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REVIEW
Mental Stress and Its Effects on Vascular

Health
Jaskanwal Deep Singh Sara, MBChB; Takumi Toya, MD; Ali Ahmad, MD;
Matthew M. Clark, PhD; Wesley P. Gilliam, PhD; Lliach O. Lerman, MD, PhD;
and Amir Lerman, MD
Abstract
Coronary artery disease continues to be a major cause of morbidity and mortality despite significant
advances in risk stratification and management. This has prompted the search for alternative
nonconventional risk factors that may provide novel therapeutic targets. Psychosocial stress, or mental
stress, has emerged as an important risk factor implicated in a higher incidence of cardiovascular
events, and although our understanding of this far ranging and interesting phenomenon has developed
greatly over recent times, there is still much to be learned regarding how to measure mental stress and
how it may impact physical health. With the current coronavirus disease 2019 global pandemic and its
incumbent lockdowns and social distancing, understanding the potentially harmful biological effects
of stress related to life-changing events and social isolation has become even more important. In the
current review our multidisciplinary team discusses stress from a psychosocial perspective and aims to
define psychological stress as rigorously as possible; discuss the pathophysiologic mechanisms by
which stress may mediate cardiovascular disease, with a particular focus to its effects on vascular
health; outline existing methods and approaches to quantify stress by means of a vascular biomarker;
outline the mechanisms whereby psychosocial stressors may have their pathologic effects ultimately
transduced to the vasculature through the neuroendocrine immunologic axis; highlight areas for
improvement to refine existing approaches in clinical research when studying the consequences of
psychological stress on cardiovascular health; and discuss evidence-based therapies directed at
reducing the deleterious effects of mental stress including those that target endothelial dysfunction. To
this end we searched PubMed and Google Scholar to identify studies evaluating the relationship be-
tween mental or psychosocial stress and cardiovascular disease with a particular focus on vascular
health. Search terms included “myocardial ischemia,” “coronary artery disease,” “mental stress,”
“psychological stress,” “mental* stress*,” “psychologic* stress*,” and “cardiovascular disease*.” The
search was limited to studies published in English in peer-reviewed journals between 1990 and the
present day. To identify potential studies not captured by our database search strategy, we also
searched studies listed in the bibliography of relevant publications and reviews.
ª 2022 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/) n Mayo Clin Proc. 2022;97(5):951-990
From the Department of
C
oronary artery disease (CAD) re- between 2006 and 2016 reaching 17.6
Cardiovascular Diseases
mains the leading causes of disease million deaths per year, of which 7.4 (J.D.S.S., T.T., A.A., A.L.),
across the globe.1 Age- million were due to CAD.1 These mortality Department of Psychiatry
and Psychology (M.M.C.),
standardized life-years lived with ischemic numbers continue to highlight the ongoing and the Division of
heart disease decreased by 47% between need to identify novel risk factors to target Nephrology and Hyper-
1990 and 2016,1 owing greatly to better for CVD prevention and treatment. A risk tension (W.P.G., L.O.L.),
Mayo Clinic, Rochester,
cardiovascular disease (CVD) risk manage- factor of great interest and of which our un- MN, USA.
ment and medical care.2,3 Nevertheless the derstanding has developed significantly
number of people actually dying of CVD over recent years is psychosocial stress, or
in the United States increased by 15% mental stress (MS).
Mayo Clin Proc. n May 2022;97(5):951-990 n https://doi.org/10.1016/j.mayocp.2022.02.004 951

www.mayoclinicproceedings.org n ª 2022 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
MAYO CLINIC PROCEEDINGS
health care workers and reported that having

ARTICLE HIGHLIGHTS a high level of perceived stress was associ-
ated with a poor quality of life and negative
d The importance of studying mental stress (MS) as a potential
health behaviors.5,6 In addition, despite var-
risk factor for cardiovascular disease has been brought to the
iations in study design, patient characteris-
fore with the coronavirus disease 2019 global pandemic and its tics and measurements of stress and clinical
associated public health policies. outcomes, most studies have shown signifi-
d Carefully defining MS involves distinguishing acute from chronic cant associations between stress and adverse
MS, accounting for coexisting biopsychosocial factors that are health outcomes.7,8 Studies have also shown
also associated with cardiovascular disease, and placing stress in a link between MS and depression,9 diabetes
its appropriate context d to this end, tools that quantify real- mellitus,10 cancer,11 and CVDs including
CAD, atrial fibrillation, and stroke.12-15 In
time physiologic reactivity to acute MS and the cumulative
the large multinational INTERHEART study
physiologic burden of chronic MS using measures that predict
MS was associated with a greater than two-
risk of disease will be of great value. fold increased risk for myocardial infarction
d The pathologic cardiovascular effects of MS are transduced (MI) even after controlling for CVD risk fac-
along the neuroendocrine immunologic axis to the vascular tors; this effect persisted after stratifying by
system by means of endothelial dysfunction and vascular sex, prior CVD, socioeconomic status
inflammation. (SES), lifestyle factors, and geographic re-
gion.16 The potential link between MS and
d Future MS studies should be more generalizable, must account
adverse health outcomes in general and
for physiologic changes that occur temporally remote from the
CVD in particular has become of even
stressor, and should develop mechanistic models that include greater importance in the context of the cur-
important coexisting biopsychosocial variables. rent coronavirus disease 2019 (COVID-19)
d Although therapies targeting MS currently lack a robust evi- global pandemic. This severe life-altering
dence base, the pathologic effects of MS on the vascular system event has affected individuals at all levels
can be addressed using existing treatment strategies that target of society across the world bringing with it
endothelial dysfunction. a constellation of stressors en masse,
including job loss or job and income insecu-
rity with furlough schemes, illness and
Mental stress is a universal and shared deaths of loved ones, dramatic changes to
experience of each of our lives. Estimates working and lifestyle habits, and (as a conse-
show that two-thirds of the general popula- quence of incumbent lockdown and social
tion has experienced MS within the past 2 distancing policies) social isolation and lone-
weeks, with almost 50% rating their stress liness. The long-term implications of the
as “moderate or high.”4 Not just a facet of COVID-19 pandemic and its accompanying
the fast-paced, globalized, and technologi- widespread social isolation on the risk of
cally advanced society of the 21st century, CVDs are yet to be realized but will form
the nature and sources of stress have been an essential area of future study.
contemplated since the time of the ancients.
Six centuries before the birth of Christ, Con- DEFINING STRESS
fucius told his pupils “life is simple, but we Stress has evolved into a variably used collo-
insist on making it complicated” whereas quialism. It is important to define this term
almost a thousand years later, the Roman carefully to study its role in disease and as
Emperor Marcus Aurelius wrote “if you are a potential therapeutic target. An important
distressed by something, it is due to your distinction should be made between the
own estimate of it.” Yet our understanding stressor as a potentially challenging external
of the biological consequences of MS is still variable, and stress as the individual’s
developing. Our research team has examined response to the challenge. This response
stress levels in a sample of more than 10,000 can be governed by several factors, only
n n
952 Mayo Clin Proc. May 2022;97(5):951-990 https://doi.org/10.1016/j.mayocp.2022.02.004
www.mayoclinicproceedings.org
VASCULAR HEALTH AND MENTAL STRESS
one of which is the external variable itself, more useful product. Thus, challenging
with other important factors including the new life circumstances may not necessarily
individual’s unique perception of the be unpleasant, but may just require more
stressor, and his/her ability to cope with it. attention, and readiness, that could result
Different personality types and character- in better life outcomes such as good perfor-
istics have been shown to be risk factors for mances in exams, sporting competitions,
stress and CVD, including the type A and job interviews. Therefore, some stress
behavior pattern (which is characterized as may be beneficial, necessary, and even
having an angry and hostile outlook),17,18 healthy. Thus, stress must always be seen
and the type D personality (which is charac- in its appropriate context before drawing
terized as having a tendency towards nega- conclusions about its potential biological
tive affectivity and social inhibition).19 consequences.
These personality traits themselves may be Stress can be acute, lasting seconds to
further modulated by underlying genetic days or even weeks, or chronic, lasting
variables, substance use, nutrition, psychiat- months or even years. Acute stressors can
ric and medical comorbidities, and sleep hy- be pinpointed to specific instances. These
giene along with other environmental and may be personal, including deaths in the
sociological variables. Depression,20 anxi- family,32 and layoffs from work,33,34 both
ety,21 psychological distress,22 and post- of which have been linked to CVD events,
traumatic stress disorder23 have all been or impersonal, relating to natural disasters
shown to be risk factors for CVD. These vari- such as earthquakes,35 or manmade disasters
ables are not synonymous with, but rather such as terrorism,36 or even from watching
consequences of, stress and so, they often World Cup Soccer.37 Chronic stressors may
co-exist with stress. Individuals living in be discrete and identifiable, and along the
poverty show physiologic evidence of lines of Freud’s maxim “happiness comes
chronic stress,24 and although those of lower when one finds pleasure in love and work”
SES have a higher prevalence of CVD risk can be separated into stressors at home,
factors25 such as diabetes,26 hypertension,27 and those in the workplace (Figure 1).
smoking,28 and unhealthy eating habits,29 Work stress can be characterized using the
adjusting for these factors does not entirely job-strain model, the effort-reward balance
attenuate these associations.30 In fact, MS model, and the organizational injustice
has been shown to have an attributable model, all of which are associated with an
CVD risk similar to that of diabetes, hyper- increased risk of CAD.38 At home, marital
lipidemia, hypertension, and cigarette stress has also been associated with recurrent
smoking.16,31 CAD events.39 Further, higher stress levels
Therefore, the term stress itself forms a have been reported in those who are
construct reflecting the synthesis of various divorced or separated compared with those
biopsychosocial factors variably interacting who are married.40 Lacking life partnership
and affecting an individual at a particular is closely related to and overlaps with social
point in his/her life. In engineering, the isolation, although studies evaluating the
application of stress to a material results in interaction between social isolation and
strain. Different types of stress applied for marital/relationship status on CVD are lack-
different periods leads to variable amounts ing. This matter is further complicated by
of strain. This may lead to no change in the fact that marriage and relationships can
the external form of the material but could be sources of stress in of themselves. Studies
result in unfavorable internal changes have also shown that stress associated with
impairing the integrity of the material. Alter- receiving a diagnosis of cancer also increases
natively, that strain could lead to outwardly the risk of CVD,41 as does caregiving to ill
visible changes to the material’s shape that family members at home.42 Financial stress
could be unfavorable, leading to break may be considered as a bridging construct
down, or desirable, leading to a new and between stress at work and at home, and is
Stressor – “potentially challenging external variable”
Acute stressors Chronic stressors
External Internal Recurrent or prolonged
Man made Natural Acute major Work Home Daily hassles and
International Earthquakes life events Job-strain Receiving a micro-stressors
Sporting events Flooding Deaths/bereavement Effort-reward Cancer/chronic Traffic
War Tsunamis Layoffs from work Imbalance disease diagnosis Chores
Terrorism Hurricanes New job Organizational Caregiver stress Personal and work-related
Protesting/rioting Injustice Financial stress goals and deadlines
Relationship issues
Duration of stressor Seconds - days Weeks - months Years
Timing of response Planning ahead Acute anticipation During Recovery Brooding/rumination

to stressor
Roles of extraneous factors Perception of

Co-existence/confounding
Interaction/effect modification
stressor, and
Buffering/additive perceived ability
to cope with it Enhanced
Beneficial attention,
Bio-psycho-social factors consequences readiness, and
performance
Psychologic Stress
Vascular health
Personality types and characteristics
Substance misuse
Pre-existing psychiatric illnesses Pathologic Cardiovascular
Resilience Individual consequences disease
response to
Biologic challenge
Social
Genetic variables
Nutrition
Earlier life experiences Neuro-endocrinologic-
Learned behaviors immunologic axis
Sleep
Observations of others
physical activity
Social support
Medical co-
Socio-economic status
morbidities
Educational level
Smoking
FIGURE 1. Schematic outline of the relationship between acute and chronic stressors and stress defined as the individual response to
challenge, stress’s dynamic interaction with extraneous bio-psycho-social factors, and beneficial and pathologic consequences of stress.
also associated with cardiovascular events.43 disease progression and worse longer-term
Chronic stress may also refer to smaller and outcomes.44 Longer periods of stress or mul-
less easily characterized microstressors that tiple separate episodes of stress may aggre-
include rush-hour traffic, performing house- gate and lead to an accumulating burden of
hold chores, social readjustment and isola- increased disease risk over time. However,
tion, as with the current COVID-19 global separating acute from chronic stress arbi-
pandemic, and work or personal goals and trarily can be problematic when considering
deadlines. that the psychologic fallout from a particular
Distinguishing acute from chronic stress stressor may persist long after the event
is useful as acute stressors tend to trigger ends, such as ruminating on a subject of
acute CVD events in those with established disagreement after fighting with a colleague.
CVD, and chronic stressors contribute to In such cases, the proximal stressor itself
n n
does not provide a good indicator of the po- may be artificially simulated in a tightly
tential disease-causing burden incurred by controlled laboratory environment to pro-
the patient. duce reliable hemodynamic and sympathetic
nervous system responses.46 These may
QUANTIFYING STRESS include recalling an anger-provoking inci-
Although important, these terms may not dent, structured public speaking tasks,
provide useful information on the actual bio- number-letter recall challenge (spiral
logical effects of MS. By contrast, physiologic omnibus), and the Stroop word-color con-
changes and reactivity that occur with the flict test.47,48 Although these experimental
cognitive appraisal of a stressor may provide stressors lack real-world ecologic validity,
a useful approach by which to quantify the they are reliable in their ability to produce
pathologic consequences of MS. If valid acute MS, allow for close control of experi-
and reliable, such tools would allow investi- mental conditions, and provide an opportu-
gators to study the adverse impacts of stress nity to study real-time pathophysiologic
in a homogenous way, permitting useful responses to stressors.
comparisons across studies from which Studying the effects of chronic stress will
more helpful conclusions could be drawn. require tools that assess the cumulative
Ideally, clinicians should be able to deter- physiologic burden of multiple acute and
mine if a patient’s subjectively reported chronic stressors over time. Given that single
stress is associated with an exaggerated acute stressors play a role in triggering acute
physiologic response, which can be CVD events, and chronic stressors
measured in a way that is correlated with contribute to disease progression and worse
an increased risk for adverse outcomes. longer term outcomes,44 the ideal mea-
This could then provide a potential prog- sure(s) would quantify the real-time physio-
nostic marker and therapeutic target. logic reactivity to acute MS as well as the
Currently, psychologists rely on patient- cumulative physiologic burden of recurrent
reported rating scales to quantitatively eval- and chronic MS where possible using a sin-
uate stress.45 Although such scales capture gle technique. By measuring both, the real-
the inherent subjectivity of stress, they do time mechanism identified in the former
not account for the various biopsychosocial may provide insight into the cumulative
factors that interact with and influence the mechanism contributing to the latter, and
degree to which the stressor may lead to so would necessarily incorporate the adverse
stress that portends increased risk (see biologic effects of stress in a way that could
Figure 1). An individual’s perception of a predict risk.
stressor may also diverge from the neuropsy-
chiatric, metabolic, and other physiologic MECHANISMS LINKING MENTAL STRESS
manifestations of stress. Thus, patient ques- AND INCIDENT CARDIOVASCULAR DISEASE
tionnaires do not relate a subjective stressful What could be the accepted standard of such
experience to the pathophysiologic mecha- a physiologic measure(s)? To answer this
nisms that provide measurable indices of question we systematically searched
increased risk for adverse outcomes. PubMed, and Google Scholar to identify pro-
In an alternative approach, individuals spective studies that examined the associa-
could be exposed to a particular stressor tion between experimental MS and incident
while being observed and having measures CVD and mortality, with the exception of
of physiologic changes. This could be per- studies that looked at incident hypertension
formed opportunistically by taking advan- and other CVD risk factors as we wished to
tage of naturally occurring stressors in the focus on end-organ disease, and specifically
environment such as earthquakes, with the included those that also included measure(s)
obvious limitations of unpredictability and of concurrent pathophysiologic mechanisms
inability to control extraneous and con- that may putatively play a role in mediating
founding factors. Alternatively, stressors CVD. Search terms included “myocardial
956
TABLE 1. Summary of All Published Prospective Cohort Studies Evaluating the Relationship Between Experimentally Induced Mental Stress and Cardiovascular Outcomes, in Addition to
Measurements of a Putative Mediating Pathologic Mechanisma
Sample
size Putative mediating
N (no. Follow-up pathologic
Reference Year of males) Population duration Experimental stressor CV outcome mechanism No. of events Principle finding Other finding(s)
49
1992 13 (10) Post MI Average 57 mo Modified Stroop test on 2 Re-infarction and/or BP, HR, and venous 5 Patients with events had Catecholamine
(range: 39-64 occasions stroke plasma larger systolic and concentrations
mo) diastolic BP responses differed between
catecholamines
to Stroop test than groups during MS, but
patients who were on only 1 of the 2 test
event-free at follow-up days
Groups did not differ on
baseline
measurements, CV
response to exercise
testing, fasting serum
lipid and glucose
concentrations, age, or
duration of follow-up
50
1995 30 (30) Stable angina pectoris and 2 y Mental arithmetic testing Nonfatal MI, unstable Continuous 14 (4 nonfatal MIs, 10 15 developed transient
Mayo Clin Proc.
ischemia on stress MPI angina ambulatory LV unstable angina) LV dysfunction during

MS
function
monitoring
At 2-year follow-up, 10 of
n
15 patients (67%) with

May 2022;97(5):951-990
MS-induced LV
dysfunction had
adverse events
compared with only 4
of 15 (27%) with no
MS-induced LV
dysfunction (P¼.025)
51
1996 126 (112) Documented CAD and Mean/median 44 Mental arithmetic, public Hospitalization, cardiac RNV imaging and 28 (2 cardiac deaths, 4 Baseline MS-induced The RR for ECG-defined
n
https://doi.org/10.1016/j.mayocp.2022.02.004
exercise-induced mo speaking, mirror trace, revascularization, MI, 48-h Holter nonfatal MIs, 10 CABG, ischemia was ischemia during
myocardial ischemia reading, and type A cardiac death 17 angioplasty d 6 had associated with exercise testing was

monitor
structured interview multiple events) significantly higher 1.9 (95% CI, 0.95-3.96;
rates of cardiac events P¼.07), and the RR for
(OR, 2.8; 95% CI, 1.0- ambulatory ECG

7.7; P<.05) ischemia was 0.75
(95% CI, 0.35-1.64;
P¼.47).
LVEF change during MS
was significantly
related to event-free
survival (RR, 2.4; 95%
Continued on next page

Mayo Clin Proc. n May 2022;97(5):951-990

TABLE 1. Continued
Sample
CI, 1. 12-5. 14; P¼.02),

controlling for age,
history of prior MI, and
baseline LVEF
This relationship
remained significant
after controlling for
n
ECG-defined ischemia
during exercise (RR,

2.2; 95% CI, 1.01-4.81;
P<.05)
52
1999 79 (76) CAD as confirmed by Median 3.5 y Mental arithmetic and a Cardiac death, nonfatal New or worsened 28 (5 cardiac deaths, 9 New or worsened LV After controlling for
previous MI or (range: 2.7 to simulated public MI, or revascularization ischemic wall MIs, 9 CABGs, and 5 wall motion baseline BP and study
coronary angiography 7.3 y) speech stress procedures angioplasties) abnormalities occurred group status
motion
or a 90% probability of in 61 patients (77%) (echocardiography vs
CAD determined by
abnormalities RNV), there was a
Bayesian analysis were monitored higher RR of
using echo subsequent events for
cardiography or patients with high vs
RNV low peak stress-
induced diastolic BP
response (RR, 2.4; 95%
CI, 1.1-5.2; P¼.03)
Peak changes in BP Survival analysis showed
and HR that 20 of 45 patients
with MS-ischemia
(44%) experienced
new cardiac events vs
those without MS
ischemia (8 of 34; 23%;
P¼.048)
Type of cardiac event did
not differ between MS
ischemiae positive vs e
negative patients
53
2002 196 (170) CAD (>50% narrowing Average 5.20.4 Speech on an assigned Cardiac death Bicycle exercise and 17 deaths Of the 17 participants EF changes during MS
in at least 1 major y (range: topic MS testing with who died, new or were similar in patients
coronary artery or 5.20.4 y) worsened wall motion who died and in
RNV imaging
verified MI, or abnormalities during survivors (P¼.9) and
evidence of myocardial MS were present in did not predict death

957
958
TABLE 1. Continued
Sample
ischemia on an 40% vs 19% of even after adjusting for

exercise treadmill test survivors (P¼.04) and resting EF (P¼.63)
conducted off anti- significantly predicted
ischemic medications) death (RR, 3.0; 95% CI,
1.04-8.36; P¼.04)
Other indicators of
ischemia during MS
(ST-segment
depression, chest pain)
did not predict death,
nor did psychological
traits, hemodynamic
responses to MS, or
markers of the
presence and severity
of ischemia during
Mayo Clin Proc.
daily life and exercise

54
2010 138 (96) Patients with stable CAD Median 5.9 y Mirror tracing and public Combined end point of Ischemia on R-wave- 32 (17 nonfatal MIs and Of the 26 patients who LVEF change during MS
speaking MI and all-cause synchronized, 15 deaths) exhibited myocardial was related to the
mortality ischemia during MS, 11 clinical events in a
gated equilibrium
(42%) sustained graded, continuous
n
RNV subsequent clinical fashion, with each 4%

May 2022;97(5):951-990
events, compared with decrease from the

21 of 112 patients LVEF at rest associated
(19%) who showed no with an adjusted HR of
MS-induced ischemia 1.7 (95% CI, 1.1-2.6,
P¼.011)
55
2012 431 (229 females) West of Scotland 16 y Mental arithmetic test CV mortality Systolic and diastolic Both systolic and diastolic
Twenty-07 Population Blood Pressure blood pressure
n
Study reactions were

response
positively associated

with CV mortality
56
2012 1470 (746 males) 1995 Nova Scotia Health 10 y Interpersonally stressful Fatal or non-fatal CV Systolic and diastolic 161 nonfatal and 10 fatal In an unadjusted model, After adjusting for age and
Survey Population interview designed to disease events BP response CV disease events those in the highest sex, and then also for
Based Study elicit anger and MS by decile of systolic BP FRS, BMI, and
asking participants reactivity were more education, this
about their than twice as likely to relationship was
characteristic have an incident CVD attenuated and not
responses to a variety event vs those in the statistically significant
of different situations decile with no
reactivity (HR, 2.33;


TABLE 1. Continued
Sample
95% CI, 1.15-4.69;

P¼.02)
Diastolic BP reactivity was
not associated with
CVD incidence in any
model
57
2015 100 (74) Systolic HF Median 48.5 mo Structured public speech Mortality BP and HR 31 deaths Mortality rates were 2 Multivariate analyses
n
task responses to MS times higher (HR, 2.04; showed that a high

95% CI, 1.15-3.60; heart rate response
P¼.014) among (>6.3 beats/min) to
patients with the acute MS was
lowest diastolic BP associated with a
responses (mean¼-2.4 reduced mortality risk
5.4 mm Hg) to MS (HR, 0.40; 95% CI,
vs in patients with an 0.16 to 1.00; P¼.051)
intermediate diastolic vs those with
BP response (mean ¼ intermediate
7.3 2.5 mm Hg), responses
adjusting for covariates
[31 patients had High diastolic BP reactivity
died (31%)] (mean ¼ 16.3 3.4
mm Hg) was not
related to mortality
(HR, 0.95; 95% CI,
0.55-1.66)
Systolic BP responses
showed a similar but
nonsignificant
association
58
2017 224 (187) Clinically stable CAD, Median 4 y Mental arithmetic, mirror Composite events that MAV, specifically, 86 patients experienced MS-induced changes in e’ Patients with a greater
NYHA functional class tracing and anger recall comprised all-cause diastolic early (e’), at least 1 composite (HR, 0.73) and s’ (HR, decrease in e’ and/or s’
I public speech mortality and/or event(s) 0 .73) were significant velocity had a higher
diastolic late (a’),
nonfatal CV events, (P<.05) predictors of probability of
resulting in an
and systolic (s’) composite events, and experiencing a
unplanned velocities the change in a’ (HR, composite event, and
hospitalization 0.74) was marginal the association of the
(P¼.05). change in a’ and
composite events was
marginal (P¼.05)
59
2017 310 (257) Stable adults with First and total rate of 125 patients had at least 1 The continuous variable Indices of exercise-
documented IHD MACE, defined as MACE (18 deaths, 220 of MS-induced LVEF induced myocardial
959

960
TABLE 1. Continued
Sample
Median 4 y Mental arithmetic, mirror Development or hospitalizations due to change was ischemia did not
(maximum 6 tracing, and anger worsening of any CV causes including 24 significantly associated predict endpoints
y) recall public speech nonfatal MIs, 81 with both endpoints
wall motion
unstable anginas, and (all P<.05)
abnormality,
31 HF exacerbations)
reduction of LVEF
8%, or ischemic
ST-segment
change on ECG
(horizontal or
downsloping
depression 1
mm in two or
more leads
all-cause mortality and For every reduction of 5% The incidence of MACE
Mayo Clin Proc.
hospitalizations for CV in LVEF induced by in MSIMI group was

causes MS, patients had a 5% 9.85% higher than
increase in the those without (P¼.08)
probability of a MACE
at the median follow-
n
up time and a 20%

May 2022;97(5):951-990
increase in the number

of MACE endured
over the follow-up
period of 6 y
All-cause mortality was
7.46% with MSIMI and
7.14% with exercise
n
induced myocardial
ischemia (P¼.19)

Systolic and diastolic 155 first events (72 CV Both systolic and diastolic For diastolic BP, high
60
2017 199 (135) Outpatients diagnosed Median 5 y Public speaking task Combined end point of
with HF, with EF death or CV BP and HR hospitalizations, and 83 BP reactivity, reactivity was
40% hospitalization deaths) quantified as marginally associated

reactivity
continuous variables, with lower risk
were inversely related compared with
to risk of death or CV intermediate reactivity
hospitalization (P<.01) (HR, 0 .767; 95% CI,
after controlling for .515-1.14; P¼.193),
established risk factors, whereas low diastolic
BP reactivity was


TABLE 1. Continued
Sample
including HF disease associated with greater

severity and etiology risk (HR, 1.49; 95% CI,
1.027-2.155; P¼.0359)
High systolic BP reactivity, No relationship of heart
compared with rate reactivity to
intermediate systolic outcome was
BP reactivity, was identified
n
associated with lower

risk (HR, 0.498; 95%

CI, .335-.742; P¼.001),
whereas low systolic
BP reactivity did not
differ from
intermediate reactivity
61
2019 549 (417) Stable CAD 3y Standardized public CV death, MI, PAT measurements 24 all-cause deaths, 14 After adjusting for
speaking stressor revascularization, and during MS CV deaths, 24 MIs, 66 demographic and CV
hospitalization for HF coronary risk factors,
compared with
revascularizations, 20 medications, and rate-
baseline: HF hospitalizations pressure product
change during MS,
those with low stress
PAT ratio were at
significantly higher risk
of adverse outcomes
(HR, 1.77; 95% CI,
1.12-2.80)
Stress PAT
response ratio:
pulse wave
amplitude
during MS/at
baseline
Median ratio was
0.68 (IQR, 0.48-
0.88), indicating
32% vaso
constriction
with MS
961
962
TABLE 1. Continued
Sample
62
2019 569 (420) Stable CAD Median (IQR): Standardized public Composite endpoint FMD was measured 74 patients experienced 360 participants (63.3%) Risk discrimination
3.0 (2.9-3.1) y speaking stressor including CV death, MI, before and 30 min MACE (13 CV deaths, developed transient statistics showed a
and unstable angina 15 MIs, 34 unstable PED (a decrease in significant model
after MS
leading to angina, 12 FMD) improvement after
revascularization and hospitalizations for addition of either post-
HF hospitalization HF) stress FMD (change in
the AUC, 0.05; 95%
CI, 0.01-0.09) or pre-
stress plus change in
FMD (change in the
AUC, 0.04; 95% CI,
0.00-0.08) compared
with conventional risk
factors
Transient PED with MS
was associated with a
Mayo Clin Proc.
78% increase (HR,

1.78; 95% CI, 1.15-
2.76) in the incidence
of MACE
Both the change in FMD
n
(post e pre HR, 1.15;

May 2022;97(5):951-990
95% CI, 1.03-1.27 for

each 1% decline) and
post-MS FMD (HR,
1.14 ;[95% CI, 1.04-
1.24 for each 1%
decline) were
associated with MACE
n
63
2020 148 (102) Participants with stable Median 3 y Series of standardized MACE - composite of CV Simultaneous brain 34 patients experienced Each increase of 1 SD in MS-induced IL-6 and high-
CAD speech/arithmetic death, MI, unstable imaging with high- MACE (2 CV deaths, 1 rmPFC activation with frequency heart rate

stressors angina with MI, 5 hospitalizations MS was associated variability explained
resolution PET:
revascularization and for HF, 26 cases of with a 21% increased 15.5% and 32.5% of
rmPFC activation
HF hospitalization unstable angina with risk of MACE (HR, the relationship

revascularization) 1.21; 95% CI, 1.08- between rmPFC
1.37) reactivity and MACE,
respectively
IL-6 levels 90 min After adjustment for Addition of rmPFC
after stress baseline demographics, reactivity to
risk factors, and conventional risk
baseline levels of IL-6 factors improved risk


TABLE 1. Continued
Sample
and high-frequency reclassification for

Heart Rate variability, MACE prediction, and
higher rmPFC stress C-statistic improved
reactivity was from 0.71 to 0.76
independently (P¼.03)
associated with higher
IL-6 and lower high-
n
frequency HR
variability with MS
High-frequency HR
variability during
MS
64
2020 148 (102) Participants with stable 2y Series of standardized Angina (assessed with the High resolution PET 54 patients experienced For every doubling in the MS-induced ischemia and
CAD speech/arithmetic Seattle Angina imaging of the angina at follow-up (35 inferior frontal lobe activation of other
stressors Questionnaire’s angina monthly, 19 daily or activation, angina brain pain processing
brain: blood flow
frequency subscale) weekly) frequency was regions (thalamus,
to the inferior increased by 13.7 units insula, and amygdala)
frontal lobe was at baseline (95% CI, accounted for 40.0%
evaluated as a 6.3-21.7; P¼.008) and and 13.1% of the total
ratio compared 11.6 units during effect of inferior
with whole brain follow-up (95% CI, frontal lobe activation
4.1-19.2; P¼.01) in a on angina severity,
flow for each scan
model adjusted for respectively
baseline demographics
65
2020 562 (427) Participants with stable Median 3 y Standardized public MACE was defined as a IL-6, MCP-1, and 71 patients experienced There was no significant There were sex-based
CAD speaking stressor composite endpoint of MMP-9 MACE (14 CV death, association between interactions for IL-6
CV death, MI, unstable 22 MI, 19 HF, and 35 inflammatory response (P¼.001) and MCP-1
angina with unstable angina with to stress and risk of (P¼.01)
revascularization, and revascularization) MACE
HF
Risk of MACE increased
56% (HR, 1.56; 95%
CI, 1.21-2.01; P¼.001)
and 30% (HR, 1.30;
95% CI, 1.09-1.55;
P¼.004) for each SD
increase in IL-6 and

963
964
TABLE 1. Continued
Sample
MCP-1 response to
MS for women, but
not in men
66
2020 417 (383) Patients hospitalized for 1 y Three different MS tasks A composite of ACS, RH-PAT at baseline 82 MACE events (63 Women were more likely In multivariate analyses
ACS and received of 6-min duration in rehospitalization, (baseline PEF) cardiac to experience MACE stratified by sex,
percutaneous random order stroke, rehospitalizations, 49 in the year following baseline PED
compared with
coronary intervention (number-letter recall revascularization, CV revascularizations, 3 ACS (RR, 2.42; 95% (EndoPAT<1.7)
challenge of increasing death, and all-cause
RH-PAT following MIs) CI, 1.53-3.84; P¼.044), (c¼8.0, P¼.005) and
length and complexity; mortality MS (post-MS PEF) and had a significantly stress PAT ratio
number subtraction; lower stress PAT ratio (c¼7.7, P¼.006),
Stroop word-color compared with were independently
conflict) women who did not predictive of MACE in
(1.00.17 vs women, but not men
1.200.17; P¼.04)
PAT measurements
Mayo Clin Proc.
during MS
compared with
baseline:
Stress PAT response
ratio: pulse wave
n
May 2022;97(5):951-990
amplitude during
MS/at baseline
a
ACS, acute coronary syndrome; AUC, area under the curve; BMI, body mass index; BP, blood pressure; CAD, coronary artery disease; CABG, coronary artery bypass graft; CV, cardiovascular; ECG, electrocardiogram; EF, ejection
fraction; FMD, flow-mediated dilatation; FRS, Framingham risk score; HF, heart failure; IL, interleukin; IHD, ischemic heart disease; LV, left ventricle; MACE, major adverse cardiovascular event; MAV, myocardial annular velocity;
MCP-1, monocyte chemoattractant protein 1; MI, myocardial infarction; MMP-9, matrix metalloproteinase 9; MPI, myocardial perfusion imaging; MS, mental stress; MSIMI, mental stress induced myocardial ischemia; NYHA, New
York Heart Association; PAT, peripheral arterial tonometry; PEF, peripheral endothelial function; PET, positron emission tomography; RH-PAT, reactive hyperemia peripheral arterial tonometry; rmPFC, Rostromedial prefrontal
cortex; RNV, radionuclide ventriculography
n

ischemia,” “coronary artery disease,” periods,67 thus fulfilling the need to look at
“mental stress,” “psychological stress,” acute reactivity and cumulative chronic
“mental* stress*,” “psychologic* stress*,” burden. Examples include the noninvasive
and “cardiovascular disease*.” The search monitoring of electrolytes and metabolites
was limited to studies published in English in sweat or saliva,67 spectroscopy biosensor
in peer-reviewed journals between 1990 assays to detect cortisol levels in saliva,68
and the present day, and included studies and electrocardiograms (ECGs) from wear-
that had a prospective cohort design, a ables to evaluate ischemia or arrhythmia.69
follow-up period of at least 6 months, and Measures of MS-induced myocardial
used a validated technique to experimentally ischemia (MSIMI) could provide a useful
induce MS. To identify potential studies not index when evaluating MS. Studies
captured by our database search strategy, we comparing exercise stress testing against
also searched studies listed in the bibliog- MS testing have revealed interesting differ-
raphy of relevant publications and reviews ences between the two. In one study, the in-
(Table 1). vestigators compared the frequency of
A variety of putative mediating patho- self-reported angina and myocardial
physiologic mechanisms were measured ischemia using positron emission tomogra-
including the reactivity to MS of blood pres- phy (PET) before and after bicycle ergome-
sure, heart rate, catecholamines, inflamma- try and before and after 2 minutes of serial
tory markers, and peripheral arterial tone; seven subtractions as a simulator of MS. Af-
myocardial ischemia using Holter moni- ter exercise, all patients reported symptoms
toring, and ventriculography; echocardio- of angina, ECG changes, and regional perfu-
graphic changes related to ischemia and sion abnormalities. After MS, however, 75%
diastology; functional brain imaging; and of all patients developed regional perfusion
measures of peripheral endothelial function abnormalities, among which only 33% also
before and after MS using flow-mediated reported angina and had ECG changes;
dilatation (FMD) and reactive hyperemia 17% had only ECG changes, and 50% had
(RH). Given the significant heterogeneity neither ECG changes nor angina.47 Thus,
in the study designs and experimental pro- the perfusion abnormalities elicited by the
cedures, it is challenging to directly compare mental stressor were more likely to be clin-
the prognostic utility of individual patho- ically silent in terms of symptoms and ECG
physiologic measures against each other. findings. Similarly discordant findings have
Desirable measures include those capable of been reported in another study,70 although
making measures that 1) predict risk of dis- the significance of these differences is un-
ease reliably and effectively, 2) are inexpen- certain. It is unknown, for example, if these
sive and do not require the use of findings show that MS testing is simply less
sophisticated technology and burdensome sensitive than exercise stress testing at elic-
methodology, and 3) offer a modifiable ther- iting ischemia, or if MS testing is in fact bet-
apeutic target that can be followed with ter at discriminating those at greatest risk.
repeat measures longitudinally. Techniques Certainly studies have shown that MSIMI
not included in these data, and which to- has prognostic value, with one study
date have not been evaluated in prospective demonstrating an almost three-fold
clinical outcome studies, include mobile increased risk in future cardiac events in
health applications and wearable electro- those with MSIMI.51 However, measuring
chemical biosensors that offer measures of ischemia requires expensive testing equip-
specific physiologic responses to acute and ment as well as specialist expertise for inter-
chronic stressors that occur naturally in the pretation. Thus, at present, the role of
lives of patients. These measures can be protesting for MSIMI in clinical practice re-
vided on a moment-to-moment basis, and mains undetermined, and further studies
can also provide summary data over longer are required to address this question.

VASCULAR MECHANISMS through the release of active substances

Endothelial dysfunction is often described as from endothelial cells that act on the
the first step in the atherosclerotic process VSMCs. Nitric oxide is a vasodilatory sub-
and is independently associated with adverse stance synthesized from L-arginine, using
CVD events.71 Studies have shown that indi- the enzyme endothelial nitric oxide syn-
viduals with minimal traditional CVD risk thase, and is released in response to shear
factors who have peripheral endothelial stress; other chemicals such as acetylcholine,
dysfunction (PED) have a higher incidence bradykinin, or serotonin; the release of
of CVD events compared with those with thrombin; and stimulation of the parasympa-
normal peripheral endothelial function.71-73 thetic nervous system.98,99 Additionally, ni-
Thus, an alternative and promising tric oxide inhibits VSMC growth, platelet
physiologic measure is peripheral and aggregation, and the adhesion, migration,
noninvasive measurements of vascular reac- and proliferation of white blood cells.100
tivity and PED in response to acute MS. An Conversely, endothelin-1, produced by
example approach includes reactive endothelial cells, VSMCs, and activated mac-
hyperemiaeperipheral arterial tonometry rophages,101 is a potent vasoconstrictor in of
(RH-PAT).74-77 Peripheral endothelial func- itself, and enhances the vasoconstricting ef-
tion can be measured at baseline, using fects of other substances including angio-
RH, and after the application of experimental tensin II, serotonin, and catecholamines.102
MS tasks. Mental stress induces transient Given its location on the inside surface of
endothelial dysfunction,78 and so measured the vascular system, the endothelium is
change in endothelial function may corre- most exposed to sources of injury, including
spond to the vascular burden of MS. Further, MS. Monkeys exposed to a new social group,
PAT corresponding to pulse-wave velocity and the associated changes to social struc-
through the digital microcirculation can be ture and environment, had increased endo-
measured during each MS task, and can be thelial cell damage and turnover in the
compared to the PAT at baseline to deter- thoracic aorta and coronary arteries,103 and
mine a stress PAT ratio that provides quanti- reduced nitric oxide availability in arteries
tative information on the real-time vascular with atherosclerosis.104 Similarly, a public
reactivity to acute MS. Table 2 summarizes speaking task105 and anger provocation 106
the results of all cross-sectional studies that were shown to be associated with an increase
have used measures of PED and/or stress in circulating endothelial cell-derived micro-
PAT to quantify stress. In the following sec- particles, derived from the membranes of
tion, we outline why the vasculature is so apoptotic endothelial cells. Mental stress
important for the stress-induced physiolog- may also adversely influence endothelial
ical response, and why it could be the prin- cell function. In animal studies, acute and
cipal site of transduction of MS into CVD chronic MS were associated with lower levels
risk (Figure 2). of nitric oxide synthase mRNA expres-
sion106,107 leading to endothelial dysfunc-
Effects on the Endothelium tion. Further, MS may lead to oxidative
The intima makes up the innermost layer of stress and the release of potent vasoconstric-
the arterial wall and is lined by longitudi- tors, such as endothelin108 and angiotensin
nally orientated endothelial cells comprising II,109 which also contribute to endothelial
the endothelium. The endothelium has the dysfunction. In one study, high serum bio-
following functions: 1) preserving vascular markers of oxidative stress were shown dur-
tone, 2) mediating thrombogenesis and fibri- ing the Great East Japan Earthquake in
nolysis, and 3) regulating the proliferation of individuals with disaster-related hyperten-
vascular smooth muscle cells (VSMCs) in sion defined as a systolic blood pressure >
the media.96,97 Vascular tone is maintained 140 mm Hg.110 Indeed, in a recently pub-
through the balance between vasodilation lished series of experiments, endothelial cells
and vasoconstriction, which is achieved appear to play a key effector role in the
n n

TABLE 2. Summary of All Published Cross-Sectional Studies Evaluating the Relationship Between Experimentally Induced Mental Stress and Peripheral Vascular Reactivitya
Sample
size
N (no. of Measure of peripheral vascular
Reference Year males) Population Experimental stressor reactivity Other measures Principle finding Other finding(s)
79
1999 40 (21) Healthy adults aged Reaction time/shock Brachial artery endothelial BP and SVR A high EDAD was associated SVR responses during MS
25e44 y avoidance, mirror trace, function measured by with lower resting systolic testing were greater for
and anger interview
ultrasonography in response and diastolic BP individuals with lower EDAD
to RH (FMD) responses
EDAD was not associated to BP
response to MS
n
78
2000 18 (18) 10 healthy males; 8 non Structured speech task Brachial artery endothelial Endothelial-independent In healthy subjects, FMD Diabetic subjects had lower
einsulin-dependent function measured by function following infusion of (5.02.1%) was significantly FMD than controls
diabetic males
ultrasonography in response nitroglycerin (P<.01) reduced at 30 and (3.01.5% vs 5.02.1%,
to RH (FMD) 90 min after MS (2.82.3% respectively; P¼.02) but
and 2.32.4%, respectively) showed no changes in FMD
and returned toward normal (2.71.1% after 30 min,
after 4 h (4.12.0%) 2.81.9% after 90 min, and
3.12.3% after 240 min) or
GTN responses after MS
MS had no effect on the
response to GTN
In studies without MS, FMD did
not change
80
2002 23 Healthy subjects Colored light response Brachial artery endothelial FMD before and after MS Endothelium-dependent Intra-arterial infusion of the
without CV risk function measured by during intra-arterial infusion vasodilation was reduced by selective endothelin-A
factors
ultrasonography in response of a selective endothelin A half for about 45 min receptor antagonist, but not
to RH (FMD) receptor antagonist (BQ- (8.01.1% vs 4.11.0%; saline prevented the
123) P<.002), whereas impairment of endothelium-
endothelium-independent dependent vasodilation
vasodilation to nitroglycerin (8.61.2 versus 9.41.3%;
NS)
Endothelial-independent remained unaffected (15.61.6 Intra-arterial infusion of
function following infusion of vs 14.31.3%; NS) norepinephrine of similar
nitroglycerin duration as MS did not inhibit
FMD
81
2004 16 (16) Previously diagnosed Mental arithmetic stress test PAT measurements during MS ERNA In 8 patients both ERNA and When considering an abnormal
CAD with positive with harassment compared to baseline PAT were abnormal PAT tracing as indicative of
exercise tress tests
MSIMI, concordance of the 2
methods was 88%
967
968
TABLE 2. Continued
Sample
size
Considered abnormal when Myocardial ischemia In 6 patients both tests were
PAT decreased by 20% diagnosed when global EF negative
from baseline fell 8% during MS or
new/worsened focal wall
motion abnormalities
In 2 cases results were
discordant
82
2006 16 (0) Postmenopausal Anger recall task (an incident Brachial artery endothelial Technetium 99m During MS testing, 6 patients No group I patients had
women with angina that made patients angry function measured by methoxyisobutylisonitrile (group I) had reversible ischemia on Holter
and normal and that involved
ultrasonography in response myocardial scintigraphy at perfusion defects on monitoring; 2 of 10 group II
coronary angiogram interpersonal
interactions)
to RH (FMD) rest, MS and exercise myocardial scintigraphy; other patients had ischemia
10 patients (group II) did not
24-h ambulatory ECG Group I patients exhibited PED
Mayo Clin Proc.
recording (Holter monitor) more frequently than those in

group II (83% vs 20%)
Myocardial scintigraphy showed
anteroapical/septal ischemia
in 5 patients and inferoapical
n
May 2022;97(5):951-990
ischemia in 1 other patient,

with both types of stress
In group II patients, none
showed a reversible
perfusion defect during
physical or MS
83
2008 211 (134) Patients with Public speaking task PAT measurements during MS BP and heart rate were Stress PAT ratio was MS induced significant changes
n
established stable
compared with baseline recorded during rest and MS significantly higher in women in systolic BP, diastolic BP,
CAD

(0.800.72) compared with heart rate, and double
men (0.590.48), P¼.032 product compared with rest
in all subjects, P<.001

Stress PAT response ratio: Remained significant after Comparing hemodynamic
pulse wave amplitude controlling for confounders, responses with MS across
during MS/at baseline P¼.037 sexes did not show
differences in systolic BP,
diastolic BP, heart rate, or
double product

TABLE 2. Continued
Sample
size
Double product (systolic BP Males had a greater double
84
2008 87 (34) Healthy subjects Three different MS tasks of RH-PAT at baseline (baseline In response to MS, male
6-min duration in PEF) compared with RH-PAT subjects had an increase in heart rate) product response to MS
random order (number-
following MS (post-MS PEF) RH-PAT compared with (27.2þ3.6% increase in
letter recall challenge of
increasing length and
baseline RH-PAT compared double product vs
complexity; number with females, who showed a 19.2þ1.7%; P¼.01)
subtraction; Stroop decline in PEF (13.7% vs
n
word-color conflict) 0.47%; P¼.01)

PAT measurements during MS Stress PAT ratio tended to be

compared with baseline greater in males than females
(0.790.07 vs 0.90.04,
respectively; P¼.07)
Stress PAT response ratio: Females who showed the least
pulse wave amplitude vasoreactivity to MS showed
during MS/at baseline the greatest decline in PEF
(10.5þ4% vs 17.4 þ 6.3%;
P<.001)
85
2009 68 (60) Patients with Anger recall periods PAT measurements during MS Single PET-CT MPI concurrent 26 developed a new perfusion Sensitivity/specificity of PAT
established stable compared with baseline with PAT testing during MS defect during MS ratio as an index of ischemia
CAD
protocol on PET-CT MPI was 0.62/
0.63
Stress PAT response ratio: Patients with a new perfusion Among patients taking ACE-I
pulse wave amplitude defect with MS had a lower the sensitivity and specificity
during MS/at baseline stress PAT ratio (0.760.04 increased to 0.86 and 0.73,
vs 0.910.05, P¼ .03) respectively
90% of patients without
ischemia were correctly
identified
86
2009 211 (134) Patients with Two phases of a public PAT measurements during MS Rest-stress MPI Vascular response in the Stress PAT ratio during speech
established stable speaking task (stress compared with baseline anticipation period (speech preparation had modest
CAD anticipation and task
preparation) was more accuracy for predicting MSIMI
performance)
pronounced than during the on MPI(AUC, 0.63; 95% CI,
actual speaking task 0.53-0.74; P¼.015)
Stress PAT response ratio: Mean preparation stress PAT
pulse wave amplitude ratio 0.640.53; mean
during MS/at baseline
969

970
TABLE 2. Continued
Sample
size
speech stress PAT ratio
0.720.60; P<.001)
74
2010 26 (0) 12 females with a Three different MS tasks of RH-PAT at baseline (baseline Plasma catecholamine levels at RH-PAT following MS was Catecholamine levels were
history of ABS; 12 6-min duration in PEF) compared with RH-PAT baseline and following MS lower in patients with ABS vs increased in patients with
post-menopausal random order (number-
following MS (post-MS PEF) tests with post-menopausal ABS vs in post-menopausal
controls; 4 with letter recall challenge of
history of MI increasing length and
controls (P<.05) controls, following MS testing
complexity; number (P<.05)
subtraction; Stroop
word-color conflict)
PAT measurements during MS Stress PAT ratios were lower in
compared with baseline patients with ABS vs with
patients with MI and post-
menopausal controls (P<.05)
Mayo Clin Proc.
Stress PAT response ratio: No differences in stress PAT

pulse wave amplitude ratio in patients with MI vs
during MS/at baseline post-menopausal controls
87
2011 25 (6) Healthy subjects Three different MS tasks of RH-PAT at baseline (baseline Arterial blood pressure signal No significant difference in RH- Lower stress PAT ratio vs
6-min duration in PEF) compared with RH-PAT amplitude using cuff attached PAT and BIOPAC arterial BIOPAC stress ratio during
n

May 2022;97(5):951-990
following MS (post-MS PEF) to a pressure transducer blood pressure signal each of the 3 MS tasks
(BIOPAC MP150 systems amplitude at rest or following
complexity; number technology d a standard MS (1.550.36 and
subtraction; Stroop polygraph device used to 1.480.19; P¼.38 and
word-color conflict) detect deception during 1.440.29 and 1.470.21;
polygraph examinations in P)¼.61, respectively)
military or law enforcement
n
applications)
PAT measurements during MS Ratio of BIOPAC arterial blood No differences in RH-PAT No difference in stress PAT

compared with baseline pressure signal amplitude ratios between male and ratios between male and
during MS to baseline arterial female subjects (P¼.75) female subjects (P> .05)
blood pressure signal

amplitude
Stress PAT response ratio:
pulse wave amplitude

TABLE 2. Continued
Sample
size
88
2011 241 (126) Healthy adolescents Three different MS tasks of PAT measurements during MS Physical activity using a self- In response to MS, male Adolescents who reported
(mean age, 10 y) 6-min duration in compared with baseline report questionnaire adolescents had a more decreased physical activity
vasoconstrictive response, over a 3-y period had
followed by a less increased arterial stiffness
complexity; number vasodilatory response, and
subtraction; Stroop needed longer time to return
n
word-color conflict) to baseline level than females


89
2013 384 (159) Patients with Standardized public speaking PAT measurements during MS 99mTc-sestamibi MPI at rest Stress PAT ratio was lower in CAD severity and extent scores
angiographically task compared with baseline and following both MS and those with vs without MSIMI were not significantly
documented CAD
physical stress testing, on MPI (0.550.36 vs different between those with
performed on separate days 0.760.52; P¼.009) or without MSIMI, whereas
they were greater in those
with compared with without
physical stress induced
ischemia (P<.04 for all)
Stress PAT response ratio: In a multivariable analysis, stress Angiographic severity and
pulse wave amplitude PAT ratio was the only extent of CAD
during MS/at baseline independent predictor of independently predicted
MSIMI on MPI (P¼.009) physical stress induced
myocardial ischemia
90
2017 660 (482) Patients with Standardized public speaking RH-PAT at baseline (baseline 99mTc sestamibi MPI at rest, 106 (16.1%) developed MSIMI, Only presence of ischemia
established stable task PEF) compared with RH-PAT with MS, and with and 229 (34.7%) had during conventional stress
CAD
following MS (post-MS PEF) conventional (exercise/ conventional stress-induced (OR, 7.1; 95% CI, 4.2-11.9),
pharmacological) stress myocardial ischemia high hemodynamic response
(OR for RPP response vs
< ROC cutoff of 1.8; 95% CI,
1.1-2.8), and high digital
vasoconstriction (OR for
stress PAT ratio < vs ROC
cutoff of 2.1; 95% CI, 1.3-3.3)
were independent predictors
of MSIMI
971

972
TABLE 2. Continued
Sample
size
Pulse wave velocity using PAT Rate-pressure-product (heart MS was associated with
measurements rate systolic blood increases in SBP, DBP, HR,
pressure) epinephrine levels epinephrine levels, PWV, and
significant decreases in FMD
and stress PAT ratio denoting
microvascular constriction
PAT measurements during MS Patients with vs without MSIMI
compared with baseline had higher hemodynamic and
digital vasoconstrictive
responses (P<.05 for both),
but did not differ in
epinephrine, endothelial (RH-
Mayo Clin Proc.
PAT after MS) or

macrovascular (FMD)
responses
n

May 2022;97(5):951-990

Endothelium-dependent FMD
before and after MS
76
2018 62 (0) 41 patients with Anger recall, mental RH-PAT at baseline (baseline Emotional arousal was During MS 10% of controls Vasoconstriction inversely
coronary vascular arithmetic, and forehead PEF) compared with RH-PAT measured (Likert scale) reported chest pain vs 41% correlated with anxiety (r¼-
dysfunction and 21 cold pressor challenge
following MS (post-MS PEF) of subjects with coronary 3.4, P¼.03), frustration (r¼-
n
controls
vascular dysfunction (P¼.01) 0.37, P¼.02), and feeling

challenged (r¼-0.37, P¼.02)

in patients with coronary
vascular dysfunction only

PAT measurements during MS RH-PAT did not change
compared with baseline significantly after MS in either
group
Stress PAT response ratio: Subjects with coronary vascular
pulse wave amplitude dysfunction had lower stress
during MS/at baseline PAT ratios vs controls during
mental arithmetic (0.54; 95%
CI, 0.15-1.46 vs 0.67; 95% CI,

TABLE 2. Continued
Sample
size
0.36-1.8; P¼.039), not
evident in the other tasks
91 99m
2018 418 (210) 306 (150 females) Standardized public speaking RH-PAT at baseline (baseline Tc-sestamibi MPI at rest, Women in both groups showed Rate of MSIMI was twice as high
subjects who were task PEF) compared with RH-PAT with MS and conventional a higher stress PAT ratio and in women as in men (22% vs
hospitalized for MI in
following MS (post-MS PEF) (exercise/pharmacological) a lower RH-PAT index after 11%, P¼.009), and ischemia
the previous 8
months
stress MS indicating enhanced with conventional stress was
n
microvascular dysfunction similarly elevated (31% vs

after MS 16%, P¼.002)

112 community PAT measurements during MS No sex differences in FMD with Stress PAT ratio and RH-PAT
controls (58 compared with baseline MS index after MS were
females) frequency
predictive of MSIMI in
matched for sex and
age
women only

Endothelium-dependent FMD
before and after MS
92
2018 678 (492) Patients with Standardized public speaking PAT measurements during MS MPI before and during MS Women (but not men) with vs Men (but not women) with vs
established stable task compared with baseline without MSIMI had a without MSIMI had a higher
CAD
significantly lower stress PAT rate-pressure product
ratio (0.5 vs 0.8) response (6500 vs 4800 mm
Hg beats/min)
Stress PAT response ratio: pulse SBP HR e rate pressure Each 0.10-U decrease in stress Each 1000-U increase in rate-
wave amplitude during MS/at product PAT ratio was associated pressure product response
baseline with 0.23% (95% CI, 0.11- was associated with 0.32%
0.35) increase in inducible (95% CI, 0.22-0.42) increase
myocardial ischemia in in inducible ischemia among
women men
Ratios <1 indicate vaso
constrictive response
75
2018 38 (32) Patients with stable Mental arithmetic testing PAT measurements during MS Invasive endothelium- MS increased the rate-pressure Stress PAT ratio correlated with
CAD defined by an compared with baseline dependent and endothelium- product by 22% (23%) and the demand-adjusted change
abnormal coronary
independent coronary constricted epicardial in CBF during MS (r¼-0.60,
angiogram
demonstrating
epicardial and microvascular coronary arteries by median, P¼.004)
973

974
TABLE 2. Continued
Sample
size
angiographic responses were measured -5.9%; IQR, -0.5% to -2.6%;
evidence of using intracoronary P¼.001, without changing
atherosclerosis with
acetylcholine and CBF
at least luminal
irregularities
nitroprusside, respectively,
and after MS
Stress PAT response ratio: Acetylcholine increased CBF by
pulse wave amplitude 38.5% (8.1%, 91.3%), P¼.001,
during MS/at baseline without epicardial coronary
diameter change (0.1%
[-10.9%, 8.2%], P¼NS)
MS-induced CBF response
correlated with endothelium-
Mayo Clin Proc.
dependent CBF changes with

acetylcholine (r¼0.38; P¼.03)
but not with the response to
nitroprusside
n
93
2019 18 (0) 8 females with a history Three different MS tasks of PAT measurements during MS Pain induced PAT ratio Stress PAT ratio was lower in Pain-induced PAT ratios were
May 2022;97(5):951-990
of ABS; 10 post- 6-min duration in compared with baseline attenuated in patients with
menopausal controls random order (number-
ABS:
complexity; number
subtraction; Stroop
word-color conflict)
n
Stress PAT response ratio: patients with ABS: Stroop test at baseline (0.940.08 vs
pulse wave amplitude (0.790.30 vs 1.240.43; 1.300.54; P<.05); and post-

during MS/at baseline P¼.01); MS (0.870.19 vs 1.240.21;
P¼.01)
Arithmetic test (0.910.27 vs Pain-induced PAT ratios

1.360.57, P¼.01). correlated significantly with
stress PAT ratios, both in
arithmetic and Stroop test
(P<.05)
94
2019 59 (44) Patients with a history Mental arithmetic testing, PAT measurements during MS PET imaging of the brain Stress response ratios below the
of stable CAD and public speaking compared with baseline median were associated with
stressors
increased stress activation in

TABLE 2. Continued
Sample
size
insula and parietal cortex, and
decreased activation in the
medial prefrontal cortex with
MS tasks compared with
control tasks
n


95
2020 486 (350) Patients with stable Series of standardized PAT measurements during MS 99mTc-sestamibi MPI at rest, After multivariable adjustment Ischemia with a conventional
coronary speech/arithmetic compared with baseline with MS, and with MSIMI was associated with stress test was not associated
atherosclerosis stressors
conventional (exercise/ 21% and 20% slower with any of the cognitive tests
pharmacological) stress completion of Trail-A and over time
Trail-B, respectively (P for all
<.01)
Stress PAT response ratio: Cognitive function assessed at After a 2-y follow-up period,
pulse wave amplitude baseline and at a 2-y follow- presence of MSIMI was
during MS/at baseline up using Trail Making Test associated with a 33% slower
parts A and B, and the verbal completion of Trail-B,
and visual memory subtests denoting cognitive decline
of the Wechsler Memory (B ¼ 0.33; 95% CI, 0.04-0.62)
Scale
A lower stress PAT ratio,
indicating greater
vasoconstriction, mediated
the association between
MSIMI and worsening Trail-B
performance by 18.2%
ABS, apical ballooning syndrome; ACE-I, angiotensin-converting enzyme inhibitor; AUC, area under the curve; BP, blood pressure; CAD, coronary artery disease; CBF, coronary blood flow; CT, computed tomography; CV,
a
cardiovascular; ECG, electrocardiogram; EDAD, endothelial-dependent arterial dilatation; EF, ejection fraction; ERNA, equilibrium radionucleotide angiocardiography; FMD, flow-mediated dilatation; GTN, sublingual glyceryl
trinitrate; MI, myocardial infarction; MPI, myocardial perfusion imaging; MS, mental stress; MSIMI, mental stresseinduced myocardial ischemia; NS, not significant; OR, odds ratio; PAT, peripheral arterial tonometry; PEF, peripheral
endothelial function; PET, positron emission tomography; PWV, pulse wave velocity; RH-PAT, reactive hyperemia peripheral arterial tonometry; ROC, receiver operating characteristic curve; RPP, rate pressure product; SVR,
systemic vascular resistance
975
↑ HR, ↑ SBP, ↑ DBP, ↑ PP, ↑ SVR Sympathetic

Hemodynamic
nervous system
changes
Angina; positive stress test upregulation
with MS or exercise; LV Ischemia
dysfunction; acute ischemic ↑ Catecholamines
events
H-P-A Axis
Atherosclerosis Microvascular upregulation
dysfunction
Dyslipidemia ↑ Cortisol
↓ FMD, RH-PAT;
↑ Vascular
reactivity to MS;
Parasympathetic ↓ CBF on coronary
nervous system angiography
withdrawal
Endothelial
↓ HR dysfunction
variability
↑ Viscosity and thromboses
Vascular smooth
Vascular
muscle cell mediated
inflammation
vasoconstriction
↑ IL-1, IL-2, IL-6,
TNF-α, NF-κβ,
CRP, Alarmins;
↑ Leukopoiesis
Adventitial
permeability
FIGURE 2. Outline of the various mechanisms by which stress pathologically affects vascular health (in boxes), and biomarkers
available to measure these effects.CBF, coronary blood flow; CRP, C-reactive protein; DBP, diastolic blood pressure; FMD, flow-
mediated dilatation; H-P-A axis, hypothalamic-pituitary-adrenal axis; HR, heart rate; IL, interleukin; LV, left ventricular; MS, mental
stress; MSIMI, mental stress induced myocardial ischemia; NF-kb; nuclear factor kappa light chain enhancer of activated B cells; PP,
pulse pressure; RH-PAT, reactive hyperemia e peripheral arterial tonometry; SBP, systolic blood pressure; SVR, systemic vascular
resistance; TNF, tumor necrosis factor.
pathophysiologic response to acute mental Concomitant endothelial dysfunction and

stress,111 which leads to the stimulation of increased endothelial cell permeability may
peripheral sympathetic nerves increasing then result in vascular inflammation, fibrous
locally available norepinephrine. Norepi- cap thinning, plaque instability, and ensuing
nephrine exerts primary effects on endothe- cardiovascular events. Thus, the endothe-
lial cells via a-adrenoceptors, leading to lium may be the site where the physiologic
upregulation of adhesion molecules and effects of MS are transduced into a measur-
release of chemokines. These effects are able index (Table 2).
secondarily enhanced via the binding of
norepinephrine to surface receptors of mac- Effects on the Adventitia
rophages and VSMCs that release chemo- The next layer out from the media is the
kines that further stimulate the effector adventitia, comprising connective tissue, fi-
endothelial cells. These effects collectively broblasts, macrophages, and mast cells. The
lead to leucocyte recruitment and adhesion. adventitia is perfused by the vasa vasorum,
n n
a microvascular bed, and is innervated by tract, liver, and spleen. Acetylcholine binds
autonomic nerves with endings at adventitial to macrophage surface receptors blocking
mast cells close to the border with the me- release of inflammatory cytokines including
dia.112 By releasing neurotransmitters that interleukin (IL) -1, -2, and -6, tumor necro-
act on vascular smooth muscle, these nerve sis factor alpha (TNF-alpha), and nuclear
endings regulate vascular tone. Sympathetic factor kappa-beta.124e126 This efferent
nervous fibers release norepinephrine, cholinergic arm of the so-called inflamma-
which, via alpha-1 receptors, cause vasocon- tory reflex can be triggered centrally via
striction.113 In a direct mechanism, MS is muscarinic acetylcholine receptor binding
associated with increased circulating levels with ligands, and acetylcholinesterase inhib-
of norepinephrine, correlating with increases itors such as galantamine.127 Therefore, MS-
in mean arterial pressure.114 Healthy indi- induced withdrawal of parasympathetic
viduals with self-reported high levels of daily nervous activity leads to enhanced release
psychosocial stress had greater microvas- of proinflammatory cytokines, underpinned
cular vasoconstriction as measured using by an important difference between MS and
laser Doppler flow and enhanced responsive- physical (exercise)erelated stress, where in
ness to norepinephrine compared with those the latter there is increased parasympathetic
with low stress.115 In an indirect mechanism, nerve discharge.128 Conversely, catechol-
MS leads to the release of corticotropin- amines bind to the beta-adrenergic receptors
releasing hormone and the related peptide of macrophages and induce the expression of
urocortin in the amygdala and the hypothal- cytokines such as C-reactive protein, IL-1,
amus, which leads to increased levels of cat- IL-6, and TNF-alpha in a process that is
echolamines, and upregulation of the enhanced under conditions of chronic
sympathetic nervous system.116,117 As well MS.129 Indeed, elevated plasma cortisol, IL-
as causing the release of norepinephrine 1 beta, IL-2, and soluble intracellular adhe-
that directly causes receptor mediated vaso- sion molecule were demonstrated in healthy
constriction, sympathetic nervous fibers males after a structured speaking task.130
also release substance P and calcitonin Stress can also lead to increased bone
gene-related peptide, which trigger mast marrow leukopoietic proliferation through
cell degranulation and the release of the the activation of beta-3-adrenergic receptors
vasoactive substances histamine and leuko- by norepinephrine on progenitor inflamma-
triene.118,119 This results in vasodilatation tory cells and macrophages.131e134 These
and increased microvascular permeability, newly released inflammatory cells then pro-
which underpins characteristic stress- duce further inflammatory cytokines and
induced symptoms such as sweating, flush- manifest greater expression of immune
ing, and gastrointestinal disturbances, and response genes in a feed-forward loop.135
can be inhibited with histamine blocking Norepinephrine binding to the beta-3-
medications.120 More than just uncomfort- adrenergic receptors of bone marrow stromal
able symptomology, MS-induced vascular cells reduces the production of C-X-C che-
mast cell degranulation has been shown to mokine ligand 12 that functions ordinarily
lead to plaque destabilization with intrapla- to retain leukocytes in the bone
que hemorrhage in areas of existing athero- marrow.131,132,136 This heightened innate
sclerosis in the animal model,121 as well as immune cellular output, combined with
intraplaque hemorrhage in advanced athero- enhanced cytokine production, can
sclerosis122 and myocardial infarction (MI) contribute to accelerated atheroscle-
in the infarct-related artery in humans.123 rosis.131,134 Further, acute MS induces IL-6
release from brown adipocytes in a beta-3-
Vascular Inflammation adrenergic receptor dependent fashion in
Parasympathetic nervous system activation the mouse model,137 highlighting the poten-
leads to release of acetylcholine in various tial role of brown adipose tissue as a stress-
organs including the heart, gastrointestinal responsive organ, and therefore potential
Acute, transient and concurrent to

stressor, measured with MS provocation
using PAT to measure vascular reactivity
Impaired perfusion
Hemodynamic Microvascular Abnormalities in Ischemia
effects dysfunction blood flow Chest pain
Arrythmia
Hypertension
Non-invasive
stress testing
Therapeutic target to
Mental Endothelial Diagnosis of holter
prevent CV sequalae
stress and events dysfunction vascular injury monitoring
Monitoring therapy CIMT
Coronary
angiography
Traditional
CV risk factors
Carotid intima media

thickening
Vascular Macrovascular
Atherosclerosis Coronary artery
inflammation dysfunction
disease
Chronic, accumulates with repeated Cardiovascular events
and prolonged stress, measured at
rest using RH-PAT to identify ED
FIGURE 3. Outline of how mental stress (MS) leads to microvascular and macrovascular endothelial dysfunction (ED), how each of
these can lead to pathologic and clinical manifestations of cardiovascular (CV) disease that can be measured, and how ED could be
used as a diagnostic and therapeutic target when managing MS and its associated risk of CV disease.CIMT, carotid intima media
thickness; PAT, peripheral arterial tonometry; RH-PAT, reactive hyperemiaeperipheral arterial tonometry.
target, implicated in arterial inflammation Atherosclerosis

and MS-related CVD. Increased rates of atherosclerosis have been
The release of peripherally circulating observed in animals with chronically
biomarkers (that have come to be known elevated levels of stress.140 Studies have
collectively as alarmins such as high mobility shown that brief episodes of experimental
group box 1 and IL-1) from ischemic brain MS are associated with prolonged impair-
after induced stoke was a critical mechanism ment of endothelial-dependent relaxation
in activating downstream inflammatory using measures such as brachial artery
pathways to exacerbate atherosclerosis.138 FMD,75,78 and RH-PAT.74,86,87 Given that
These molecules are prevalent in acute endothelial dysfunction represents the first
ischemic events and are linked to both stage of atherosclerosis, and is associated
heightened vascular inflammation and with plaque progression and
atherosclerotic disease progression and pla- vulnerability,141e146 it follows that MS
que vulnerability.138 Indeed, vascular inflam- incurred on a repeated or ongoing basis
mation and endothelial dysfunction are may lead to the initiation, acceleration, and
tightly coupled, as shown in an animal complication of atherosclerotic CVD.
model that was exposed to chronic mild Indeed, atherosclerosis has a long preclinical
stress, in which impaired endothelial- period, during which multiple potentially
dependent smooth muscle dilatation was injurious risk factors act on the arterial
improved after treatment with the TNF- wall. Studies have shown greater carotid in-
alpha inhibitor infliximab.139 tima media thickness, a marker of early
n n
atherosclerotic disease, in individuals from glycosaminoglycans within the vascular ma-

lower SES,147 and those with anxiety148 trix.155 This remodeling is associated with
and depression.149 Moreover, rats exposed changes in the concentration of vasoactive
to chronic stress showed increases in the substances such as nitric oxide, angiotensin
serum concentration of total cholesterol, tri- II, and norepinephrine leading to the devel-
glycerides, low-density lipoprotein choles- opment and progression of hypertension,156
terol, very low-density lipoprotein which itself is associated with increased phys-
cholesterol, and atherogenic index, without ical stress on blood vessel walls and further
any change to high-density lipoprotein remodeling. Elevations in pulse pressure,
cholesterol concentrations.150 Chronic un- which result mainly from increased rigidity
predictable stress combined with a high-fat of large arteries, is an important risk factor
diet weakens reverse cholesterol transport, for CVD morbidity and mortality indepen-
a process that removes excess cholesterol, dent of absolute blood pressure.157 Increased
which in turn exacerbates atherosclerosis.151 pulse pressure transmitted to the capillary
Chronic stress also promotes visceral fat endothelium also contributes further to endo-
accumulation, as opposed to subcutaneous thelial cell injury.158 Finnish men with
fat, with subsequent progression of athero- greater systolic and diastolic blood pressure
sclerosis and incident CVD events.152 reactivity to experimental MS had higher de-
grees of carotid intima media thickness at
Hemodynamic Effects baseline,159 as well as greater increases in ca-
Both physical stress and MS are associated rotid intima media thickness at 4-years
with increases in heart rate and blood pres- follow-up.160
sure, with incumbent increases in stroke vol- Hemodynamic responses to stress can be
ume and cardiac output.153 An important influenced by a number of interacting fac-
difference between the two types of stress is tors. First, women respond predominantly
that physical stress is associated with periph- with an increase in heart rate, whereas men
eral vasodilatation, such that the augmented respond with increases in diastolic blood
cardiac output can match increased demands, pressure and peripheral vascular resistance.
resulting in an increase in oxygen consump- Women also have comparatively lower
tion. However, MS tends to either be associ- vascular resistance at rest and with MS.161
ated with a slight decrease in systemic Second, African American men had higher
vascular resistance, characterized by a pre- peripheral vascular resistance than White
emptive “fight or flight” response similar to men during public speaking tasks.161 Third,
that which precedes physical stress, or more individuals with concurrent high levels of
commonly an increase in vascular resistance depressive symptoms have greater increases
associated with no change in oxygen con- in systemic vascular resistance in response
sumption.154 Changes in hemodynamic pa- to mirror tracing.162 Fourth, individuals of
rameters associated with MS including lower SES have delayed blood pressure re-
blood pressure and left ventricular function covery after stress, and have greater carotid
are outlined in Table 1. These changes may intima media thickness than individuals
represent acute triggers for CVD events, or who have normal blood pressure recovery af-
may lead to CVD progression and worse ter stress or those in higher SES groups.163
longer-term prognosis.44 Repeated and pro-
longed episodes of stress lead to vasoconstric- Ischemia
tion, endothelial dysfunction, vascular Myocardial blood flow is regulated through
hypertrophy, and changes in vessel architec- changes in microvascular resistance, which oc-
ture that include a decreased lumen diameter curs through the sympathetic nervous system
and reduced density of microvessels. This oc- innervating the coronary arterioles via alpha-
curs in parallel with increased large arterial ri- adrenergic receptors, and the myocardium
gidity secondary to increased collagen via beta-adrenergic receptors.164 These recep-
deposition, and loss of elastin and tors are the sites where the catecholamines
epinephrine and norepinephrine bind and representative of the cumulative and dynamic
cause vasoconstriction. Thus, MSIMI is the impact of MS that could then form an index
downstream clinical manifestation of the com- of risk and therapeutic target (see Figure 3).
bined physiologic effects of increased heart
rate and blood pressure, endothelial dysfunc- THE CONNECTIONS BETWEEN
tion, and altered coronary blood flow70 in NEUROPSYCHIATRY AND
response to MS. Interestingly, angiographically CARDIOVASCULAR DISEASE
normal epicardial coronary arteries show vaso- Our brains are continuously processing
dilatation and increased coronary blood flow streams of stimuli, only a small fraction of
in the setting of MS.165 Conversely, MS is asso- which are selected for further processing in
ciated with local vasoconstriction in segments our salience network. Within this system,
with epicardial atherosclerotic disease and ste- the amygdala plays an important role
nosis, although the reductions in coronary through its connections with the hypothala-
blood flow are above and beyond that which mus, and thence the pituitary gland in the
can be explained by epicardial vasoconstric- hypothalamic-pituitary-adrenal (HPA)
tion alone, implicating the role of stress- axis170 leading to the well-characterized
induced increases in the resistance of the coro- “fight or flight” autonomic and hormonal
nary microcirculation.166 This was confirmed stress responses. The amygdala also forms
in a study using coronary Doppler flow, which further connections to the periaqueductal
showed greater microvascular resistance in the gray which influences our behavior.171 In
setting of MS in patients with nonobstructive addition, the prefontal cortex is involved in
CAD.167 Further, patients with CAD exposed cognitive appraisal of sensory stimuli and,
to MS while undergoing myocardial perfusion through its downstream neuronal projec-
imaging had reduced coronary blood flow in tions onto the amygdala and brainstem, it
territories without epicardial stenosis, suggest- can further modulate the stress response
ing the presence of heightened microvascular with higher order regulation.172 Further,
resistance.166 An important shortcoming of the dorsal anterior cingulate cortex also
such diagnostic imaging techniques relates to plays a role in regulating cardiovascular
the fact that 80% of the resistance to blood reactivity to cognitively demanding tasks,173
flow in the coronary circulation is regulated as well as the expression of proinflammatory
by the microvasculature, which comprises cytokines and preclinical atherosclerosis af-
most of the endothelium. Noninvasive stress ter reappraisal of emotional stimuli.174 In
tests are poor predictors of endothelial- contrast, greater social support levels are
dependent and -independent coronary micro- associated with lesser activity in the dorsal
vascular abnormalities168 as they lack the anterior cingulate cortex175 further support-
sensitivity to detect the subendocardial ing the notion of differential regional modu-
ischemia associated with these microvascular lation of the neurally mediated stress
changes. They also rely on identifying areas response.
of myocardium with relatively lower levels of Neuroimaging modalities such as 18F-flu-
perfusion compared with adjacent areas, orodeoxyglucose (18F-FDG) PET/computed
whereas microvascular dysfunction typically tomography (CT) are used to determine
produces diffuse ischemia.169 Additionally, resting metabolic activity in different parts
imaging modalities such as echocardiography of the body, including the brain. Studies in
and myocardial perfusion imaging only pro- primates have shown that increased amyg-
vide a single snapshot of certain indices of dala uptake is associated with an anxious
function, such as left ventricular ejection frac- disposition in adults,176 and predicts future
tion, at one cross-section in time. On the other temperament in juveniles.177 In addition,
hand, markers of endothelial function may functional magnetic resonance imaging
provide an integrated index of vascular injury (fMRI) and PET alone can provide insight
that has been accrued over time. Therefore, into neural activity and connectivity between
such indices may provide information more regions of the brain that can be correlated
n n
with the timing of stressors. Studies using perceptions of one’s circumstance can influ-
both fMRI and PET have shown that stress- ence regional brain activity and subsequent
ful stimuli lead to the activation of the amyg- disease. In this way, the pathogenic effects
dala, which then through its connections of stress seem to be transduced along a
with the hypothalamus results in activation neuroendocrine immunologic axis, terminat-
of the HPA axis, enhanced sympathetic ner- ing downstream on the vasculature where it
vous activity and withdrawal of parasympa- then manifests as CVD.
thetic nervous activity, and stimulation of
the renin-angiotensin-aldosterone sys- FUTURE DIRECTIONS
tem.170,178,179 Thus, through its connections Although there is evidence that stress is
with the limbic system, where the amygdala associated with CVD, there are critics who
is located, the cerebral cortex transmits the postulate that stress may in fact be a marker
experience of MS into a systemic physiolog- rather than a mechanism for CVD.187 This
ical response mediated by catecholamines notion is based on the lack of high-quality
and stress hormones such as cortisol. robust evidence supporting the mechanism
Stress-induced catecholamine and cortisol hypothesis. Indeed, current studies evalu-
underpin important hemodynamic, immu- ating the relationship between stress and
nologic, and vascular changes that CVD have a number of limitations. Below
contribute not only to hypertension, we outline some suggested areas for
adiposity, and insulin resistance,180 but improvement for future studies evaluating
also to atherosclerotic disease progression. the biological effects of MS.
In one study using fMRI, individuals with
heightened amygdala activation and func- Generalizability
tional connectivity between the amygdala Studies using experimentally created MS
and anterior cingulate cortex had a greater tasks within the laboratory setting have
burden of subclinical atherosclerosis.181 questionable generalizability. Physiologic re-
When using 18F-FDG PET/CT, amygdala ac- sponses to stress are vulnerable to situation
tivity, adjusted for temporal lobe or prefron- and individual factors,188 and these variables
tal cortex activity, was associated with CVD are often not easy to identify or control for.
events that occurred with increased circu- Opportunities for improving the real-life val-
lating inflammatory markers and leukopoi- idity and generalizability of the effects of
etic activity, and greater degrees of experimental MS include the following: 1)
atherosclerosis.182 In another study using by using the aggregation of scores across
18
F-FDG PET/CT with concurrent CT coro- multiple tasks and within tasks across all
nary angiography increased, adjusted amyg- laboratory periods of stress including base-
dala activity was associated with greater line, anticipation, reactivity, and recovery d
bone marrow leukopoietic activity and each measurement contains random error
atherosclerosis, including noncalcified coro- that can be reduced by using multiple mea-
nary plaque volume.183 Further, increased surements, whereas aggregating scores en-
adjusted amygdala activity was associated hances the diversity of situations sampled
with incident diabetes independent of that may be more representative of real-life;
adiposity,184 as well as increased leukopoi- 2) reducing error by performing multiday
etic activity, abnormal myocardial perfusion, ambulatory assessments at home, similar to
and decreased left ventricular function in fe- those used when assessing for hypertension d
male patients.185 Curiously, amygdala activ- ambulatory blood pressure monitoring bet-
ity varies among individuals, even if all are ter predicts CVD than office blood pressure
uniformly exposed to stress; and individuals recordings189; and 3) social tasks may be
with lower amygdala activity despite expo- more representative of daily life stressors
sure to stress were protected from CVD.186 than traditionally used cognitive
Such neurobiological-resilient individuals activities. Type A interviews, discussing
may provide insight into how individual anger-provoking events, and listening to a
competitor all show greater generalizability certain gene-environment interactions

and ecologic validity.190e192 related to stress and CVD and, in one study,
individuals with at least one copy of a partic-
Timing of Stress ular allele had greater blood pressure reac-
Pathologic effects of stress should be tivity to stress than those who lacked the
ascribed to the cumulative duration of the allele.201 Studies using 18FDG-PET/CT imag-
physiologic responses to stress, and not ing showed that individuals from lower SES
just to the temporal exposure to the stressor neighborhoods202 and those exposed to
itself. Thus, pathogenicity increases not only transportation noise exposure203 had
with repeated or chronic exposure to a increased amygdala activity, increased
stressor, but also when cognitive and atherosclerosis, and increased subsequent
emotional processes perpetuate physiologic CVD events, suggesting that socioeconomic
responses even in the temporal absence of hardship can lead physiologically susceptible
that stressor, such as when ruminating. individuals to experience the effects of stress.
Indeed, recall of an anger-provoking event Therefore, genetic, environmental, and other
increased the difficulty in terminating ven- biopsychosocial risk factors should be evalu-
tricular tachycardia in arrhythmia-prone pa- ated in the context of the stressor to help
tients193 and reduced left ventricular fraction better elucidate mechanistic pathways, iden-
in patients with CVD.194 There is currently tify individuals at risk, and target interven-
no accepted method for measuring anticipa- tions appropriately.
tion or recovery from MS and most
commonly the “change in scores from base-
TREATMENT STRATEGIES
line” and “time to return to baseline” have
been used.195 Delayed recovery in blood Stress Management, Resiliency, and
pressure from a laboratory psychological Pharmacotherapy d Targeting Mental
stressor has been shown to be predictive of Stress
incident hypertension even after accounting In the 2016 European clinical guidelines for
for initial blood pressure and traditional the prevention of CVD, MS is acknowledged
risk factors.196,197 Thus, future studies eval- as a potential contributing factor to both
uating the impact of stress should develop development and progression of disease, for
models that also account for the physiologic which a targeted rather than universal man-
effects of anticipating, recovering from, and agement strategy is recommended. The evi-
ruminating over a stressor. dence for MS as a CVD risk factor is rated
as class IIa, indicating that the weight of ev-
Other Interacting Factors idence favors efficacy such that managing
The causes of CVD are not completely un- stress as a risk factor “should be considered.”
derstood by examining single factors in Thus, assessing and managing MS in individ-
isolation, but instead through the consider- uals with established CVD or at high risk of
ation of a constellation of variably interact- disease is now guideline-recommended.204
ing factors such as behaviors, environment, Candidate therapeutic options targeting
and genetic predispositions. Epidemiologic stress to reduce risk of CVD include non-
studies have shown that migration from ru- pharmacological strategies (such as relaxa-
ral to urban environments is associated tion techniques, “mental exercise”
with higher blood pressures in those living including basic changes in philosophic
in urban compared with rural areas.198e200 outlook and empirically based cognitive
Although this effect was attributed to adopt- behavioral therapy [CBT], meditation,
ing Western lifestyle patterns, the changes in graded adaptation to stressors, and physical
blood pressure were not the universal expe- activity) and pharmacological strategies.
rience of all migrants, suggesting inter- Although of considerable interest, mental
individual differences in susceptibility. Phar- training remains poorly defined and inade-
macogenetics studies have highlighted quately studied. Broadly speaking,
n n
meditation is designed to “improve concen- and for monitoring progress and efficacy of
tration, increase awareness of the present treatment. Along these lines, considerable
moment, and familiarize a person with the attention and research activities have
nature of the mind.”205 In summary, current focused on virtual reality, high-density elec-
evidence shows the following: 1) non- troencephalogram neurofeedback and other
randomized studies suggest that meditative methods to reduce MS.209 These tools offer
practices are beneficial in reducing the risk objective measures of neural activity that
of CVD; 2) no firm conclusions can be can be observed in real-time during stress
made on the effects of meditation on endo- management activities and could provide
thelial function, subclinical atherosclerosis, the basis for goal-directed training and
or metabolic syndrome; and 3) although pri- tracking longitudinal progress over time.
mary prevention studies report reductions in From a pharmacologic perspective, the
mortality, secondary prevention studies do serotonin reuptake inhibitor escitalopram
not show any clear benefit.205 Indeed, cur- has been studied in randomized controlled
rent evidence is limited by small sample trials, including two 6-week long studies in
sizes, heterogeneous study populations, patients with stable CAD and baseline
implementation of different strategies for MSIMI. Both studies showed that the inci-
stress reduction, and varying study end- dence of MSIMI at follow-up was reduced
points, making it challenging to draw firm in the experimental group compared with
conclusions. Similarly, although evidence placebo.59,210 The mechanism of escitalo-
for the effectiveness of CBT is robust for psy- pram’s actions in this context is unclear
chological distress in the general popula- but may relate to the regulation and binding
tion,206 effectiveness of CBT in CVD is affinity of platelet serotonin receptors.59,210
unclear. Yet, given that meditation and Interestingly, in a study that included 152
CBT-based strategies are low-cost, low-risk adult outpatients with confirmed COVID-
approaches, and have the potential for wide- 19 who were randomized to the serotonin
spread application, they could be considered reuptake inhibitor fluvoxamine vs placebo,
as adjuncts to additional established lifestyle those taking fluvoxamine had a lower likeli-
measures. As an example, a randomized hood of clinical deterioration within 15
controlled trial did show fewer adverse days.211 These data have recently been repli-
CVD events in individuals who underwent cated in high-risk outpatients in a study that
stress management in addition to cardiac included more than 1400 participants.212
rehabilitation, compared with cardiac reha- Although the mechanism of this effect re-
bilitation alone, prompting the incorporation mains to be determined, unlike other seroto-
of stress management into cardiac rehabilita- nin reuptake inhibitors, fluvoxamine
tion programs.207 Nonetheless, the benefits interacts strongly with the sigma-1 receptor,
of meditation and other nonpharmacological a protein inside cells that helps regulate the
strategies remain to be clearly demonstrated, body’s inflammatory response as well as
and adequately powered, well-designed ran- reducing anxiety and depression.213 In this
domized controlled trials are required. way the sigma-1 receptor could potentially
Further, given that exercise training im- offer a novel therapeutic target that could
proves endothelial function, reduces cate- be the basis of future studies targeting the ef-
cholamine release, and increases peripheral fects of MS. Further, given that the patho-
oxygen extraction,208 it is likely to also genesis of stress-induced CVD and MSIMI
have benefits in stress management, is related to vasoconstriction and microcir-
although randomized trials here are also culatory disease, alpha- and beta-blocking
lacking. In both mental and physical drugs as well as angiotensin II receptor
training, digital health, wearables, and blockers214 would seem to be useful agents,
remote monitoring are likely to play impor- but randomized trials evaluating their effi-
tant roles in study design as well as in devel- cacy in managing stress-related CVD are
oping individualized patient “prescriptions,” lacking. Given our evolving insight into the
neuroendocrine immunologic axis mediating Further, applying treatment strategies tar-

between MS and vascular disease, exploring geted to the adverse vascular effects of one
the potential role of novel therapeutics tar- risk factor may help to mitigate the delete-
geting proinflammatory cytokines such as rious effects of another risk factor without
canakinumab,215 among others, may also addressing the second risk factor directly.
be of great value. For example, regular aerobic exercise
training has been shown to mitigate endo-
CVD Risk Prevention d Targeting thelial dysfunction related to insufficient
Endothelial Dysfunction sleep, and in doing so could reduce CVD
As the putative link between MS and CVD risk associated with habitual insufficient
appears to be mediated by vascular injury nightly sleep.219 In this way, although thera-
and endothelial dysfunction, risk prevention pies that target MS itself presently lack
strategies should also be targeted to the conclusive evidence and are continuing to
latter. In this way, increased vascular reac- be studied, patients with MS can still be
tivity and endothelial dysfunction could be effectively managed by harnessing our exist-
detected to diagnose the pathologic effects ing knowledge of how best to manage CVD
of MS on the vascular system (Figure 3). risk factors using endothelial dysfunction
Endothelial dysfunction could then be used as the integrated target that ultimately medi-
as a therapeutic target to prevent CVD and ates CVD.
its consequences, and its measurements
could be followed longitudinally to monitor CONCLUSION
treatment response. Traditional and other Conventional clinical practice often fails to
nonconventional CVD risk factors, such as incorporate an assessment of MS and its po-
unhealthy nutrition and sleep deprivation, tential role as a risk factor for CVD. Our
also lead to endothelial dysfunction and rapidly evolving understanding of the role
contribute to CVD risk; therefore, the quan- that stress plays in CVD may change this.
tity of measured endothelial dysfunction This has been brought even more greatly to
may not consistently correspond to a given the fore with the current COVID-19 global
amount of MS per se. However, the identifi- pandemic with its incumbent policies of so-
cation of endothelial dysfunction as an inte- cial distancing, and our increasing awareness
grated index of risk accumulated through of the deleterious health consequences of
the net effects of beneficial and harmful fac- life-changing events and loneliness. In fact,
tors would signify the presence of vascular assessing and managing MS in individuals
injury and increased cardiovascular risk, with established CVD or at high risk of dis-
and thus would still prompt CVD preventive ease is now guideline-recommended. Never-
efforts. This could be achieved by not only theless, greater recognition of the dangers of
screening for and managing MS itself to pre- MS and its impact on CVD will center on
vent vascular injury, but also by targeting more carefully defining stress when commu-
the vascular injury itself. Traditional behav- nicating in scientific circles, and in making
ioral interventions known to prevent CVD use of ways to quantify the physiologic re-
including smoking cessation, diet modifica- sponses and disease-causing consequences
tion, and physical activity could be imple- of stress, particularly with respect to endo-
mented.216 Similarly, pharmacologic thelial function and vascular health where
strategies such as statins that are known to the downstream impact of stress appears to
improve endothelial dysfunction and the be transduced. Developing these methods
risk of CVD217 could also be used. Other for widespread clinical use will rely on
traditional CVD risk factors that are known improved study design as well as developing
to separately contribute to vascular injury disease causative models that factor in addi-
such as diabetes mellitus and hypertension tional biopsychosocial factors that also
should also be identified and treated in contribute to CVD. Greater attention must
accordance with practice guidelines.218 also be given to developing treatment
n n
strategies that target MS and endothelial 9. Madsen IEH, Nyberg ST, Magnusson Hanson LL, et al. Job
strain as a risk factor for clinical depression: systematic review
dysfunction directly along the neuroendo- and meta-analysis with additional individual participant data.
crine immunologic axis in ways that effec- Psychol Med. 2017;47(8):1342-1356.
tively reduced the risk of CVD. Digital 10. Hackett RA, Steptoe A. Type 2 diabetes mellitus and psycho-
logical stress d a modifiable risk factor. Nat Rev Endocrinol.
health and remote monitoring will likely 2017;13(9):547-560.
play a role in this which, similar to stress, 11. Batty GD, Russ TC, Stamatakis E, Kivimaki M. Psychological
distress in relation to site specific cancer mortality: pooling
will undoubtedly continue being pervasive of unpublished data from 16 prospective cohort studies.
elements in all our lives. BMJ. 2017;356:j108.
12. Kivimaki M, Kawachi I. Work stress as a risk factor for cardio-
vascular disease. Curr Cardiol Rep. 2015;17(9):630.
Abbreviations and Acronyms: CAD, coronary artery dis- 13. Dragano N, Siegrist J, Nyberg ST, et al. Effort-reward imbal-
ease; CBT, cognitive behavioral therapy; CVD, cardiovascular ance at work and incident coronary heart disease: a multico-
disease; FMD, flow-mediated dilatation; IL, interleukin; MI, hort study of 90,164 individuals. Epidemiology. 2017;28(4):
myocardial infarction; MS, mental stress; MSIMI, mental 619-626.
stress induced myocardial ischemia; PAT, peripheral arterial 14. Kivimaki M, Jokela M, Nyberg ST, et al. Long working hours
tonometry; PED, peripheral endothelial dysfunction; PET, and risk of coronary heart disease and stroke: a systematic re-
view and meta-analysis of published and unpublished data for
positron emission tomography; RH, reactive hyperemia;
603,838 individuals. Lancet. 2015;386(10005):1739-1746.
SES, socioeconomic status; TNF, tumor necrosis factor;
15. Huang Y, Xu S, Hua J, et al. Association between job strain
VSMC, vascular smooth muscle cells and risk of incident stroke: a meta-analysis. Neurology. 2015;
85(19):1648-1654.
16. Rosengren A, Hawken S, Ounpuu S, et al. Association of psy-
Potential Competing Interests: The authors report no po- chosocial risk factors with risk of acute myocardial infarction in
tential competing interests. 11,119 cases and 13,648 controls from 52 countries (the
INTERHEART study): case-control study. Lancet. 2004;
Correspondence: Address to Amir Lerman, MD, Division 364(9438):953-962.
of Cardiovascular Diseases and Department of Internal 17. Hemingway H, Marmot M. Evidence based cardiology: psy-
Medicine, Mayo College of Medicine, 200 First Street SW, chosocial factors in the aetiology and prognosis of coronary
heart disease. Systematic review of prospective cohort studies.
Rochester, MN, 55905 USA (lerman.amir@mayo.edu).
BMJ. 1999;318(7196):1460-1467.
18. Chida Y, Steptoe A. The association of anger and hostility with
future coronary heart disease: a meta-analytic review of pro-
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Since January 2020 Elsevier has created a COVID-19 resource centre with

free information in English and Mandarin on the novel coronavirus COVID-

Elsevier hereby grants permission to make all its COVID-19-related

Mental Stress and Its Effects on Vascular

From the Department of

Mayo Clin Proc. n May 2022;97(5):951-990 n https://doi.org/10.1016/j.mayocp.2022.02.004 951

health care workers and reported that having

Stressor – “potentially challenging external variable”

Acute stressors Chronic stressors

External Internal Recurrent or prolonged

Duration of stressor Seconds - days Weeks - months Years

Timing of response Planning ahead Acute anticipation During Recovery Brooding/rumination

Roles of extraneous factors Perception of

ischemia on stress MPI angina ambulatory LV unstable angina) LV dysfunction during

15 patients (67%) with

MAYO CLINIC PROCEEDINGS

(OR, 2.8; 95% CI, 1.0- ambulatory ECG

Continued on next page

VASCULAR HEALTH AND MENTAL STRESS

CI, 1. 12-5. 14; P¼.02),

during exercise (RR,

Continued on next page

ischemia on an 40% vs 19% of even after adjusting for

daily life and exercise

RNV subsequent clinical fashion, with each 4%

events, compared with decrease from the

Study reactions were

MAYO CLINIC PROCEEDINGS

Continued on next page

VASCULAR HEALTH AND MENTAL STRESS

95% CI, 1.15-4.69;

task responses to MS times higher (HR, 2.04; showed that a high

Continued on next page

hospitalizations for CV in LVEF induced by in MSIMI group was

up time and a 20%

increase in the number

MAYO CLINIC PROCEEDINGS

40% hospitalization deaths) quantiﬁed as marginally associated

Continued on next page

VASCULAR HEALTH AND MENTAL STRESS

including HF disease associated with greater

associated with lower

risk (HR, 0.498; 95%

78% increase (HR,

(post e pre HR, 1.15;

95% CI, 1.03-1.27 for

MAYO CLINIC PROCEEDINGS

HF hospitalization unstable angina with risk of MACE (HR, the relationship

Continued on next page

VASCULAR HEALTH AND MENTAL STRESS

and high-frequency reclassiﬁcation for

Continued on next page

MAYO CLINIC PROCEEDINGS

Mayo Clin Proc. n May 2022;97(5):951-990 n https://doi.org/10.1016/j.mayocp.2022.02.004 965

VASCULAR MECHANISMS through the release of active substances

VASCULAR HEALTH AND MENTAL STRESS

recording (Holter monitor) more frequently than those in

ischemia in 1 other patient,

MAYO CLINIC PROCEEDINGS

word-color conﬂict) 0.47%; P¼.01)