Curr Treat Options Cardio Med (2019) 21: 23

DOI 10.1007/s11936-019-0724-5

Prevention (K Aragam, Section Editor)

Psychosocial Stress
and Cardiovascular Disease
Tawseef Dar, MD1,2
Azar Radfar, MD, PhD1,2
Shady Abohashem, MD1,2
Roger K. Pitman, MD3
Ahmed Tawakol, MD1,2
Michael T. Osborne, MD1,2,4,*
Address
1
Cardiac MR-PET-CT Program, Department of Radiology, Massachusetts General
Hospital, Boston, MA, USA
2
Cardiology Division, Massachusetts General Hospital and Harvard Medical School,
55 Fruit St, Boston, MA, USA
3
Department of Psychiatry, Massachusetts General Hospital and Harvard Medical
School, Boston, MA, USA
*,4
Cardiology Division, Massachusetts General Hospital and Harvard Medical
School, 165 Cambridge Street, Suite 400, Boston, MA, 02114-2750, USA
Email: mosborne@mgh.harvard.edu

Published online: 26 April 2019

* Springer Science+Business Media, LLC, part of Springer Nature 2019

Tawseef Dar and Azar Radfar contributed equally to this work.

This article is part of the Topical Collection on Prevention

Keywords Psychosocial stress I Cardiovascular disease I PET imaging I Amygdalar activity

Abstract
Purpose of review This manuscript reviews the epidemiological data linking psychosocial
stress to cardiovascular disease (CVD), describes recent advances in understanding the
biological pathway between them, discusses potential therapies against stress-related
CVD, and identifies future research directions.
Recent findings Metabolic activity of the amygdala (a neural center that is critically
involved in the response to stress) can be measured on 18F-fluorodeoxyglucose positron
emission tomography/computed tomography (18F-FDG-PET/CT) yielding a neurobiological
signal that independently predicts subsequent CVD events. Furthermore, a serial pathway
from ↑amygdalar activity → ↑hematopoietic tissue activity → ↑arterial inflammation →
↑CVD events has been elucidated, providing new insights into the mechanism linking
stress to CVD.
Summary Psychosocial stress and stress conditions are independently associated with CVD
in a manner that depends on the degree and duration of stress as well as the individual
response to a stressor. Nevertheless, the fundamental biology remains incompletely
defined, and stress is often confounded by adverse health behaviors. Thus, most clinical
23 Page 2 of 17 Curr Treat Options Cardio Med (2019) 21: 23

guidelines do not yet recognize psychosocial stress as an independent CVD risk factor or
advocate for its treatment in CVD prevention. Clarification of this neurobiological pathway
provides a better understanding of the underlying pathophysiology and suggests oppor-
tunities to develop novel preventive strategies and therapies.

Introduction
In early psychoanalytic psychiatry, neurosis was theo- multiple pathologies including CVD [19]. In contrast,
rized to “cathect” organs to produce physical disease [1]. the end product of the HPA axis, viz., corticosterone in
However, even now, the biology underlying this associ- rodents and cortisol in humans, is well known for its
ation remains incompletely defined. Current science anti-inflammatory effects, although under certain cir-
requires the discovery of pathophysiologic mechanisms cumstances, it may also be pro-inflammatory [20].
linking the brain to periphery to understand the associ- These two systems are variably stimulated in different
ation between the mental and physical. Ultimately, the individuals by different stressors over different time
impact of an organism’s environment, including psy- courses. Upstream nervous system factors modulate
chosocial stress, must be understood at organic, tissue, both the SNS and HPA axis based upon individual
cellular, and molecular levels. experience and deployment of coping strategies. The
Stress, which may exist in many forms, is an unavoid- salience network of the brain, a network of connected
able element of human existence that often leads to a neural centers (which prominently include the amygda-
maladaptive physiological response [2]. Although acute la), represents one of these upstream factors and plays a
emotional stress has long been linked to acute cardio- critical role in governing individual autonomic and hor-
vascular events [3–7], the long-term effects of chronic monal responses [21••, 22–24].
stress on physical well-being, and specifically cardiovas- Recent research has harnessed advanced multi-
cular disease (CVD), have only recently been recognized system 18F-fluorodeoxyglucose positron emission
[8–11, 12••, 13]. Nevertheless, clinical guidelines con- tomography/computed tomography (18F-FDG-PET/
tinue to lag behind this evidence. CT), and more recently magnetic resonance imag-
Although some guidelines recommend stress man- ing (18F-FDG-PET/MRI), simultaneously to evaluate
agement in patients at high risk of CVD [14], such a metabolic activity in neural centers and disparate
practice is not yet established as a method of primary organ systems to make important discoveries about
prevention in the general population [15, 16]. Because how the environment impacts the brain and leads
the prevalence of chronic stress and stress conditions is to downstream pathology. Specifically, it has been
rapidly increasing in the modern world [17], the identi- shown that increased resting metabolic activity in
fication of stress as an independent risk factor for CVD the amygdala, an important center in the emotion-
and the development of novel preventive strategies have al and physiological response to stress, on 18F-
emerged as public health challenges needing urgent FDG-PET/CT is increased in chronic stress condi-
attention. tions and associates with perceived stress [21••,
A key next step in addressing this need is elucidating 25–27]. Furthermore, amygdalar activity associates
the mechanistic neurobiological pathways that link downstream with increased bone marrow activity
stress to CVD. It has been established that external (indicative of leukopoiesis) and arterial wall activity
stressors trigger a coordinated response from the two (indicative of inflammation). Amygdalar activity, in
main effector limbs of the stress response, the sympa- series with bone marrow and arterial wall activity, as
thetic nervous system (SNS) and the hypothalamic- well as independently, predicts adverse CVD events
pituitary-adrenal (HPA) axis. The former mobilizes nec- and also independently predicts incident diabetes
essary resources for flight or fight, whereas the latter mellitus [21••, 28••, 29]. Characterization of this
(among other things) protects the individual from the mechanism has created the opportunity to evaluate
adverse effects of this mobilization to maintain homeo- novel interventions aimed at different targets within
stasis [18]. SNS activation increases inflammation and this pathway with the hopes of attenuating the path-
inflammatory cell output, which is known to drive ophysiologic consequences of stress.
Curr Treat Options Cardio Med (2019) 21: 23 Page 3 of 17 23

In this review, we discuss existing evidence and recent the association between stress and CVD, potential ther-
insights into different types of psychosocial stress, the apies targeting stress-related CVD, and future directions
forms of CVD associated with psychosocial stress in for further research on this topic.
epidemiological studies, the mechanisms underlying

Forms of psychosocial stress

Psychosocial stress may result from a variety of etiologies and circumstances.
The experience of stress and its impact are often unique to an individual
organism. Nevertheless, psychosocial stress ultimately activates the same stress
response systems (SNS and HPA axis) regardless of its source. Psychosocial
stress can occur acutely or chronically, and the duration of the stress response
has an impact on both the incidence and the type of CVD consequences. As
such, we have categorized psychosocial stress according to its duration as acute
or chronic for the purposes of the discussion below.

Acute psychosocial stress

The potential impact of acute psychosocial stress (APS) on CVD has frequently
been assessed by evaluating the aftermath of happenstance natural disasters and
adverse emotional events (e.g., receiving a cancer diagnosis, gambling losses).
APS is associated with an increased risk for acute cardiovascular complications
such as myocardial infarction (MI), left ventricular dysfunction, and arrhyth-
mias. Following the Northridge earthquake in 1994 in Los Angeles, CA, a 2–5-
fold increase in the rate of CVD deaths was observed in and around the city,
with the greatest risk in individuals with underlying coronary artery disease
(CAD) [3, 4]. Other earthquake studies have shown a relative increase in SNS
activity manifest in increases in heart rate, low-frequency/high-frequency heart
rate variability ratio [30], and blood viscosity with risk of thromboembolism
[31, 32]. In the absence of underlying CAD, APS is also being recognized as a
likely precipitant of Takotsubo cardiomyopathy, an acute but usually transient
heart failure syndrome, with elevated levels of circulating catecholamines in
response to acute stressors playing a key role in the underlying pathophysiology
[7, 33]. Similarly, an association has been reported between acute emotional
stress and aortic dissection [34].
Although disasters and acute stressors provide opportunities to study the
association between APS and CVD, these studies are inevitably confounded by
consequent lifestyle changes, which include changes in diet and exercise,
skipped medications, and exposure to toxins, among others. To control for such
factors, researchers have tried to study the association between APS and CVD in
the laboratory setting. This approach remains limited, as there are few ways that
experimental psychological stress can be ethically implemented, and the gen-
eralizability of these methods to real-world stressors remains questionable. For
example, in one such experimental study with these limitations, Dimsdale and
Moss reported that epinephrine levels increased approximately threefold
among resident physicians making formal presentations at conferences; the
increase was even more pronounced in those whose presentations were
23 Page 4 of 17 Curr Treat Options Cardio Med (2019) 21: 23

interrupted by a sudden blowout of the projector bulb [35].

Similarly, a large body of laboratory research has been performed to assess
acute cardiovascular responses to mental stress. Acute mental stress has not only
been shown to have adverse changes in blood pressure and heart rate variability
but has also been shown to alter myocardial perfusion [30, 36]. Within this
paradigm, Deanfield et al. carried out an experiment in 16 patients with stable
angina, in which they compared findings on rubidium-82 PET imaging be-
tween a physical (bicycle ergometry) and a mental (serial seven subtraction)
stressor. Both physical and mental stress elicited abnormal regional perfusion in
12 patients. With physical stress, abnormal perfusion correlated well with ST
segment changes and anginal symptoms. In contrast, there was discordance
among perfusion abnormalities, ST segment changes, and chest pain in the
group subjected to mental stress [37]. However, several other studies have
shown that mild acute mental stress, like mental arithmetic, can induce myo-
cardial ischemia. Importantly, this holds true even at low heart rates and blood
pressure, suggesting that the mechanism is most likely mediated by impaired
local vascular endothelial function rather than increased hemodynamic de-
mand [38–40].
In a study by Jiang et al., a series of patients with known CAD were assessed
using radionuclide ventriculography to evaluate left ventricular ejection fraction
(LVEF) and regional wall motion in response to mental arithmetic. They
observed that 67% of CAD patients showed either wall motion abnormalities
or a 9 5% drop in LVEF in response to the acute mental stress; those who
developed a drop in LVEF were more than twice as likely to have an adverse
CVD event during 4 years of follow-up [41]. Sheps et al. similarly showed that
the degree of wall motion abnormality in response to acute mental stress
(public speaking) predicted all-cause mortality in CAD patients in 5 years of
follow-up [11].

Chronic psychosocial stress

Chronic psychosocial stress (CPS) can arise from major life changes (e.g., job
stress, marital discord, death of a spouse or loved one, burden of caregiving),
adverse socioeconomic factors (e.g., income, crime, education, racial inequali-
ty), and chronic psychiatric conditions (e.g., anxiety, depression, post-traumatic
stress disorder). There is a wealth of data linking CPS and CVD; the magnitude
of risk for CVD events associated with CPS has been reported to be equal to that
attributed to traditional CVD risk factors [9]. For example, the rate of implanted
defibrillator firings was higher than expected in the months following the 2001
terrorist attack on the World Trade Center in New York, irrespective of the
nature of the underlying cardiomyopathy [42]. Similarly, in a cohort study from
the Nurses’ Health Study, the stress from caring for a sick spouse almost
doubled the risk of CVD mortality [43].
Although many of the studies evaluating the association of CPS with CVD
focus on the effects of chronic major stressors (e.g., marital dissolution, death of
a spouse or a loved one), the role of chronic milder stressors in the pathogenesis
of CVD has been increasingly recognized. For example, Johansen et al. showed
that chronic stress related to upcoming deadlines at work was associated with a
sixfold increase in MI incidence [44]. Further, in women with underlying CAD,
Curr Treat Options Cardio Med (2019) 21: 23 Page 5 of 17 23

CPS from daily marital tension was associated with a threefold increased risk of
CVD events [13].
Depression and anxiety have consistently been shown to associate with CVD
and adverse CVD events. In fact, the 2012 European guidelines for cardiovas-
cular disease prevention recognize depression, anxiety, and psychosocial
stressors as risk factors for incident CVD and a worsened prognosis in patients
with known CVD [45]. Depression independently associates with CVD events
in patients with or without pre-existent CAD [46–48] and has been shown to
almost double the risk of developing new CVD [49]. Furthermore, depression is
a significant predictor of both survival and subsequent adverse cardiovascular
events after an index acute coronary syndrome [49, 50] and among individuals
with heart failure [51]. Moreover, depressed patients with CAD and heart failure
are more likely to have a poorer quality of life and greater physical limitations
even after adjusting for CVD severity [52, 53].
Similarly, chronic anxiety has been found to confer an approximate three-
fold increased risk of CVD events [54, 55]. In a recent meta-analysis, individuals
with anxiety disorder were at increased risk for incident CAD and CV death,
independent of traditional CVD risk factors [56]. These results have been
corroborated in large prospective cohort studies [57, 58]. Additionally, post-
traumatic stress disorder (PTSD) is strongly associated with CVD (both incident
and progressive). For example, World War II veterans with PTSD had signifi-
cantly increased risk of CAD and hypertension [59]. Another prospective cohort
study showed that women with PTSD are more than three times more likely to
develop CAD, even after adjusting for depression, anxiety, and traditional CVD
risk factors [60].
Specific cardiovascular diseases related to psychosocial stress
In this section, we review some of the key manifestations of CVD that have been
associated with psychosocial stress in epidemiologic studies (Table 1).

Coronary artery disease and myocardial infarction

In addition to the previously described data, there is a substantial body of
literature linking CPS to CAD, and APS to acute coronary events, independent
of other cardiovascular risk factors [61, 62]. The landmark INTERHEART study
included a sample of approximately 25,000 people from more than 50 coun-
tries. It showed that individuals with chronic daily stress had more than twice
the risk of developing an MI compared to those without chronic stress after
adjusting for confounding factors [9]. APS more frequently incites acute MI than
physical exertion, and the risk of MI immediately following an anger outburst is
about twice baseline [5, 6, 63].

Cerebrovascular disease
Although individual studies of the association between psychosocial stress and
stroke have yielded less consistent results, a meta-analysis by Booth et al.
showed that CPS is independently associated with increased risk of stroke [64].
Likewise, depression and PTSD have been found to confer an increased stroke
risk [65, 66•].
23 Page 6 of 17 Curr Treat Options Cardio Med (2019) 21: 23

Table 1. Cardiovascular manifestations of different types of psychosocial stress

Psychosocial stress duration Examples of inciting stressors Cardiovascular effects

Acute Natural disasters Hypertension
Acute emotional stressors Tachycardia
Reduced heart rate variability
Takotsubo syndrome
Myocardial ischemia
Myocardial infarction
Sudden death
Acute aortic dissection
Pulmonary embolism
Chronic Job stress Hypertension
Marital discord Coronary artery disease
Death of a loved one Myocardial infarction
Burden of caregiving Cerebrovascular disease
Racial inequality Peripheral vascular disease
Low socioeconomic status Congestive heart failure
Psychiatric conditions (e.g., anxiety, depression, Atrial fibrillation
posttraumatic stress disorder)

Sudden cardiac death and ventricular arrhythmias

APS has been identified as a significant precipitant of sudden cardiac death in
the setting of natural disasters [4] and stressful life events. In fact, even height-
ened stress from viewing World Cup soccer has been associated with a twofold
increased risk of an acute cardiovascular event [67]! Individuals at the highest
risk appear to be those with underlying CAD. Findings from these studies and
others suggest that APS likely leads to acute plaque rupture due to locally
increased shear stress, or more fatal arrhythmias secondary to increased SNS
activity and exaggeration of regional myocardial ischemia [30, 68, 69]. De-
pression is independently associated with a more than threefold increased risk
of sudden cardiac death [70].

Atrial fibrillation
In a prospective multi-cohort study, CPS in the form of long work hours was
independently associated with an increased risk of atrial fibrillation [71]. Sim-
ilar results were published by Fransson et al. in a separate prospective cohort
study and meta-analysis [72].

Heart failure
Whereas APS is known to associate with acute left ventricular dysfunction as in
Takotsubo cardiomyopathy, CPS has also been shown to have adverse out-
comes in established heart failure (HF) patients. Endrighi et al. showed in a
prospective study that CPS was a significant predictor of cardiovascular mor-
bidity and all-cause mortality in HF patients [73]. The association between CPS
and incident HF is rather weak and has largely been reported in individuals with
poor health at baseline [74]. As previously described, depression has also been
shown to increase the risk of all-cause mortality and contribute to impaired
Curr Treat Options Cardio Med (2019) 21: 23 Page 7 of 17 23

quality of life and physical and social functioning in HF [65, 70, 75, 76].

Hypertension
A growing body of research has identified CPS as a potential independent risk
factor for the development of hypertension (HTN). For example, high job strain
has been associated with HTN in multiple studies [77, 78]. Interestingly, racial
discrimination has also been suggested as a cause of increased risk for the
development of HTN and may provide one explanation for the high prevalence
of HTN among African Americans living in the USA [79]. Chronic stress con-
ditions, including PTSD, have also shown to be associated with increased risk of
HTN [80].

Peripheral vascular disease

Although the relationship between psychosocial stress and peripheral artery
disease (PAD) has not been studied in the same detail as other forms of CVD, a
recent abstract by Thomas et al. reported increased perceived stress in patients
with new onset PAD [81]. In individuals with established PAD, increased CPS
independently associates with diminished walking ability and quality of life
[82].

Other cardiovascular risk factors

Although the independent association between stress and CVD is increasingly
apparent, it remains of tantamount importance to be aware of the contribution
of adverse behavioral changes (e.g., smoking, reduced physical activity, poor
dietary habits) that often accompany chronic stress [83]. Adverse health be-
haviors account for a substantial proportion of the excess CVD risk associated
with stress [84]. Increased psychosocial stress also increases the risk for the
development of metabolic diseases (e.g., obesity and type 2 diabetes mellitus),
which in turn can contribute to CVD [85, 86]. Notably, however, these stress-
associated health behaviors do not nearly explain the relationships between
stress and CVD [87–89].

Mechanistic insights
Despite the long-hypothesized biological link between stress and physical
disease [1], and the knowledge that stress triggers increased SNS, HPA axis, and
systemic inflammatory activity [90, 91], the detailed mechanistic underpin-
nings have only recently begun to be clarified.
An organism’s response to stress is triggered by its nervous system. The
hypothalamus receives afferents from several neural structures involved in the
response to stress. The hypothalamus in turn activates the SNS, and (through
the anterior pituitary gland) HPA axis, leading to increased cortisol levels in
humans. Increased cortisol has many somatic effects, including increased in-
sulin resistance, central redistribution of adiposity, increased blood pressure,
and impaired immune response [92]. The SNS activates the adrenal medulla
and the peripheral sympathetic nerves, leading to increased circulating levels of
catecholamines (mainly epinephrine and norepinephrine respectively), which
increase insulin resistance, blood pressure, and heart rate as well as drive
23 Page 8 of 17 Curr Treat Options Cardio Med (2019) 21: 23

systemic inflammation by increasing interleukin-6 and C-reactive protein [93,

94].
SNS and HPA axis activity can both lead to endothelial dysfunction [95, 96].
Increased inflammatory activity serves a critical role in bridging the gap between
stress and atherosclerotic disease [97, 98••]. In a macaque model, increased
stress due to social subordination led to alterations in the immune system,
including changes in immune cell proportions, cell type-specific gene expres-
sion, and response to an immune challenge [99]. Similarly, mice under chronic
stress were observed to have enhanced bone marrow activity via SNS activation
of myelopoiesis, resulting in heightened production of innate immune cells
and cytokines [100]. Several animal studies have taken the next step and shown
that chronic stress exposure leads to increased arterial inflammation. Specifi-
cally, in one study, subordinate mice with low social status developed prema-
ture atherosclerotic lesions with high inflammatory cell burden when chroni-
cally confronted by dominant mice [101]. In a second study, mice under
chronic stress exhibited worsening arterial inflammation with unstable plaque
features [100].
Although the downstream biology is becoming clearer, the upstream drivers
of these biological changes consequent to stress remained undefined until
recently. Several neural centers in the brain’s salience network play a critical role
in an organism’s response to its environment. The amygdala is one important
component of this network that is involved in the emotional perception and
physiological response to stressors [21••, 22, 23, 102–104]. The activity of the
amygdala is relatively stable, is increased in chronic stress conditions, and
associates with perceived stress [19, 21••, 105]. Furthermore, its efferents
provide input to the HPA axis and the SNS [24, 106]. Accordingly, we hypoth-
esized that increased amygdalar activity could trigger leukopoiesis in the bone
marrow and, ultimately, lead to an increase in arterial inflammation and CVD
events [21••, 100, 107].
To test this hypothesis, our group employed 18F-FDG-PET/CT imaging to
evaluate simultaneously the relationship between amygdalar metabolic activity,
bone marrow activity, arterial inflammation, and CVD events within 5 years in
a cohort of 293 patients without baseline CVD. In this study, we identified a
robust association between amygdalar activity and CVD through a serial path-
way of ↑amygdalar activity → ↑hematopoietic tissue activity → ↑arterial in-
flammation → ↑CVD event risk [21••]. This finding suggests a neurobiological
mechanism that links stress to CVD with several potential targets for interven-
tion and paves the way for further investigation (Fig. 1).

Potential therapies against cardiovascular diseases related to

psychosocial stress
The recently reported pathway by which stress may lead to CVD suggests
multiple targets (e.g., brain, hematopoietic tissues, arteries) with the potential
to attenuate the harmful effects of stress and decrease the risk for subsequent
CVD-related morbidity and mortality.
Potentially effective pharmacologic therapies include selective serotonin
reuptake inhibitors (SSRIs), beta blockers, and anti-inflammatories. Different
Curr Treat Options Cardio Med (2019) 21: 23 Page 9 of 17 23

Fig. 1. Proposed neurobiological mechanism linking psychosocial stress to cardiovascular disease, with imaging examples, and
potential therapies targeting involved tissues. BBs beta blockers, CBT cognitive behavioral therapy, MACE major adverse cardio-
vascular events, RR relaxation response, SNS sympathetic nervous system, SSRIs selective serotonin reuptake inhibitors.

types of SSRIs have had mixed effects on CVD risk [108]; however, a recent
meta-analysis demonstrated that SSRIs significantly decreased the risk of car-
diovascular events, especially MI, among individuals with baseline depression
and known CVD [109•]. Beta-adrenergic blocking agents attenuate the “fight or
flight” reaction by antagonizing stress-induced catecholamine responses, both
centrally (including in the amygdala) and peripherally. Such antagonism could
potentially suppress the effect of noradrenaline on leukopoiesis in bone mar-
row and thereby inhibit cellular migration to periphery and hinder the pro-
motion of downstream inflammatory atherosclerosis [21••, 100, 110]. Multi-
ple randomized clinical trials have investigated the effect of anti-inflammatory
therapies on vascular inflammation. Statins are the best studied agents and have
been shown to significantly reduce arterial inflammation as well as the inci-
dence of future cardiovascular events, perhaps independent of their lipid-
lowering effects [97, 111, 112]. In 2018, results from the CANTOS trial
(Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) showed that
independent of cholesterol-lowering therapies, anti-inflammatory treatment
with canakinumab significantly reduced the rate of recurrent CVD via
interleukin-1β inhibition [98••]. Currently, several other anti-inflammatory
agents with different mechanisms or targets are under investigation. Ultimately,
these and other agents may have a role for primary and secondary prevention in
individuals with greater psychosocial stress.
In addition to pharmacologic therapies, non-pharmacologic interventions (e.g.,
mindfulness-based stress reduction, meditation, cognitive behavioral therapy)
23 Page 10 of 17 Curr Treat Options Cardio Med (2019) 21: 23

either in isolation or in combination with other therapies (e.g., pharmacological,

education, exercise) have recently gained attention [113, 114•]. For example, in
one study, yoga was more effective at diminishing CVD risk compared to other
lifestyle modification interventions with an effect comparable to smoking cessation
[115]. Mindfulness-based stress reduction has been shown to reduce blood pres-
sure in untreated subjects with stage one essential hypertension potentially in part
through effects on the modification of the transcription of key genes involved in
inflammation [116•]. Furthermore, among individuals with clinical CVD who
were enrolled in cardiac rehabilitation, the addition of stress-management training
to cardiac rehabilitation improved stress levels and reduced CVD events beyond
standard treatment in a prospective clinical trial [117]. Stress reduction strategies
may impart this benefit against CVD through positive, lasting, process-specific
changes in key neural centers involved in stress perception and triggering the stress
response. In fact, mindfulness-based stress reduction has resulted in reductions in
perceived stress and amygdalar gray matter density on MRI [118]. While these
pharmacologic and non-pharmacologic therapies show promise for forestalling
CVD consequent to chronic stress, additional carefully designed prospective re-
search is required to evaluate their clinical efficacy.
Future directions
The neurobiology underlying the relationship between stress and CVD has only
begun to emerge, but it already provides fertile ground for future research. Pro-
spective studies should be performed to evaluate the roles of additional candidate
mediating factors in the mechanistic pathway, including SNS activity and gluco-
corticoid levels, and to assess the efficacy of pharmacologic and non-
pharmacologic therapies targeting components of this mechanism, taking into
consideration potential confounders such as substance use, diet, and physical
activity. Further, investigations into the relationship between upstream factors that
contribute to psychosocial stress and amygdalar activity, such as socioeconomic
status and environmental conditions, should be performed. The relationship
between amygdalar activity and other downstream manifestations of CVD should
be examined. Additionally, it is important to evaluate the roles of other neural
centers involved in the response to stress (e.g., hippocampus, hypothalamus,
prefrontal cortex, insula) in this mechanism. Given limitations in the direct mea-
surement of perceived stress in current clinical practice, the role of amygdalar
activity as a quantifiable and potentially modifiable proxy measure of perceived
stress should be investigated. Finally, the impact of genetic and neurobiological
factors in determining an individual’s resilience and susceptibility to disease con-
sequent to psychosocial stress merits investigation. The answers to these important
questions should further inform our understanding of the relationship between
stress and CVD and provide opportunities to improve clinical care.

Conclusions
Psychosocial stress is an unavoidable consequence of daily human life that
associates with an increased risk for CVD events that is on par with the risk from
traditional CVD risk factors. The CVD consequences of stress ultimately depend
upon its degree and duration, as well as on individual differences in responses
Curr Treat Options Cardio Med (2019) 21: 23 Page 11 of 17 23

to a stressor. Recent identification of a neurobiological mechanism in humans

that bridges the gap from psychosocial stress to CVD identifies multiple novel
interventions, such as anti-inflammatory medications and stress reduction with
potentially high impact for preventing and treating the adverse CVD effects of
stress. Furthermore, these findings take the next step towards demonstrating a
causal relationship between psychosocial stress and CVD and facilitating the
broad inclusion of therapies against psychosocial stress in CVD prevention and
treatment guidelines.

Funding
This work is supported in part by the following grants: AHA 18CDA34110366 and National Center for
Advancing Translational Sciences NIH KL2TR002542 (MTO) and NIH/NHLBI P01HL131478 (AT).

Compliance with Ethical Standards

Conflict of Interest
The authors declare that they have no conflicts of interest.

Human and Animal Rights And Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been
highlighted as:
• Of importance
•• Of major importance
1. Selye H. A syndrome produced by diverse nocuous Determinants of Myocardial Infarction Onset Study
agents. 1936. J Neuropsychiatr Clin Neurosci. Investigators. Circulation. 1995;92(7):1720–5.
1998;10(2):230–1. https://doi.org/10.1176/jnp.10.2. 6. Strike PC, Perkins-Porras L, Whitehead DL, McEwan J,
230a. Steptoe A. Triggering of acute coronary syndromes by
2. Steptoe A, Kivimaki M. Stress and cardiovascular dis- physical exertion and anger: clinical and
ease. Nat Rev Cardiol. 2012;9(6):360–70. https://doi. sociodemographic characteristics. Heart.
org/10.1038/nrcardio.2012.45. 2006;92(8):1035–40. https://doi.org/10.1136/hrt.
3. Kloner RA, Leor J, Poole WK, Perritt R. Population- 2005.077362.
based analysis of the effect of the Northridge earth- 7. Watanabe H, Kodama M, Okura Y, Aizawa Y, Tanabe
quake on cardiac death in Los Angeles County, Cali- N, Chinushi M, et al. Impact of earthquakes on
fornia. J Am Coll Cardiol. 1997;30(5):1174–80. Takotsubo cardiomyopathy. JAMA. 2005;294(3):305–
4. Leor J, Poole WK, Kloner RA. Sudden cardiac death 7. https://doi.org/10.1001/jama.294.3.305.
triggered by an earthquake. N Engl J Med. 8. Nabi H, Kivimaki M, Batty GD, Shipley MJ, Britton A,
1996;334(7):413–9. https://doi.org/10.1056/ Brunner EJ, et al. Increased risk of coronary heart dis-
NEJM199602153340701. ease among individuals reporting adverse impact of
5. Mittleman MA, Maclure M, Sherwood JB, Mulry RP, stress on their health: the Whitehall II prospective co-
Tofler GH, Jacobs SC, et al. Triggering of acute myo- hort study. Eur Heart J. 2013;34(34):2697–705.
cardial infarction onset by episodes of anger. https://doi.org/10.1093/eurheartj/eht216.
23 Page 12 of 17 Curr Treat Options Cardio Med (2019) 21: 23

9. Rosengren A, Hawken S, Ounpuu S, Sliwa K, Zubaid M, 17. Jackson M. The stress of life: a modern complaint?
Almahmeed WA, et al. Association of psychosocial risk Lancet. 2014;383(9914):300–1.
factors with risk of acute myocardial infarction in 18. McEwen BS. Protective and damaging effects of stress
11119 cases and 13648 controls from 52 countries (the mediators. N Engl J Med. 1998;338(3):171–9. https://
INTERHEART study): case-control study. Lancet. doi.org/10.1056/nejm199801153380307.
2004;364(9438):953–62. https://doi.org/10.1016/ 19. Brotman DJ, Golden SH, Wittstein IS. The cardiovas-
S0140-6736(04)17019-0. cular toll of stress. Lancet. 2007;370(9592):1089–100.
10. Batty GD, Russ TC, Stamatakis E, Kivimaki M. Psycho- https://doi.org/10.1016/S0140-6736(07)61305-1.
logical distress and risk of peripheral vascular disease, 20. Yeager MP, Pioli PA, Guyre PM. Cortisol exerts bi-
abdominal aortic aneurysm, and heart failure: pooling phasic regulation of inflammation in humans. Dose-
of sixteen cohort studies. Atherosclerosis. Response. 2011;9(3):332–47. https://doi.org/10.
2014;236(2):385–8. https://doi.org/10.1016/j. 2203/dose-response.10-013.Yeager.
atherosclerosis.2014.06.025. 21.•• Tawakol A, Ishai A, Takx RA, Figueroa AL, Ali A, Kaiser
11. Sheps DS, McMahon RP, Becker L, Carney RM, Y, et al. Relation between resting amygdalar activity
Freedland KE, Cohen JD, et al. Mental stress-induced and cardiovascular events: a longitudinal and cohort
ischemia and all-cause mortality in patients with cor- study. Lancet. 2017;389(10071):834–45. https://doi.
onary artery disease: results from the Psychophysio- org/10.1016/s0140-6736(16)31714-7.
logical Investigations of Myocardial Ischemia study. The results of this multi-system 18F-FDG-PET/CT study provide
Circulation. 2002;105(15):1780–4. novel mechanistic insights into the pathway linking stress to
12.•• Stewart RAH, Colquhoun DM, Marschner SL, Kirby subsequent CVD. Increased metabolic activity of amygdala, a
AC, Simes J, Nestel PJ, et al. Persistent psychological key neural center involved in the perception of stress, was
distress and mortality in patients with stable coronary found to be an independent predictor of CVD events via a
artery disease. Heart. 2017;103(23):1860–6. https:// pathway that involves increased bone marrow activity (an
doi.org/10.1136/heartjnl-2016-311097. index of leukopoiesis) and arterial inflammation.
This retrospective longitudinal study investigated the link be- 22. Lagraauw HM, Kuiper J, Bot I. Acute and chronic psy-
tween psychosocial stress and cardiovascular and all-cause chological stress as risk factors for cardiovascular dis-
mortality in individuals with stable CVD. The study identifies a ease: insights gained from epidemiological, clinical
significant association between stress and both outcomes. and experimental studies. Brain Behav Immun.
13. Orth-Gomer K, Wamala SP, Horsten M, Schenck- 2015;50:18–30. https://doi.org/10.1016/j.bbi.2015.
Gustafsson K, Schneiderman N, Mittleman MA. Mari- 08.007.
tal stress worsens prognosis in women with coronary 23. Wang SS, Yan XB, Hofman MA, Swaab DF, Zhou JN.
heart disease: the Stockholm Female Coronary Risk Increased expression level of corticotropin-releasing
Study. JAMA. 2000;284(23):3008–14. hormone in the amygdala and in the hypothalamus in
14. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, rats exposed to chronic unpredictable mild stress.
Catapano AL, et al. 2016 European Guidelines on Neurosci Bull. 2010;26(4):297–303. https://doi.org/
cardiovascular disease prevention in clinical practice: 10.1007/s12264-010-0329-1.
The Sixth Joint Task Force of the European Society of 24. LeDoux JE, Iwata J, Cicchetti P, Reis DJ. Different pro-
Cardiology and Other Societies on Cardiovascular jections of the central amygdaloid nucleus mediate
Disease Prevention in Clinical Practice (constituted by autonomic and behavioral correlates of conditioned
representatives of 10 societies and by invited experts) fear. J Neurosci. 1988;8(7):2517–29.
Developed with the special contribution of the Euro- 25. Bremner JD, Vermetten E, Schmahl C, Vaccarino V,
pean Association for Cardiovascular Prevention & Re- Vythilingam M, Afzal N, et al. Positron emission to-
habilitation (EACPR). Eur Heart J. 2016;37(29):2315– mographic imaging of neural correlates of a fear ac-
81. https://doi.org/10.1093/eurheartj/ehw106. quisition and extinction paradigm in women with
15. Pearson TA, Blair SN, Daniels SR, Eckel RH, Fair JM, childhood sexual-abuse-related post-traumatic stress
Fortmann SP, et al. AHA guidelines for primary pre- disorder. Psychol Med. 2005;35(6):791–806.
vention of cardiovascular disease and stroke: 2002 26. Fox AS, Oler JA, Shelton SE, Nanda SA, Davidson RJ,
update: consensus panel guide to comprehensive risk Roseboom PH, et al. Central amygdala nucleus (Ce)
reduction for adult patients without coronary or other gene expression linked to increased trait-like Ce me-
atherosclerotic vascular diseases. American Heart As- tabolism and anxious temperament in young primates.
sociation science advisory and coordinating commit- Proc Natl Acad Sci U S A. 2012;109(44):18108–13.
tee. Circulation. 2002;106(3):388–91. https://doi.org/10.1073/pnas.1206723109.
16. Anderson TJ, Gregoire J, Pearson GJ, Barry AR, Couture 27. Zhu Y, Du R, Zhu Y, Shen Y, Zhang K, Chen Y, et al. PET
P, Dawes M, et al. 2016 Canadian cardiovascular soci- mapping of neurofunctional changes in a posttrau-
ety guidelines for the management of dyslipidemia for matic stress disorder model. J Nucl Med.
the prevention of cardiovascular disease in the adult. 2016;57(9):1474–7. https://doi.org/10.2967/jnumed.
Can J Cardiol. 2016;32(11):1263–82. https://doi.org/ 116.173443.
10.1016/j.cjca.2016.07.510. 28.•• Osborne MT, Ishai A, Hammad B, Tung B, Wang Y,
Baruch A, et al. Amygdalar activity predicts future
Curr Treat Options Cardio Med (2019) 21: 23 Page 13 of 17 23

incident diabetes independently of adiposity. 40. Arrighi JA, Burg M, Cohen IS, Kao AH, Pfau S, Caulin-
Psychoneuroendocrinology. 2018;100:32–40. https:// Glaser T, et al. Myocardial blood-flow response during
doi.org/10.1016/j.psyneuen.2018.09.024. mental stress in patients with coronary artery disease.
This manuscript reports that heightened amygdalar metabolic Lancet. 2000;356(9226):310–1. https://doi.org/10.
activity measured on 18F-FDG-PET/CT is associated with in- 1016/s0140-6736(00)02510-1.
creased risk of incident type II diabetes independent of adi- 41. Jiang W, Babyak M, Krantz DS, Waugh RA, Coleman
posity and other diabetes risk factors. Further analysis also RE, Hanson MM, et al. Mental stress—induced myo-
demonstrated a synergistic relationship between amygdalar cardial ischemia and cardiac events. JAMA.
activity and adiposity to augment the risk of new subsequent 1996;275(21):1651–6.
diabetes. 42. Steinberg JS, Arshad A, Kowalski M, Kukar A, Suma V,
29. Goyal A, Dey AK, Chaturvedi A, Elnabawi YA, Aberra Vloka M, et al. Increased incidence of life-threatening
TM, Chung JH, et al. Chronic stress-related neural ac- ventricular arrhythmias in implantable defibrillator
tivity associates with subclinical cardiovascular disease patients after the World Trade Center attack. J Am Coll
in psoriasis: a prospective cohort study. JACC Cardiol. 2004;44(6):1261–4. https://doi.org/10.1016/
Cardiovasc Imaging. 2018. https://doi.org/10.1016/j. j.jacc.2004.06.032.
jcmg.2018.08.038. 43. Lee S, Colditz GA, Berkman LF, Kawachi I. Caregiving
30. Huang JL, Chiou CW, Ting CT, Chen YT, Chen SA. and risk of coronary heart disease in U.S. women: a
Sudden changes in heart rate variability during the prospective study. Am J Prev Med. 2003;24(2):113–9.
1999 Taiwan earthquake. Am J Cardiol. 44. Johansen C, Feychting M, Moller M, Arnsbo P, Ahlbom
2001;87(2):245–8 A9. A, Olsen JH. Risk of severe cardiac arrhythmia in male
31. Matsuo T, Suzuki S, Kodama K, Kario K. Hemostatic utility workers: a nationwide Danish cohort study. Am
activation and cardiac events after the 1995 Hanshin- J Epidemiol. 2002;156(9):857–61.
Awaji earthquake. Int J Hematol. 1998;67(2):123–9. 45. Perk J, De Backer G, Gohlke H, Graham I, Reiner Z,
32. Watanabe H, Kodama M, Tanabe N, Nakamura Y, Verschuren M, et al. European guidelines on cardio-
Nagai T, Sato M, et al. Impact of earthquakes on risk for vascular disease prevention in clinical practice (version
pulmonary embolism. Int J Cardiol. 2012). The Fifth Joint Task Force of the European
2008;129(1):152–4. https://doi.org/10.1016/j.ijcard. Society of Cardiology and Other Societies on Cardio-
2007.06.039. vascular Disease Prevention in Clinical Practice (con-
33. Wittstein IS, Thiemann DR, Lima JA, Baughman KL, stituted by representatives of nine societies and by
Schulman SP, Gerstenblith G, et al. Neurohumoral invited experts). Eur Heart J. 2012;33(13):1635–701.
features of myocardial stunning due to sudden emo- https://doi.org/10.1093/eurheartj/ehs092.
tional stress. N Engl J Med. 2005;352(6):539–48. 46. Rudisch B, Nemeroff CB. Epidemiology of comorbid
https://doi.org/10.1056/NEJMoa043046. coronary artery disease and depression. Biol Psychiatry.
34. Hatzaras IS, Bible JE, Koullias GJ, Tranquilli M, Singh 2003;54(3):227–40.
M, Elefteriades JA. Role of exertion or emotion as in- 47. Carney RM, Freedland KE. Depression, mortality, and
citing events for acute aortic dissection. Am J Cardiol. medical morbidity in patients with coronary heart dis-
2007;100(9):1470–2. https://doi.org/10.1016/j. ease. Biol Psychiatry. 2003;54(3):241–7.
amjcard.2007.06.039. 48. Rugulies R. Depression as a predictor for coronary heart
35. Dimsdale JE, Moss J. Short-term catecholamine re- disease. A review and meta-analysis. Am J Prev Med.
sponse to psychological stress. Psychosom Med. 2002;23(1):51–61.
1980;42(5):493–7. 49. Nicholson A, Kuper H, Hemingway H. Depression as
36. Carroll D, Ginty AT, Painter RC, Roseboom TJ, Phillips an aetiologic and prognostic factor in coronary heart
AC, de Rooij SR. Systolic blood pressure reactions to disease: a meta-analysis of 6362 events among 146 538
acute stress are associated with future hypertension participants in 54 observational studies. Eur Heart J.
status in the Dutch Famine Birth Cohort Study. Int J 2006;27(23):2763–74. https://doi.org/10.1093/
Psychophysiol. 2012;85(2):270–3. https://doi.org/10. eurheartj/ehl338.
1016/j.ijpsycho.2012.04.001. 50. Meijer A, Conradi HJ, Bos EH, Anselmino M, Carney
37. Deanfield JE, Shea M, Kensett M, Horlock P, Wilson RM, Denollet J, et al. Adjusted prognostic association
RA, de Landsheere CM, et al. Silent myocardial ischae- of depression following myocardial infarction with
mia due to mental stress. Lancet. 1984;2(8410):1001– mortality and cardiovascular events: individual patient
5. data meta-analysis. Br J Psychiatry. 2013;203(2):90–
38. Burg MM, Jain D, Soufer R, Kerns RD, Zaret BL. Role of 102. https://doi.org/10.1192/bjp.bp.112.111195.
behavioral and psychological factors in mental stress- 51. Jiang W, Alexander J, Christopher E, Kuchibhatla M,
induced silent left ventricular dysfunction in coronary Gaulden LH, Cuffe MS, et al. Relationship of depres-
artery disease. J Am Coll Cardiol. 1993;22(2):440–8. sion to increased risk of mortality and rehospitaliza-
39. Rozanski A, Blumenthal JA, Kaplan J. Impact of psy- tion in patients with congestive heart failure. Arch
chological factors on the pathogenesis of cardiovascu- Intern Med. 2001;161(15):1849–56.
lar disease and implications for therapy. Circulation. 52. Ruo B, Rumsfeld JS, Hlatky MA, Liu H, Browner WS,
1999;99(16):2192–217. Whooley MA. Depressive symptoms and health-related
23 Page 14 of 17 Curr Treat Options Cardio Med (2019) 21: 23

quality of life: the Heart and Soul Study. JAMA. analysis. BMC Neurol. 2015;15:233. https://doi.org/
2003;290(2):215–21. https://doi.org/10.1001/jama. 10.1186/s12883-015-0456-4.
290.2.215. 65. Pan A, Sun Q, Okereke OI, Rexrode KM, Hu FB. De-
53. Gottlieb SS, Kop WJ, Ellis SJ, Binkley P, Howlett J, pression and risk of stroke morbidity and mortality: a
O'Connor C, et al. Relation of depression to severity of meta-analysis and systematic review. Jama.
illness in heart failure (from Heart Failure And a Con- 2011;306(11):1241–9. https://doi.org/10.1001/jama.
trolled Trial Investigating Outcomes of Exercise Train- 2011.1282.
ing [HF-ACTION]). Am J Cardiol. 2009;103(9):1285– 66.• Remch M, Laskaris Z, Flory J, Mora-McLaughlin C,
9. https://doi.org/10.1016/j.amjcard.2009.01.025. Morabia A. Post-traumatic stress disorder and cardio-
54. Kubzansky LD, Kawachi I, Weiss ST, Sparrow D. Anxi- vascular diseases: a cohort study of men and women
ety and coronary heart disease: a synthesis of epide- involved in cleaning the debris of the World Trade
miological, psychological, and experimental evidence. Center Complex. Circ Cardiovasc Qual Outcomes.
Ann Behav Med. 1998;20(2):47–58. https://doi.org/ 2018;11(7):e004572. https://doi.org/10.1161/
10.1007/bf02884448. circoutcomes.117.004572.
55. Albert CM, Chae CU, Rexrode KM, Manson JE, This observational prospective cohort study reports an inde-
Kawachi I. Phobic anxiety and risk of coronary heart pendent association between PTSD and CVD events in first
disease and sudden cardiac death among women. Cir- responders who participated in cleaning of the debris of the
culation. 2005;111(4):480–7. https://doi.org/10. World Trade Center. There was a higher incidence of MI or
1161/01.Cir.0000153813.64165.5d. stroke during 4-year follow-up among these workers.
56. Roest AM, Martens EJ, de Jonge P, Denollet J. Anxiety 67. Wilbert-Lampen U, Leistner D, Greven S, Pohl T, Sper
and risk of incident coronary heart disease: a meta- S, Volker C, et al. Cardiovascular events during World
analysis. J Am Coll Cardiol. 2010;56(1):38–46. https:// Cup soccer. N Engl J Med. 2008;358(5):475–83.
doi.org/10.1016/j.jacc.2010.03.034. https://doi.org/10.1056/NEJMoa0707427.
57. Janszky I, Ahnve S, Lundberg I, Hemmingsson T. Early- 68. Kario K, Matsuo T, Kobayashi H, Yamamoto K,
onset depression, anxiety, and risk of subsequent cor- Shimada K. Earthquake-induced potentiation of acute
onary heart disease: 37-year follow-up of 49,321 young risk factors in hypertensive elderly patients: possible
Swedish men. J Am Coll Cardiol. 2010;56(1):31–7. triggering of cardiovascular events after a major earth-
https://doi.org/10.1016/j.jacc.2010.03.033. quake. J Am Coll Cardiol. 1997;29(5):926–33.
58. Nabi H, Hall M, Koskenvuo M, Singh-Manoux A, 69. Yamabe H, Hanaoka J, Funakoshi T, Iwahashi M,
Oksanen T, Suominen S, et al. Psychological and so- Takeuchi M, Saito K, et al. Deep negative T waves and
matic symptoms of anxiety and risk of coronary heart abnormal cardiac sympathetic image (123I-MIBG) af-
disease: the health and social support prospective co- ter the Great Hanshin Earthquake of 1995. Am J Med
hort study. Biol Psychiatry. 2010;67(4):378–85. Sci. 1996;311(5):221–4.
https://doi.org/10.1016/j.biopsych.2009.07.040. 70. Lahtinen M, Kiviniemi AM, Junttila MJ, Kaariainen M,
59. Kang HK, Bullman TA, Taylor JW. Risk of selected Huikuri HV, Tulppo MP. Depressive symptoms and
cardiovascular diseases and posttraumatic stress disor- risk for sudden cardiac death in stable coronary artery
der among former World War II prisoners of war. Ann disease. Am J Cardiol. 2018;122(5):749–55. https://
Epidemiol. 2006;16(5):381–6. https://doi.org/10. doi.org/10.1016/j.amjcard.2018.05.006.
1016/j.annepidem.2005.03.004. 71. Kivimaki M, Nyberg ST, Batty GD, Kawachi I, Jokela M,
60. Kubzansky LD, Koenen KC, Jones C, Eaton WW. A Alfredsson L, et al. Long working hours as a risk factor
prospective study of posttraumatic stress disorder for atrial fibrillation: a multi-cohort study. Eur Heart J.
symptoms and coronary heart disease in women. 2017;38(34):2621–8. https://doi.org/10.1093/
Health Psychol. 2009;28(1):125–30. https://doi.org/ eurheartj/ehx324.
10.1037/0278-6133.28.1.125. 72. Fransson EI, Nordin M, Magnusson Hanson LL,
61. Stansfeld SA, Fuhrer R, Shipley MJ, Marmot MG. Psy- Westerlund H. Job strain and atrial fibrillation—results
chological distress as a risk factor for coronary heart from the Swedish Longitudinal Occupational Survey of
disease in the Whitehall II study. Int J Epidemiol. Health and meta-analysis of three studies. Eur J Prev
2002;31(1):248–55. Cardiol. 2018;25(11):1142–9. https://doi.org/10.
62. Hemingway H, Marmot M. Evidence based cardiology: 1177/2047487318777387.
psychosocial factors in the aetiology and prognosis of 73. Endrighi R, Waters AJ, Gottlieb SS, Harris KM,
coronary heart disease. Systematic review of prospec- Wawrzyniak AJ, Bekkouche NS, et al. Psychological
tive cohort studies. Bmj. 1999;318(7196):1460–7. stress and short-term hospitalisations or death in pa-
63. Tofler GH, Stone PH, Maclure M, Edelman E, Davis tients with heart failure. Heart. 2016;102(22):1820–5.
VG, Robertson T, et al. Analysis of possible triggers of https://doi.org/10.1136/heartjnl-2015-309154.
acute myocardial infarction (the MILIS study). Am J 74. Ogilvie RP, Everson-Rose SA, Longstreth WT Jr,
Cardiol. 1990;66(1):22–7. Rodriguez CJ, Diez-Roux AV, Lutsey PL. Psychosocial
64. Booth J, Connelly L, Lawrence M, Chalmers C, Joice S, factors and risk of incident heart failure: the multi-
Becker C, et al. Evidence of perceived psychosocial ethnic study of atherosclerosis. Circ Heart Fail.
stress as a risk factor for stroke in adults: a meta-
Curr Treat Options Cardio Med (2019) 21: 23 Page 15 of 17 23

2016;9(1):e002243. https://doi.org/10.1161/ Hispanic/Latino adults. Ann Epidemiol.

circheartfailure.115.002243. 2015;25(2):84–9. https://doi.org/10.1016/j.
75. Adelborg K, Schmidt M, Sundboll J, Pedersen L, annepidem.2014.11.002.
Videbech P, Botker HE et al. Mortality risk among heart 86. Kumari M, Head J, Marmot M. Prospective study of
failure patients with depression: a nationwide social and other risk factors for incidence of type 2
population-based cohort study. J Am Heart Assoc. diabetes in the Whitehall II study. Arch Intern Med.
2016;5(9). doi:https://doi.org/10.1161/jaha.116. 2004;164(17):1873–80. https://doi.org/10.1001/
004137. archinte.164.17.1873.
76. Rumsfeld JS, Havranek E, Masoudi FA, Peterson ED, 87. Stewart-Knox B, E Duffy M, Bunting B, Parr H, Vas de
Jones P, Tooley JF, et al. Depressive symptoms are the Almeida MD, Gibney M. Associations between obesity
strongest predictors of short-term declines in health (BMI and waist circumference) and socio-demographic
status in patients with heart failure. J Am Coll Cardiol. factors, physical activity, dietary habits, life events, re-
2003;42(10):1811–7. silience, mood, perceived stress and hopelessness in
77. Markovitz JH, Matthews KA, Whooley M, Lewis CE, healthy older Europeans. BMC Public Health.
Greenlund KJ. Increases in job strain are associated 2012;12:424. https://doi.org/10.1186/1471-2458-12-
with incident hypertension in the CARDIA study. Ann 424.
Behav Med. 2004;28(1):4–9. https://doi.org/10.1207/ 88. Aschbacher K, Kornfeld S, Picard M, Puterman E, Havel
s15324796abm2801_2. PJ, Stanhope K, et al. Chronic stress increases vulnera-
78. Guimont C, Brisson C, Dagenais GR, Milot A, Vezina bility to diet-related abdominal fat, oxidative stress,
M, Masse B, et al. Effects of job strain on blood pres- and metabolic risk. Psychoneuroendocrinology.
sure: a prospective study of male and female white- 2014;46:14–22. https://doi.org/10.1016/j.psyneuen.
collar workers. Am J Public Health. 2006;96(8):1436– 2014.04.003.
43. https://doi.org/10.2105/ajph.2004.057679. 89. Mooy JM, de Vries H, Grootenhuis PA, Bouter LM,
79. Brondolo E, Rieppi R, Kelly KP, Gerin W. Perceived Heine RJ. Major stressful life events in relation to
racism and blood pressure: a review of the literature prevalence of undetected type 2 diabetes: the Hoorn
and conceptual and methodological critique. Ann study. Diabetes Care. 2000;23(2):197–201.
Behav Med. 2003;25(1):55–65. https://doi.org/10. 90. McCanlies EC, Araia SK, Joseph PN, Mnatsakanova A,
1207/s15324796abm2501_08. Andrew ME, Burchfiel CM, et al. C-reactive protein,
80. Kibler JL, Joshi K, Ma M. Hypertension in relation to interleukin-6, and posttraumatic stress disorder
posttraumatic stress disorder and depression in the US symptomology in urban police officers. Cytokine.
National Comorbidity Survey. Behav Med. 2011;55(1):74–8. https://doi.org/10.1016/j.cyto.
2009;34(4):125–32. https://doi.org/10.3200/bmed. 2011.03.025.
34.4.125-132. 91. Lampert R, Tuit K, Hong KI, Donovan T, Lee F, Sinha R.
81. Merrill Thomas DMB, Krishna K, Patel KG, Smolderen Cumulative stress and autonomic dysregulation in a
K. Mental health concerns in patients presenting with community sample. Stress. 2016;19(3):269–79.
new or an exacerbation of peripheral arterial disease https://doi.org/10.1080/10253890.2016.1174847.
symptoms: insights from the international portrait 92. Girod JP, Brotman DJ. Does altered glucocorticoid
registry. J Am Coll Cardiol 71(11). doi: https://doi.org/ homeostasis increase cardiovascular risk? Cardiovasc
10.1016/S0735-1097(18)32581-6. Res. 2004;64(2):217–26. https://doi.org/10.1016/j.
82. Aquarius AE, De Vries J, Henegouwen DP, Hamming cardiores.2004.07.006.
JF. Clinical indicators and psychosocial aspects in pe- 93. Huang QH, Takaki A, Arimura A. Central noradrener-
ripheral arterial disease. Arch Surg. 2006;141(2):161– gic system modulates plasma interleukin-6 production
6; discussion 6. https://doi.org/10.1001/archsurg.141. by peripheral interleukin-1. Am J Phys. 1997;273(2 Pt
2.161. 2):R731–8. https://doi.org/10.1152/ajpregu.1997.
83. Lallukka T, Lahelma E, Rahkonen O, Roos E, 273.2.R731.
Laaksonen E, Martikainen P, et al. Associations of job 94. Goebel MU, Mills PJ, Irwin MR, Ziegler MG.
strain and working overtime with adverse health be- Interleukin-6 and tumor necrosis factor-alpha produc-
haviors and obesity: evidence from the Whitehall II tion after acute psychological stress, exercise, and in-
Study, Helsinki Health Study, and the Japanese Civil fused isoproterenol: differential effects and pathways.
Servants Study. Soc Sci Med. 2008;66(8):1681–98. Psychosom Med. 2000;62(4):591–8.
https://doi.org/10.1016/j.socscimed.2007.12.027. 95. Mangos GJ, Walker BR, Kelly JJ, Lawson JA, Webb DJ,
84. Hamer M, Molloy GJ, Stamatakis E. Psychological dis- Whitworth JA. Cortisol inhibits cholinergic vasodila-
tress as a risk factor for cardiovascular events: patho- tion in the human forearm. Am J Hypertens.
physiological and behavioral mechanisms. J Am Coll 2000;13(11):1155–60.
Cardiol. 2008;52(25):2156–62. https://doi.org/10. 96. Eisenach JH, Clark ES, Charkoudian N, Dinenno FA,
1016/j.jacc.2008.08.057. Atkinson JL, Fealey RD, et al. Effects of chronic sym-
85. Isasi CR, Parrinello CM, Jung MM, Carnethon MR, pathectomy on vascular function in the human fore-
Birnbaum-Weitzman O, Espinoza RA, et al. Psychoso- arm. J Appl Physiol (1985). 2002;92(5):2019–25.
cial stress is associated with obesity and diet quality in https://doi.org/10.1152/japplphysiol.01025.2001.
23 Page 16 of 17 Curr Treat Options Cardio Med (2019) 21: 23

97. Singh P, Emami H, Subramanian S, Maurovich-Horvat atherosclerosis. Nature. 2012;487(7407):325–9.

P, Marincheva-Savcheva G, Medina HM et al. Coronary https://doi.org/10.1038/nature11260.
plaque morphology and the anti-inflammatory impact 108. Nezafati MH, Eshraghi A, Vojdanparast M, Abtahi S,
of atorvastatin: a multicenter 18F-fluorodeoxyglucose Nezafati P. Selective serotonin reuptake inhibitors
positron emission tomographic/computed tomo- and cardiovascular events: a systematic review. J Res
graphic study. Circ Cardiovasc Imaging. 2016;9(12). Med Sci. 2016;21:66. https://doi.org/10.4103/1735-
doi:https://doi.org/10.1161/circimaging.115.004195. 1995.189647.
98.•• Ridker PM, Everett BM, Thuren T, MacFadyen JG, 109.• Kim Y, Lee YS, Kim MG, Song YK, Kim Y, Jang H, et al.
Chang WH, Ballantyne C, et al. Antiinflammatory The effect of selective serotonin reuptake inhibitors on
therapy with canakinumab for atherosclerotic disease. major adverse cardiovascular events: a meta-analysis
N Engl J Med. 2017;377(12)):1119–31. https://doi. of randomized-controlled studies in depression. Int
org/10.1056/NEJMoa1707914. Clin Psychopharmacol. 2018. https://doi.org/10.
In this randomized trial, comparing canakinumab with place- 1097/YIC.0000000000000238.
bo among patients with a history of myocardial infarction and This meta-analysis of ten randomized controlled trials showed
elevated high-sensitivity C-reactive protein, it was shown that that the use of selective serotonin reuptake inhibitors in pa-
direct modulation of an inflammatory pathway (i.e., IL-1β tients with depression and prior cardiovascular events signifi-
blockade) was associated with reduced adverse cardiovascular cantly decreased the risk of future myocardial infarctions and
events independent of lipid reduction. This study reiterates the major adverse cardiovascular events overall.
role of inflammation in cardiovascular diseases. 110. Nahrendorf M, Swirski FK. Lifestyle effects on hema-
99. Snyder-Mackler N, Sanz J, Kohn JN, Brinkworth JF, topoiesis and atherosclerosis. Circ Res.
Morrow S, Shaver AO, et al. Social status alters immune 2015;116(5):884–94. https://doi.org/10.1161/
regulation and response to infection in macaques. Sci- circresaha.116.303550.
ence. 2016;354(6315):1041–5. https://doi.org/10. 111. Baigent C, Blackwell L, Emberson J, Holland LE, Reith
1126/science.aah3580. C, Bhala N, et al. Efficacy and safety of more intensive
100. Heidt T, Sager HB, Courties G, Dutta P, Iwamoto Y, lowering of LDL cholesterol: a meta-analysis of data
Zaltsman A, et al. Chronic variable stress activates from 170,000 participants in 26 randomised trials.
hematopoietic stem cells. Nat Med. 2014;20(7):754– Lancet. 2010;376(9753):1670–81. https://doi.org/
8. https://doi.org/10.1038/nm.3589. 10.1016/s0140-6736(10)61350-5.
101. Razzoli M, Nyuyki-Dufe K, Gurney A, Erickson C, 112. Tawakol A, Fayad ZA, Mogg R, Alon A, Klimas MT,
McCallum J, Spielman N et al. Social stress shortens Dansky H, et al. Intensification of statin therapy re-
lifespan in mice. Aging Cell. 2018:e12778. sults in a rapid reduction in atherosclerotic inflam-
doi:https://doi.org/10.1111/acel.12778. mation: results of a multicenter fluorodeoxyglucose-
102. Muscatell KA, Dedovic K, Slavich GM, Jarcho MR, positron emission tomography/computed tomogra-
Breen EC, Bower JE, et al. Greater amygdala activity phy feasibility study. J Am Coll Cardiol.
and dorsomedial prefrontal-amygdala coupling are 2013;62(10):909–17. https://doi.org/10.1016/j.jacc.
associated with enhanced inflammatory responses to 2013.04.066.
stress. Brain Behav Immun. 2015;43:46–53. https:// 113. Tan MP, Morgan K. Psychological interventions in
doi.org/10.1016/j.bbi.2014.06.201. cardiovascular disease: an update. Curr Opin Psychi-
103. Gray TS, Bingaman EW. The amygdala: corticotropin- atry. 2015;28(5):371–7. https://doi.org/10.1097/yco.
releasing factor, steroids, and stress. Crit Rev 0000000000000181.
Neurobiol. 1996;10(2):155–68. 114.• Levine GN, Lange RA, Bairey-Merz CN, Davidson RJ,
104. Kalin NH, Shelton SE, Davidson RJ. The role of the Jamerson K, Mehta PK et al. Meditation and cardio-
central nucleus of the amygdala in mediating fear and vascular risk reduction: a scientific statement from the
anxiety in the primate. J Neurosci. American Heart Association. J Am Heart Assoc.
2004;24(24):5506–15. https://doi.org/10.1523/ 2017;6(10). doi:https://doi.org/10.1161/jaha.117.
jneurosci.0292-04.2004. 002218.
105. Schaefer SM, Abercrombie HC, Lindgren KA, Larson This consensus statement from the American Heart Association
CL, Ward RT, Oakes TR, et al. Six-month test-retest describes the existing evidence for meditation in the preven-
reliability of MRI-defined PET measures of regional tion of cardiovascular disease. It concludes that meditation
cerebral glucose metabolic rate in selected subcortical may serve as a potentially effective adjunct to guideline-
structures. Hum Brain Mapp. 2000;10(1):1–9. directed therapy for CVD risk reduction and prevention and
106. Drevets WC, Price JL, Bardgett ME, Reich T, Todd RD, recommends design and implementation of further longitu-
Raichle ME. Glucose metabolism in the amygdala in dinal prospective studies to investigate the effect of meditation
depression: relationship to diagnostic subtype and on cardiovascular disease.
plasma cortisol levels. Pharmacol Biochem Behav. 115. Chu P, Pandya A, Salomon JA, Goldie SJ, Hunink
2002;71(3):431–47. MG. Comparative effectiveness of personalized life-
107. Dutta P, Courties G, Wei Y, Leuschner F, Gorbatov R, style management strategies for cardiovascular dis-
Robbins CS, et al. Myocardial infarction accelerates ease risk reduction. J Am Heart Assoc.
Curr Treat Options Cardio Med (2019) 21: 23 Page 17 of 17 23

2016;5(3):e002737. https://doi.org/10.1161/jaha. rehabilitation with stress management training: a

115.002737. randomized, Clinical Efficacy Trial. Circulation.
116.• Bhasin MK, Denninger JW, Huffman JC, Joseph MG, 2016;133(14):1341–50. https://doi.org/10.1161/
Niles H, Chad-Friedman E, et al. Specific tran- CIRCULATIONAHA.115.018926.
scriptome changes associated with blood pressure re- 118. Holzel BK, Carmody J, Evans KC, Hoge EA, Dusek JA,
duction in hypertensive patients after relaxation re- Morgan L, et al. Stress reduction correlates with
sponse training. J Altern Complement Med. structural changes in the amygdala. Soc Cogn Affect
2018;24(5):486–504. https://doi.org/10.1089/acm. Neurosci. 2010;5(1):11–7. https://doi.org/10.1093/
2017.0053. scan/nsp034.
In this single-arm prospective trial, authors provided the first
insights into the molecular mechanisms underlying the bene-
ficial effects of the relaxation response (RR) on hypertension. It
was shown that the RR-induced reduction of blood pressure
Publisher’s Note
was associated with differential expression of genes in a select
Springer Nature remains neutral with regard to juris-
set of biological pathways.
117. Blumenthal JA, Sherwood A, Smith PJ, Watkins L, dictional claims in published maps and institutional
Mabe S, Kraus WE, et al. Enhancing cardiac affiliations.