientists utilized intravenous injection of antioxidants directly into the brains of mice in order
to comprehend the advantages of this mode of administration. This approach decreased
neurological abnormalities but had no effect on brain damage.
Rehabilitation: People who have a stroke may experience both temporary and permanent
impairments. Sensorimotor impairment and visual impairment are common, and everyday
activities like walking and using the restroom are frequently affected. The goal of
rehabilitation is to increase a stroke victim's level of functional independence. It entails
collaborating with patients and their families to offer post-stroke counseling and supportive
services to stable patients 48 hours following a stroke attack. Rehabilitation following a
stroke may entail speech, occupational, physical, and/or cognitive therapy. It is intended to
help patients regain their capacity for problem-solving, gain access to psychological and
social support, increase their range of motion, and become [Link]-term
potentiation and neurobiological tasks intended to reduce the effects of cognitive dysfunction
and promote synaptic plasticity may also be included in rehabilitation [18]. Neuromodulators
are essential for inducing the expression of particular genes that support the formation of
synapses, dendritic spines, axon regeneration, and cell replacement therapy. Stroke patients
can better manage their physical disability with task-oriented approaches like arm training
and walking, and visuomotor neuronal plasticity has been shown to be enhanced by visual
computer-assisted gaming activities.
Physical activity
WHO defines physical activity as “ any bodily movement produce by skeletal muscles that
requires energy expenditure” Is called physical activity.

The prevalent impairments experienced by stroke victims are typically linked to a low level of
physical activity. After a stroke, staying physically active can help with general health and
function by lowering the risk of stroke and its associated risk factors, such as lipid
dysfunction and hypertension, as well as the chance of another stroke. [34]

Lower levels of physical activity are linked to an increased risk of either hemorrhagic or
ischemic stroke as a first experience. Physical activity is likely to lower the risk of recurrent
stroke, according to risk modeling studies based on data from primary prevention studies.
Therefore, for stroke survivors, the American Heart Association (AHA) advises 20–60
minutes of medium–to–high intensity exercise, which is defined as 40–70% of either peak
oxygen uptake or heart rate reserve, three–seven days a week [35].

Rationale
Research on the degree of physical activity among chronic stroke patients is scarce, according
to the literature.
Despite having a high stroke rate, Pakistan does not have enough information on its level of
physical activity. The purpose of this study was to determine how much physical activity
chronic stroke patients in Peshawar's tertiary care hospitals engaged in.
 REFRENCES

1. Shakir R. The struggle for stroke reclassification. Nat. Rev. Neurol. 2018;14:447–448.
doi: 10.1038/s41582-018-0036-5. [PubMed] [CrossRef] [Google Scholar]

2. Roger V.L., Go A.S., Lloyd-Jones D.M., Adams R.J., Berry J.D., Brown T.M.,
Carnethon M.R., Dai S., de Simone G., Ford E.S., et al. Heart disease and stroke
statistics--2011 update: A report from the American Heart Association. Circulation.
2011;123:e18–e209. doi: 10.1161/CIR.0b013e3182009701. [PMC free article] [PubMed]
[CrossRef] [Google Scholar]

3. Collaborators G.S. Global, regional, and national burden of stroke, 1990-2016: A

systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol.
2019;18:439–458. [PMC free article] [PubMed] [Google Scholar]

4. Musuka T.D., Wilton S.B., Traboulsi M., Hill M.D. Diagnosis and management of acute
ischemic stroke: Speed is critical. CMAJ. 2015;187:887–893. doi: 10.1503/cmaj.140355.
[PMC free article] [PubMed] [CrossRef] [Google Scholar]

5. Broughton B.R., Reutens D.C., Sobey C.G. Apoptotic mechanisms after cerebral ischemia.
Stroke. 2009;40:e331–e339. doi: 10.1161/STROKEAHA.108.531632. [PubMed] [CrossRef]
[Google Scholar]

6. Woodruff T.M., Thundyil J., Tang S.C., Sobey C.G., Taylor S.M., Arumugam T.V.
Pathophysiology, treatment, and animal and cellular models of human ischemic stroke. Mol.
Neurodegener. 2011;6:11. doi: 10.1186/1750-1326-6-11. [PMC free article] [PubMed]
[CrossRef] [Google Scholar]

7. Flaherty M.L., Woo D., Haverbusch M., Sekar P., Khoury J., Sauerbeck L., Moomaw
C.J., Schneider A., Kissela B., Kleindorfer D., et al. Racial variations in location and risk
of intracerebral hemorrhage. Stroke. 2005;36:934–937. doi:
10.1161/[Link].0000160756.72109.95. [PubMed] [CrossRef] [Google Scholar]

[Link] J., Zhao X. Molecular pathophysiology of cerebral hemorrhage: Secondary

brain injury. Stroke. 2011;42:1781–1786. doi: 10.1161/STROKEAHA.110.596718.
[PMC free article] [PubMed] [CrossRef] [Google Scholar]

[Link] D., Benjamin E.J., Go A.S., Arnett D.K., Blaha M.J., Cushman M., Das
S.R., de Ferranti S., Després J.P., Fullerton H.J., et al. Executive Summary: Heart
Disease and Stroke Statistics--2016 Update: A Report From the American Heart
Association. Circulation. 2016;133:447–454. doi: 10.1161/CIR.0000000000000366.
[PubMed] [CrossRef] [Google Scholar]

10. George M.G., Tong X., Kuklina E.V., Labarthe D.R. Trends in stroke hospitalizations
and associated risk factors among children and young adults, 1995–2008. Ann. Neurol.
2011;70:713–721. doi: 10.1002/ana.22539. [PubMed] [CrossRef] [Google Scholar]
 [Link] M.K., Fang J., Hill M.D., Silver F., Richards J., Jaigobin C., Cheung A.M.,
Investigators of the Registry of the Canadian Stroke Network Sex differences in stroke
care and outcomes: Results from the Registry of the Canadian Stroke Network. Stroke.
2005;36:809–814. doi: 10.1161/[Link].0000157662.09551.e5. [PubMed] [CrossRef]
[Google Scholar]

[Link]-Flores S., Rabinstein A., Biller J., Elkind M.S., Griffith P., Gorelick P.B.,
Howard G., Leira E.C., Morgenstern L.B., Ovbiagele B., et al. Racial-ethnic disparities in
stroke care: The American experience: A statement for healthcare professionals from the
American Heart Association/American Stroke Association. Stroke. 2011;42:2091–2116.
doi: 10.1161/STR.0b013e3182213e24. [PubMed] [CrossRef] [Google Scholar]

13. Easton J.D., Saver J.L., Albers G.W., Alberts M.J., Chaturvedi S., Feldmann E.,
Hatsukami T.S., Higashida R.T., Johnston S.C., Kidwell C.S., et al. Definition and
evaluation of transient ischemic attack: A scientific statement for healthcare
professionals from the American Heart Association/American Stroke Association Stroke
Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular
Radiology and Intervention; Council on Cardiovascular Nursing; and the
Interdisciplinary Council on Peripheral Vascular Disease. The American Academy of
Neurology affirms the value of this statement as an educational tool for neurologists.
Stroke. 2009;40:2276–2293. [PubMed] [Google Scholar]

14. Seshadri S., Beiser A., Pikula A., Himali J.J., Kelly-Hayes M., Debette S., DeStefano
A.L., Romero J.R., Kase C.S., Wolf P.A. Parental occurrence of stroke and risk of stroke
in their children: The Framingham study. Circulation. 2010;121:1304–1312. doi:
10.1161/CIRCULATIONAHA.109.854240. [PMC free article] [PubMed] [CrossRef]
[Google Scholar]

15. Matarin M., Brown W.M., Singleton A., Hardy J.A., Meschia J.F., For the ISGS
Investigators Whole genome analyses suggest ischemic stroke and heart disease share an
association with polymorphisms on chromosome 9p21. Stroke. 2008;39:1586–1589. doi:
10.1161/STROKEAHA.107.502963. [PMC free article] [PubMed] [CrossRef]
[Google Scholar]

16. Bevan S., Traylor M., Adib-Samii P., Malik R., Paul N.L., Jackson C., Farrall M.,
Rothwell P.M., Sudlow C., Dichgans M., et al. Genetic heritability of ischemic stroke
and the contribution of previously reported candidate gene and genomewide associations.
Stroke. 2012;43:3161–3167. doi: 10.1161/STROKEAHA.112.665760. [PubMed]
[CrossRef] [Google Scholar]

17.O’Donnell M.J., Xavier D., Liu L., Zhang H., Chin S.L., Rao-Melacini P., Rangarajan
S., Islam S., Pais P., McQueen M.J., et al. Risk factors for ischaemic and intracerebral
haemorrhagic stroke in 22 countries (the INTERSTROKE study): A case-control study.
Lancet. 2010;376:112–123. doi: 10.1016/S0140-6736(10)60834-3. [PubMed] [CrossRef]
[Google Scholar]

[Link] Kuriakose and Zhicheng Xiao. Pathophysiology and Treatment of Stroke:

Present Status and Future Perspectives.2020 [NCBI]

 [Link] J.R., Morris J., Pikula A. Stroke prevention: Modifying risk factors. Ther.
Adv. Cardiovasc. Dis. 2008;2:287–303. doi: 10.1177/1753944708093847. [PMC free
article] [PubMed] [CrossRef] [Google Scholar]

[Link] M., Connolly S.J., Gold M.R., Morillo C.A., Capucci A., Muto C., Lau
C.P., Van Gelder I.C., Hohnloser S.H., Carlson M., et al. Temporal relationship between
subclinical atrial fibrillation and embolic events. Circulation. 2014;129:2094–2099. doi:
10.1161/CIRCULATIONAHA.113.007825. [PubMed] [CrossRef] [Google Scholar]

[Link] L., Cecchetti A., Annoni V., Merli M.F., Ablondi F., Valenti G. The role of
lipid profile in determining the risk of ischemic stroke in the elderly: A case-control
study. Arch. Gerontol. Geriatr. 2003;37:51–62. doi: 10.1016/S0167-4943(03)00020-7.
[PubMed] [CrossRef] [Google Scholar]

[Link] K., Fossati-Bellani M., Traylor A., Martin-Schild S. Epidemic of illicit drug use,
mechanisms of action/addiction and stroke as a health hazard. Brain Behav. 2011;1:44–
54. doi: 10.1002/brb3.7. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

[Link] V.M., Cole J.W., Sorkin J.D., Wozniak M.A., Malarcher A.M., Giles W.H., Stern
B.J., Kittner S.J. Dose-response relationship between cigarette smoking and risk of ischemic
stroke in young women. Stroke. 2008;39:2439–2443. doi:
10.1161/STROKEAHA.107.510073. [PMC free article] [PubMed] [CrossRef] [Google
Scholar]

24. Song Y.M., Cho H.J. Risk of stroke and myocardial infarction after reduction or
cessation of cigarette smoking: A cohort study in korean men. Stroke. 2008;39:2432–
2438. doi: 10.1161/STROKEAHA.107.512632. [PubMed] [CrossRef] [Google Scholar]

25. Larsson S.C., Orsini N., Wolk A. Dietary potassium intake and risk of stroke: A
dose-response meta-analysis of prospective studies. Stroke. 2011;42:2746–2750. doi:
10.1161/STROKEAHA.111.622142. [PubMed] [CrossRef] [Google Scholar]

26. Estruch R., Ros E., Martínez-González M.A. Mediterranean diet for primary
prevention of cardiovascular disease. N. Engl. J. Med. 2013;369:676–677. doi:
10.1056/NEJMoa1200303. [PubMed] [CrossRef] [Google Scholar]

27. Hoyte L., Barber P.A., Buchan A.M., Hill M.D. The rise and fall of NMDA
antagonists for ischemic stroke. Curr. Mol. Med. 2004;4:131–136. doi:
10.2174/1566524043479248. [PubMed] [CrossRef] [Google Scholar]

28. Kotoda M., Hishiyama S., Ishiyama T., Mitsui K., Matsukawa T. Amiodarone
exacerbates brain injuries after hypoxic-ischemic insult in mice. BMC Neurosci.
2019;20:62. doi: 10.1186/s12868-019-0544-2. [PMC free article] [PubMed] [CrossRef]
[Google Scholar]

29. Segura T., Calleja S., Jordan J. Recommendations and treatment strategies for the
management of acute ischemic stroke. Expert Opin. Pharmacother. 2008;9:1071–1085.
doi: 10.1517/14656566.9.7.1071. [PubMed] [CrossRef] [Google Scholar]
30. Angeli F., Verdecchia P., Reboldi G.P., Gattobigio R., Bentivoglio M., Staessen J.A.,
Porcellati C. Calcium channel blockade to prevent stroke in hypertension: A meta-
analysis of 13 studies with 103,793 subjects. Am. J. Hypertens. 2004;17:817–822. doi:
10.1016/S0895-7061(04)00863-5. [PubMed] [CrossRef] [Google Scholar]

31. Ono S., Hishikawa T., Ogawa T., Nishiguchi M., Onoda K., Tokunaga K., Sugiu K.,
Date I. Cerebral Vasospasm. Springer; Vienna, Austria: 2008. Effect of deferoxamine-
activated hypoxia inducible factor-1 on the brainstem following subarachnoid
haemorrhage; pp. 69–73. Acta Neurochirurgica Supplement, Volume 104. [Google
Scholar]

32. Shuaib A., Lees K.R., Lyden P., Grotta J., Davalos A., Davis S.M., Diener H.C.,
Ashwood T., Wasiewski W.W., Emeribe U., et al. NXY-059 for the treatment of acute
ischemic stroke. N. Engl. J. Med. 2007;357:562–571. doi: 10.1056/NEJMoa070240.
[PubMed] [CrossRef] [Google Scholar]

33. Shirley R., Ord E.N., Work L.M. Oxidative Stress and the Use of Antioxidants in
Stroke. Antioxidants. 2014;3:472–501. doi: 10.3390/antiox3030472. [PMC free article]
[PubMed] [CrossRef] [Google Scholar]

34. Camila Lima Gervásio Mendes, Júlia Caetano Martins, Dayanne da Silva Ferreira,
Deijanira Rocco de Souza. Physical activity level of post-stroke individuals that use the
Brazilian public health system; systemic review 2022,
35. .Matthew J. Field,1Nick Gebruers, 2Thavapriya Shanmuga Sundaram,3Sarah
Nicholson,1and Gillian MeadPhysical Activity after Stroke: A Systematic Review and Meta-
Analysis 2013