Stroke

TOPICAL REVIEW

Impact of Exercise on Cerebrovascular

Physiology and Risk of Stroke
Justin A. Edward , MD; William K. Cornwell III , MD, MSCS

ABSTRACT: Ischemic heart disease and stroke are the number 1 and number 2 causes of death worldwide, respectively. A lifelong
commitment to exercise reduces the risk of these adverse events and is also associated with several cardiometabolic improvements,
including reductions in blood pressure, cholesterol, and inflammatory markers, as well as improved glucose control. Routine exercise
also reduces the risk of developing comorbidities that increase the risk of cardiovascular or cerebrovascular disease. While the
benefits of a lifelong commitment to exercise are well documented, there is a complex interaction between exercise and stroke
risk, such that the risk of ischemic or hemorrhagic stroke may increase acutely during or immediately following exercise. In this
article, we discuss the physiological responses to different types of exercise, as well as the determinants of resting and exertional
cerebrovascular perfusion, and explore the complex interaction between atrial fibrillation, exercise, and stroke risk. Finally, we
highlight the increased risk of stroke during different types of exercise, as well as factors that may alleviate this risk.

Key Words: atrial fibrillation ◼ blood glucose ◼ blood pressure ◼ cause of death ◼ exercise ◼ hemorrhagic stroke ◼ ischemic stroke

G
lobally, stroke ranks as the second most common number of cardiometabolic improvements. Nevertheless,
cause of death, superseded only by ischemic heart the hemodynamic response to exercise and downstream
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disease.1 On average, every 40 seconds, someone
in the United States experiences a stroke, and every 4
minutes, someone dies from cerebrovascular disease.
Because of statistics such as these, the Centers for Dis-
ease Control and Prevention and Centers for Medicare and
Medicaid Services launched the Million Hearts Collabora-
tion in 2015 with the overall goal of reducing the number
of heart attacks and strokes by 1 million by the year 2022.
This ambitious goal relies on collaborations between local,
state, and national government entities to implement and
promote a number of healthy lifestyle choices including
reduction of sodium intake and tobacco products, increase
in physical activity for the American population as a whole,
as well as participation in cardiac rehabilitation for eligible
patients. Indeed, routine exercise is recognized by organi-
zations such as the American Stroke Association, Ameri-
can Heart Association, Department of Health and Human
Services, and the US Preventive Services Task Force as a
mainstay of therapy for primary and secondary prevention
of cerebrovascular and cardiovascular disease.
A lifelong commitment to exercise clearly reduces
risk of these adverse events and is associated with a
effects on dependent organs such as the brain are highly
complex and depend on the type of exercise performed.
Historically, it was thought that cerebral perfusion was
relatively stable and unaffected by exercise. However, it
is now recognized that there are multiple determinants of
cerebral blood flow (CBF) during exercise, including local
and systemic metabolic byproducts of exercise, sympa-
thetic tone, and to some extent, cardiac output (Qc) and
blood pressure (BP). Further, there is a risk of ischemic
and hemorrhagic stroke during and shortly after any
acute bout of exercise, the risk of which varies according
to the type, duration, and intensity of exercise. Therefore,
it is important to understand the metabolic and hemody-
namic responses to exercise and the downstream effects
on end-organ function, including the brain.
CLASSIFICATION OF DIFFERENT TYPES
OF EXERCISE
The hemodynamic response to exercise—including
changes in BP, Qc, and hence perfusion of dependent

Correspondence to: William K. Cornwell III, MD, MSCS, University of Colorado Anschutz Medical Campus, 12631 E 17th Ave, B130, Office 7107, Aurora, CO 80045.
Email william.cornwell@cuanschutz.edu
For Sources of Funding and Disclosures, see page 2409.
© 2022 American Heart Association, Inc.
Stroke is available at www.ahajournals.org/journal/str

2404   July 2022 Stroke. 2022;53:2404–2410. DOI: 10.1161/STROKEAHA.121.037343

 Edward et al
organs including the brain—varies according to the type
of activity being performed (Figure 1).2,3 Sports are gen-
erally stratified according to the intensity of endurance
and strength that is necessary to sustain the activity. The
endurance, or dynamic component of exercise, refers
to the intensity of exercise as a proportion of an indi-
vidual’s maximal oxygen uptake (VO2).4 The strength, or
static component of exercise, depends on the intensity
of static muscle contractions undertaken, as a proportion
of an individual’s maximal voluntary contraction. Differ-
ent sports and exercise types are categorized based on
these factors for 2 reasons: first, the acute hemodynamic
responses to static and dynamic exercise are different;
second, cardiac remodeling, that is, chronic changes in
heart structure and function that occur in response to
long-term participation in sports, differs according to the
type of sport and the hemodynamic demands placed on
the cardiovascular system.4–6
While mean arterial pressure (MAP), the product of
Qc and total peripheral resistance, increases during both
dynamic and static exercise, the determinants of BP, and
the overall hemodynamic response, vary dramatically
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Figure 1. The classification of different sports/exercises is based on the relative contribution of static vs dynamic exercise
intensity.
Reprinted from Levine et al2 with permission. Copyright ©2015, the American Heart Association, Inc, and the American College of Cardiology
Foundation. Reprinted from Mitchell et al3 with permission. Copyright ©2005, the American College of Cardiology Foundation.
Stroke. 2022;53:2404–2410. DOI: 10.1161/STROKEAHA.121.037343
Relationship Between Exercise and Stroke Risk
according to the type of exercise undertaken.7–9 Dynamic
exercise such as running or cycling is associated with a
Topical Review
reduction in total peripheral resistance due to peripheral
vasodilatation at exercising muscle beds to accommo-
date increases in blood flow necessary to meet meta-
bolic demand. Qc increases in proportion to the degree
of increase in VO2, generally by 5 to 6 L/min for every
1-L/min increase in VO2.10,11 This Qc:VO2 relationship
is generally an inviolate principle of exercise physiology
across the spectrum of age, sex, health, and disease,
except perhaps for patients with severe heart failure,
where the relationship is blunted due to reductions
in contractile reserve of the failing left ventricle.7 This
increase in Qc offsets the reduction in total peripheral
resistance such that MAP increases above resting values
during dynamic exercise. During static exercise, systolic
and diastolic BP rise rapidly during muscle contraction
as a result of mechanical compression of blood vessels,
the exercise presser reflex, and Valsalva response.9 The
larger the muscle mass that is incorporated into exer-
cise, the greater the increase in BP,12–14 and in extreme
cases, systolic BP may increase to 300 to 400 mm Hg.9
July 2022   2405
 Edward et al
These factors increase left ventricular afterload, which
prevents any meaningful increase in stroke volume dur-
Topical Review
ing static exercise.15 For that reason, increases in Qc dur-
ing static exercise are modest and are driven primarily by
an increase in heart rate.15 Thus, static exercise imputes
a large pressure load on the cardiovascular system, in
stark contrast to dynamic exercise, which confers a large
volume load, with very different hemodynamic responses.
FACTORS INFLUENCING
CEREBROVASCULAR PERFUSION
DURING EXERCISE
Traditionally, it was assumed that CBF is relatively unaf-
fected by exercise and is maintained at a relatively con-
stant rate of ≈50 to 60 mL per 100 g/min.16 However, it
is now recognized that there are a variety of factors that
determine CBF at rest and during exercise (Figure 2).17
Under resting conditions, CBF is exquisitely sensitive
to PaCO2, typically increasing by 3% to 5% for each
1-mm Hg rise in PaCO2 and decreasing by 1% to 3%
for each 1-mm Hg reduction in PaCO2.18 CBF is coupled
to cerebral metabolism, as determined by the exchange
of oxygen, glucose, and lactate across the cerebral vas-
cular bed, and upward or downward changes in CBF
occur in response to increases or decreases in neuronal
activity, such as occurs during exercise. The change in
CBF that occurs during exercise may involve biphasic
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components (Figure 2).17 Generally, CBF increases dur-
ing submaximal exercise in concert with exercise inten-
sity. However, as the ventilatory threshold is exceeded
(typically around 60%–70% of maximal oxygen uptake
depending on an individual’s level of fitness), cerebral
perfusion may plateau or actually decline as a result of
Figure 2. Changes in cardiac output (Qc), cerebral blood flow
(CBF), and PaCO2 in response to progressive increase in
exercise intensity.
Vertical dashed line indicates ventilatory threshold. Max indicates
maximum; and Min, minimum.
2406   July 2022
Relationship Between Exercise and Stroke Risk
hyperventilation-induced hypocapnia (Figure 3).17,19–21
Despite multiple variables that contribute to overall cere-
bral perfusion, PaCO2 is the primary determinant of CBF
during incremental exercise. This finding has been nicely
demonstrated through elegant physiology studies involv-
ing forced/artificial increases in PaCO2, achieved by CO2
clamping, which led to increases in CBF during exercise
above values obtained during exercise undertaken.22,23
For example, one study monitored middle cerebral arte-
rial velocity (MCAV) among cyclists during 2 exercise
tests: one as a control and another with end-tidal carbon
dioxide levels clamped and held constant by a rebreath-
ing circuit.22 End-tidal carbon dioxide at peak workload
above ventilatory threshold was significantly greater
during clamped versus control exercise tests (39.7±5.2
versus 29.6±4.7 mm Hg; P<0.01), and MCAV was signif-
icantly greater in clamped versus control test (92.6±15.9
versus 73.6±12.5 cm/s; P<0.01).22
The direct contribution of BP to CBF during exercise
is difficult to discern.17 During dynamic exercise, BP may
increase by ≥30% from rest to peak exercise, but the
aforementioned leveling off or reduction of CBF above
ventilatory threshold clearly indicates that BP in and of
itself is not the primary driver of cerebral perfusion dur-
ing dynamic exercise, particularly at workloads above
ventilatory threshold.17 However, for static exercise, sud-
den contraction of large muscle groups may cause rapid
increases in BP, leading to an acute and large increase in
CBF.24 Cerebral autoregulatory processes operate over a
period of several seconds, meaning that cerebrovascu-
lar resistance vessels cannot immediately buffer acute,
large oscillations in BP that occur during static exer-
cise.25,26 Thus, exercise that incorporates large muscle
groups may lead to transient but large increases in CBF.
For example, when healthy individuals performed high-
resistance exercise with lower-extremity leg press, MCAV
changed directly in response to fluctuations in MAP.24
This observation indicates that sudden large increases in
MAP are directly transmitted to the cerebral vasculature,
leading to large increases in CBF before autoregulatory
processes are engaged.24 Similar findings were observed
when healthy rowers performed repetitive ergometry
rowing while MCAV and BP were continuously moni-
tored.27 Both MAP (86±6 to 97±6 mm Hg) and MCAV
(57±3 to 67±5 cm/s) fluctuated in a sinusoidal pattern
from rest to peak force applied to the oars with repetitive
rowing motion.27 These observations indicate that large
acute changes in BP occurring particularly during highly
static exercises may lead to sudden increases in CBF,
which raises concerns on the safety of these types of
exercises for individuals in whom cerebral autoregulation
is impaired, or have preexisting hypertension and are at
risk of unsafe increases in BP during activity.17
Qc in and of itself does not appear to play a signifi-
cant role in determining CBF during exercise. Observed
increases in CBF during incremental exercise tests are
Stroke. 2022;53:2404–2410. DOI: 10.1161/STROKEAHA.121.037343
 Edward et al
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Figure 3. Hemodynamic response to exercise in a 59-y-old
healthy man during cardiopulmonary exercise test during
stationary upright cycle ergometry, demonstrating initial
increase in middle cerebral arterial velocity during exercise,
followed by leveling off and eventual reduction in velocity
during exercise above ventilatory threshold.
Blood pressure was obtained from radial arterial catheterization.
Middle cerebral arterial velocity was obtained from transcranial
Doppler during exercise. Gas exchange parameters were obtained
by breath-by-breath indirect calorimetry. VCO2 indicates carbon
dioxide production; and VO2, oxygen uptake. Unpublished data
from senior author (https://www.clinicaltrials.gov; unique identifier:
NCT03232736).
modest compared with the 3- to 5-fold increases in Qc
from rest to peak effort during dynamic exercises that are
observed among healthy individuals.17 Further, the plateau,
and in some cases, decline of CBF at workloads above the
ventilatory threshold, despite ongoing increases in Qc, sug-
gests that during exercise, the majority of Qc is distributed
to exercising muscle in a supply-demand fashion.17 Thus,
changes in Qc do not appear to be the predominant factor
that determines CBF during exercise. This observation is
perhaps best illustrated by analysis of the cerebrovascular
response to exercise among individuals who have received
Stroke. 2022;53:2404–2410. DOI: 10.1161/STROKEAHA.121.037343
Relationship Between Exercise and Stroke Risk
a heart transplantation.28 Because the heart is denervated
in transplant recipients, the heart rate response to exer-
Topical Review
cise is blunted compared with controls.29 While stroke
volume increases in the transplanted heart,29,30 the overall
increase in Qc during exercise is blunted, with an ≈2-fold
increase from rest to peak exercise,29 compared with 3-
to 5-fold increases that are typical of healthy individuals.7
Despite those differences, increases in MCAV among
heart transplant recipients are similar to levels achieved
among age-matched controls (MCAV at peak exercise:
45±11 versus 53±8 cm/s for transplant patients versus
controls, respectively).28
CEREBROVASCULAR AND
CARDIOMETABOLIC BENEFITS OF
PHYSICAL ACTIVITY
A lifelong commitment to physical activity has been shown
to reduce the risk of cardiovascular disease, stroke, and
all-cause mortality.1,31,32 Several cardiometabolic improve-
ments occur as well, including reductions in BP in a dose-
dependent fashion,33 as well as improvements in lipid
profile,33,34 a reduction in inflammatory markers,35 and
improved glucose control and insulin sensitivity.1 In a long-
term follow-up study of veterans, for each 1-unit increase in
fitness, as measured by peak metabolic equivalent (MET)
achieved on exercise stress testing, the hazard ratio for all-
cause mortality declined by 12%, and when compared with
the least-fit individuals (defined as ≤4 METs), the mortal-
ity risk was 38% lower for individuals who achieved 5.1
to 6.0 METs and 61% lower for individuals who achieved
>9 METs.31 In the Cooper Center Longitudinal Study, low
cardiorespiratory fitness was associated with a greater risk
of cardiovascular-related death over 30 years of follow-
up.32 Given the overwhelming evidence of the benefits
associated with a commitment to lifelong exercise, the
Department of Health and Human Services,36 as well as
the American Heart Association, recommends that adults
engage in at least 150 minutes of moderate-intensity or 75
to 150 minutes of vigorous-intensity aerobic physical activ-
ity per week, as well as muscle-strengthening activities of
moderate or greater intensity at least twice weekly.
In the REGARDS study (Reasons for Geographic and
Racial Differences in Stroke), regular exercise of at least
4× per week was associated with a significant reduction in
risk of stroke or transient ischemic attack over an ≈6-year
period of follow-up.37 This finding has been replicated in
studies and meta-analyses that have shown that a commit-
ment to moderate physical activity reduces the risk of total,
ischemic, and hemorrhagic stroke over time.38,39 However,
it should be noted that in the REGARDS study,37 the asso-
ciation between incident stroke and physical activity was
partially attenuated after adjustment for traditional stroke
risk factors (eg, hypertension and diabetes). This observa-
tion suggests that the reduction in stroke risk results is at
July 2022   2407
 Edward et al
least in part from an interaction between physical activity
and an attenuation of typical risk factors for stroke.
Topical Review
ASSOCIATION BETWEEN EXERCISE,
ATRIAL FIBRILLATION, AND STROKE
The presence of atrial fibrillation obviously increases the
risk of stroke.1,40 However, routine physical activity has
been shown in multiple studies to reduce both the risk of
incident atrial fibrillation41 and the amount of time spent
in atrial fibrillation.42 Interestingly, there appears to be a
U-shaped dose-dependent relationship between routine
physical activity and incident atrial fibrillation.41 This rela-
tionship is such that moderate levels of physical activity
reduce the risk of atrial fibrillation compared with sed-
entary individuals. However, at the extremes of exercise,
such as highly trained endurance athletes, the risk of atrial
fibrillation begins to increase and approximates the same
risk observed among sedentary individuals.41 The mecha-
nism for this association between extreme exercise and
risk of atrial fibrillation is unclear but has been attributed
to atrial remodeling, inflammation, or atrial fibrosis.43,44
Interestingly, it does not appear that this increase in risk of
incident atrial fibrillation among endurance athletes trans-
lates into an increase in risk of stroke. In a large analysis
of Swedish cross-country skiers, the incidence of stroke
among athletes with atrial fibrillation was not higher than
the incidence of stroke observed among nonathletes with
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atrial fibrillation.45 This observation suggests that exercise
has beneficial effects on other stroke risk factors, which
offset increases in stroke risk that might otherwise occur
as a result of atrial fibrillation.
STROKE RISK DURING EXERCISE
Despite the well-documented reductions in risk of car-
diovascular and cerebrovascular events associated with a
lifelong commitment to physical activity, there remains a
risk of stroke for any acute bout of exercise. In this regard,
the Stroke Onset Study46 reported several informative
pieces of information: first, there is a >2-fold increase
in risk of ischemic stroke within 1 hour of completion of
moderate-vigorous physical activity. However, the stroke
risk during/immediately following exercise was greater
among sedentary individuals (defined as individuals who
exercise <3× per week) as compared with active indi-
viduals (those who routinely exercise ≥3× per week).46
Specifically, the risk of stroke was 6.8-fold higher among
sedentary individuals during/immediately following exer-
cise versus only 2-fold higher for active individuals. Finally,
within 1 hour after lifting heavy objects (defined as 50 lbs
[23 kg]), the risk of ischemic stroke was 2.6× higher than
exercise without heavy lifting.46 In ACROSS (Australasian
Cooperative Research on Subarachnoid Hemorrhage
Study), individuals who participated in moderate-extreme
2408   July 2022
Relationship Between Exercise and Stroke Risk
exercise (defined as ≥5 METs) had a 3-fold increase in
risk of subarachnoid hemorrhage within 2 hours of com-
pleting the exercise bout.47 This risk in hemorrhagic stroke
was not attenuated by habitual exercise. These findings
mirror other analyses characterizing the increased risk of
myocardial infarction or sudden cardiac death shortly fol-
lowing bouts of moderate-extreme exercise.48–51 Thus, it
may be that a lifelong commitment to exercise reduces the
risk of ischemic stroke but not subarachnoid hemorrhage,
at least in the period during or immediately following a
bout of exercise. It is plausible that the temporal relation-
ship between moderate-extreme exertion and subarach-
noid hemorrhage risk is mediated by BP since exercises
that are highly static in nature lead to large and sudden
increases in BP. This hypothesis is supported by previous
observations documenting a circadian pattern to the onset
of subarachnoid hemorrhage, intracerebral hemorrhage,
and strokes in general, with the risk being the highest in
the morning, around the time of the typical diurnal surge in
BP and heart rate.52–54
BLOOD BIOMARKERS OF STROKE
There has been great interest in identifying biomark-
ers suggestive of acute stroke.55–57 Potential biomark-
ers have included glial structure proteins such as GFAB
(glial fibrillary acidic protein)58 and S100B,57 MMPs
(matrix metalloproteinases),59,60 and BNP (brain natri-
uretic peptide),61 among others. GFAB has been shown
to effectively differentiate hemorrhagic and ischemic
strokes.58 S100B is a sensitive marker for acute stroke
but is limited by low specificity, as this biomarker is also
elevated in other pathological states such as traumatic
brain injury and malignancies.62,63 MMP-9 concentration
during stroke is correlated with infarct size, as well as
poststroke complications and poor outcomes.59,60 BNP
levels are elevated in response to ischemic and cardio-
embolic stroke,61 as well as intracerebral hemorrhage64
and subarachnoid hemorrhage.65
Several of these biomarkers may be elevated follow-
ing an acute bout of exercise. GFAP has been shown
to increase acutely following exercise in rat models.66
S100B is increased following running, but notably,
S100B is present in skeletal muscle, and the increased
level may be a result of skeletal muscle damage.67
An acute bout of static types of exercise leads to an
increase in MMP-9; however, obesity lowers baseline
MMP-9 concentrations.68 Thus, body habitus may con-
found MMP concentrations during/after exercise. BNP
increases may occur as a result of myocardial wall stress
and are particularly elevated following long-duration
exercise.69 Currently, there are little data available to
describe whether these increases in biomarker concen-
tration predict stroke risk during or following activity. Fur-
ther research is needed in this area, particularly since
other factors such as myocardial wall stress and skeletal
Stroke. 2022;53:2404–2410. DOI: 10.1161/STROKEAHA.121.037343
 Edward et al
muscle damage, as well as body habitus, as opposed to
an acute stroke, may alter biomarker concentration dur-
ing/immediately following exercise.
CONCLUSIONS
Cerebrovascular disease is one of the most common
causes of morbidity and mortality throughout the world
and in the United States in particular, given the preva-
lence of stroke-related risk factors. During any acute
bout of exercise, there is a finite risk of stroke during and
immediately following activity, and the specific hemo-
dynamic responses, along with downstream effects on
dependent organs such as the brain, may vary according
to the type of exercise undertaken. Further, CBF during
exercise is highly dynamic and fluctuates in response to
multiple factors, most notably, changes in PaCO2 that
occur with progressive increases in workload.
Despite the acute risks, however, a lifelong commit-
ment to exercise or habitual physical activity is associ-
ated with reductions in major adverse cerebrovascular
and cardiovascular events, along with a host of cardio-
metabolic improvements.
ARTICLE INFORMATION
Affiliation
Downloaded from http://ahajournals.org by robsonsant@gmail.com on November 29, 2022
Department of Medicine–Cardiology (J.A.E., W.K.C.) and Clinical Translational Re-
search Center (W.K.C.), University of Colorado Anschutz Medical Campus, Aurora.
Sources of Funding
Dr Cornwell has received funding by a National Institutes of Health (NIH)/Na-
tional Heart, Lung, and Blood Institute Mentored Patient-Oriented Research Ca-
reer Development Award (No. 1K23HLI32048), as well as the NIH/National
Center for Advancing Translational Sciences (No. UL1TR002535), Medtronic,
Inc, Bioventrix, Inc, and Riva, Inc.
Disclosures
Dr Cornwell is a consultant for Medtronic, Inc, and Bioventrix, Inc. The other au-
thor reports no conflicts.
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