429

REVIEW

Postgrad Med J: first published as 10.1136/pgmj.2004.028977 on 5 July 2005. Downloaded from http://pmj.bmj.com/ on April 29, 2020 by guest. Protected by copyright.
Psychosocial stress and cardiovascular diseases
S Vale
...............................................................................................................................

Postgrad Med J 2005;81:429–435. doi: 10.1136/pgmj.2004.028977

Fifty five years after the first finding relating mood ventrolateral prefrontal cortical regions are of
particular importance for the generation of
disturbances and cardiovascular diseases, there is still emotional experiences and behaviour in response
debate on the formation of a cogent conception embracing to these stimuli and they probably congregate the
all the fragments of insight within the various aspects neural efferent activation that links the perceived
psychosocial problem with the ‘‘stress response’’
relating psychosocial stress to cardiovascular diseases. The that will finally cause, among other somatic
clinical comorbidity is empirically evident, but there are responses, the cardiovascular disease (CVD).10
ambiguous research results limiting the value of the
Peripheral pathophysiological mechanisms
proposed pathophysiological mechanisms. Psychosocial The main mechanisms linking the acute and
stress represents here any event that relates psychological intense mental stress to CVD consist in a rapid
phenomena to the social environment and to the associated increase in arterial pressure and heart rate by
means of increased sympathetic activity and
pathophysiological changes. Stress denotes the external or vagal withdrawal coupled with transitory
environmental factors to which people are exposed, as well endothelial dysfunction, and atherothrombotic
as the behavioural or biological reaction to it (response activation.11 In addition, there is also a brief
activation of the hypothalamus-pituitary-adrenal
that some authors call ‘‘distress’’). Cardiovascular diseases (HPA) axis with modifications in the immune
will be considered here only when being the consequence state (reviewed below, in the section of chronic
of chronic inflammatory disease of arteries stress). A brief description of the central patho-
physiological changes during acute stress will be
(atherosclerosis).The question is: Are there explained:
pathophysiological reliable mechanisms relating (1) Sympathetic activation mediates the
psychosocial stress to the development of cardiovascular increase in arterial pressure and heart rate
causing a higher demand of oxygen in the
diseases? myocardium.12 The endothelium dependent
........................................................................... vasodilatation secondary to increased shear
stress (resulting from the augmented blood flow)
is reduced in atherosclerosis, an effect that may
underlie the susceptibility of people with psy-
chosocial stress (PSS) to the augmented sympa-
ACUTE PSYCHOSOCIAL STRESS AND thetic tone.13 Moreover, it has been shown that
CARDIOVASCULAR DISEASES impaired vascular endothelium responses may
The consensus view is that high intensity mental predispose blood vessels to spasm.14 Hence, the
stress may be a trigger of transient myocardial paradoxical vasodilatation response to norepi-
ischaemia, myocardial infarction, ventricular nephrine (NE) in coronary arteries, which is
arrhythmia, and sudden cardiac death.1 2 For mediated by the endothelium (by nitric oxide
example, after an earthquake, the number of overriding the NE vasoconstriction),15 does not
hospital admissions for acute myocardial infarc- occur in patients with atherosclerotic endothelial
tion increases by about 35%.3 Anger and hostility damaged responses.
can also contribute to atrial fibrillation.4 Recent (2) Short term sympathetic activation by
researches show that the association sustains mental stress, physical exercise, or catechola-
only for anger, but not for hostility, and only in mine infusions induces activity of blood clotting
men.4 5 This effect occurs in patients with factors and platelets. b2 adrenergic receptor
....................... previous ischaemic heart disease.6 7 Type A sensitivity secondary to increased plasma cate-
personality is not related to ventricular fibrilla- cholamine activity may mediate this pro-coagu-
Correspondence to: tion or atherosclerosis.4 On the one hand, lant response to acute stressors.16 Thereby, the
Dr Salvador Vale, platelet aggregability occurring during emotional
Departemanto de reacting with anger can also detonate stroke8
Investigación, Indesalud, although the association is only true for young stress may generate micro-circulatory occlusive
Calle 14 por 49, Altos men with increased cholesterol concentrations. effects.17 This clustering of thromobotic risk
Hospital Manuel Campos, On the other hand, hostility associated to factors goes from an increase of plasminogen
Colonia Centro, 24010,
Campeche, Mexico; depression can also be related to stroke.9
svalemayorga@yahoo. A neural net participates in the regulation of Abbreviations: CVD, cardiovascular disease; PSS,
com.mx the somatic responses to emotion. The ventral psychosocial stress; SNS, sympathetic nervous system;
striatum, dorsomedial nucleus of the thalamus, HPA, hypothalamo-pituary-adrenal; CRF, corticotrophin
Submitted releasing factor; GR, glucocorticoid receptor; IL,
21 September 2004 amygdale, and anterior insula seem to be interleukin; TNFa, tumour necrosis factor a; VCAM,
Accepted3December2004 important for the identification of emotionally vascular cell adhesion molecule; COX 2, cyclooxygenase
....................... salient stimuli. However, the ventromedial and 2

www.postgradmedj.com
430 Vale

activator inhibitor preventing fibrinolysis to an increased proportionality) generates several molecular cascades mod-
fibrinogen activity, providing a plausible link between bio- ifying the immune state of the organism. PSS reactions start

Postgrad Med J: first published as 10.1136/pgmj.2004.028977 on 5 July 2005. Downloaded from http://pmj.bmj.com/ on April 29, 2020 by guest. Protected by copyright.
behavioural factors and coronary artery disease.18 in the brain and their consequences are labelled ‘‘stress
(3) Endothelial dysfunction reduces nitric oxide (NO) in response’’. Here, brain controlled centrifugal pathways such
the vascular wall.19–21 The reduced endothelial NO may also as the HPA axis and the sympathetic nervous system (SNS)
cause the production of the ‘‘tissue factor’’, a molecule that in are activated. These sub-systems discharge glucocorticoids
the disrupted atherosclerotic plaques induces prothrombotic and catecholamines respectively. The HPA and SNS pathways
changes.22 Moreover, circulating endothelin 1 concentrations are interconnected and the activation of one of them modifies
are raised in hypertensive patients with a high risk profile for the other (fig 1).
CVD, and might favour the development of acute vascular However, downstream signals (the triggers) converting
damage. This phenomenon can be prevented by selective PSS into cellular dysfunction and finally into vascular disease
endothelin A receptor antagonism.23 are still largely unknown. Nevertheless, recent data have
showed interplay among stress released corticotrophin
CARDIOVASCULAR DISEASES WHEN THE PSS releasing factor (CRF) and sympathetic nerve responses to
PERSISTS stress. The finding that there is an adrenergic signalling
Many everyday adverse life situations have been taken into pathway that explains the rapid increase in activation of the
consideration as possible precursors of CVD. In this way, nuclear factor kB (NFkB) in peripheral blood mononuclear
hopelessness and pessimism (being the expression of a cells shortly after exposure to PSS (see below), may be the
depressive disease or as the consequence of any life link among PSS to mononuclear cell activation, the subse-
condition) are associated with an increased risk of mortality quent changes in the immune system, and the final
related to arteriosclerosis. Severe hopelessness increases the cardiovascular damage.
risk of having a fatal ischaemic heart disease.24 In the case of
cerebrovascular disease, (although with different risk factors HPA AXIS IN THE STRESS RESPONSE 3 9 – 4 4
when compared with CVD, derived from different haemody- Overview
namical conditions) self reported high stress intensity was Centrally, mental stress causes cognitive and emotional
associated with the risk of stroke, even though the statistical modifications. Centrifugally, as the hypothalamus is an
results do not provide strong evidence of independent risk efferent branch of the visceral brain, it is sensitive to
factors for fatal stroke. Because of the space limitation, a brief information from the periphery and it integrates this
outline of reports on depression, anxiety, some personality information with the internal environment. The main
traits, absence of social support, etc, in relation to the component and the coordinator of the HPA system is the
development of CVD, is presented in table 1.25 CRF. The hypothalamus influences the pituitary gland
through several polypeptides, called group releasing factors.
Peripheral pathophysiological mechanisms Among them, the CRF controls the release of corticotropin
During the acute PSS reactions, patients should have (ACTH) from the anterior pituitary gland, which acts
previous atherosclerotic vascular damage because of their systemically. The final result of HPA axis activation is the
vulnerability. During chronic PSS, the CVD appears as a release to circulation of glucocorticoids from the adrenal
consequence of the psychosocial insult (sometimes concur- cortex.
ring with other somatic risk factors). Commonly, PSS
presents itself in clusters. Poverty, a known risk factor for Cortisol and glucocorticoid receptors
stress, is an example of the cumulative burden that may During stress, the increased concentrations of glucocorticoids
overcome human capacity of tolerance. It may exert its effects (cortisol in humans) have important immunosuppressive
by creating not only non-satisfactory conditions for living, effects on the lymphoreticular system and antiallergic and
family disruption, unemployment, and bad/hostile neigh- anti-inflammatory effects as well. In leucocytes, macro-
bourhoods, but by promoting unhealthy activities like misuse phages, lymphocytes, and in various target tissues, glucocor-
of alcohol or recreational drugs use, proneness to crime, and ticoids decrease cytokines and other molecules that mediate
other risky behaviours. On the biological side, malnutrition the inflammatory reactions. Raised cortisol concentrations
during poverty can produce depression,37 38 with a synergistic are down regulated through the hypothalamic glucocorticoid
effect for stress responses. receptors (GRa), which when activated, suppress CRF, ACTH,
The mental suffering experienced during chronic PSS and cortisol. There are, at least, two GR subtypes: the high
(irrespective of their objective or subjective sources and their affinity GRa receptors, and the very low affinity GRb

Table 1 Chronic psychosocial stress associated with cardiovascular diseases

PSS associated to CVD Mediator mechanisms proposed References

Work stress
High effort and few reward Increased BMI and increased cholesterol 26, 27
concentration
Exhaustive coping style (competitive) Impaired fibrinolytic capacity 28
Home stress
Marital dissolution in women Mental stress no otherwise specified 29
Caregiving for a spouse with dementia Mental stress no otherwise specified 30
Social solation (and self neglect) Hyperfibrinogenaemia and hypercortisolism 31–33
Low income (poverty) Blunted serotonergic responsivity. 34, 35
Chronic emotional disorders
Anxiety Low grade inflammation and atherosclerosis 25
Hopelessness* Autonomic dysfunction (vagal withdrawal) 36
Hopelessness plus depression Low grade inflammation and atherosclerosis. 24
Depression Low grade inflammation and atherosclerosis 25

*Hopelessness may reflect a current or past ‘‘life situation’’ or can be a symptom of depression. PSS, psychosocial
stress; CVD, cardiovascular diseases; BMI, body mass index.

www.postgradmedj.com
Markers of CVD fragility during PSS are needed 431

Figure 1 ‘‘The components of the

‘‘stress response’’. Both arms of the

Postgrad Med J: first published as 10.1136/pgmj.2004.028977 on 5 July 2005. Downloaded from http://pmj.bmj.com/ on April 29, 2020 by guest. Protected by copyright.
Psychosocial stress/ stress reaction may cause chronic
central brain diseases in which inflammatory
activation components (like endothelial
Acute reactions
dysfunction and consequent
to stress atherosclerosis) are the
pathophysiological core. Broken line in
bold corresponds to inhibition;
Chronic Centrifugal Catecholamines continuous lines represent activation.
Corticotropin, NFkB, nuclear factor kB; IL6, interleukin
hippocampal brain
ACTH, cortisol 6; TNFa, tumour necrosis factor a; CRP,
atrophy pathways
C reactive protein.

Atrophy of Macrophages
other neural Liver
tissues
NF-kB, IL-6, TNFα

Low grade
inflammation "Sickness
syndrome"

IMMUNODEFICIENCY Acute phase

response: CRP,
fibrinogen,
Chronic diseases
endothelial
with inflammatory
dysfunction,
components:
etc.
atherosclerosis,
Insulin resistance depression, diabetes,
Visceral obesity etc.

receptors.45 The GRb can be up-regulated in some cases of hippocampus also modifies the HPA reactivity, even its
peripheral HPA dysfunction leading to cortisol resistance. The functional damages lead to an increased glucocorticoid
consensus view is that this situation occurs in glucocorticoid release.43
resistant asthma, chronic sinusitis, ulcerative colitis, among
other disorders.39 46 Sometimes, the depressive disease may Cortisol, abdominal obesity, and atherogenesis
present cortisol resistance as some previously depressed During acute PSS, a rapid feedback inhibition of ACTH occurs
patients suffer with chronic amplification of their inflamma- in the brain and pituitary. However, chronic cortisolaemia in
tory responses thereafter.47 Prolonged or repetitive exposure the stress range redistributes stored energy toward an intra-
to proinflammatory cytokines also increases the activity of abdominal distribution, not only by its hyperphagic and
the low affinity GRb, promoting glucocorticoid resistance.46 antithermogenic effects but also because visceral adipose
tissue has more cells per mass units, higher blood flow, and
Glucocorticoids and immune suppression more glucocorticoid receptors. Hence, glucocorticoids affect
Glucocorticoids’ effects are produced, in part, by controlling abdominal fat to a greater extent than subcutaneous adipose
the expression of specific target genes. In this way, they tissue. In turn, visceral obesity represents an important risk
down-regulate multiple inflammatory cytokines, some che-
factor associated with atherosclerosis as the intra-abdominal
mokines, and some adhesion molecules. Most of these effects
adipose tissue is an important source of the pro-inflamma-
are mediated by the inhibition of the transcription factor
tory cytokine interleukin 6 (IL6).51 However, specific genetic
NFkB by several molecular mechanisms (reviewed
background may accentuate this visceral fat accumulation in
below).39 46
some people exposed to stress. Additionally, released cortisol
Glucocorticoids excess in neural tissues in the long term will cause: (a) salt retention, (b) insulin
During chronic stress, the resultant hypercortisolaemia in resistance, (c) visceral fat syndrome, and (d) higher
addition to its effects on metabolic and anti-inflammatory concentrations of LDL cholesterol. Most of the effects of
processes have also extensive modulatory effects on neuro- these changes are also atherogenic.52
transmission and in neural cell survival. In this case, there is
an association between the excess in glucocorticoids and Cortisol, aging, and cytokines
hippocampal atrophy.48 Memory and learning deficits that Aging causes increased responses to stress, characterised by
may appear late in depression, where hypercortisolaemia is higher levels of glucocorticoids. One of the causes is the
frequently present, are related partially to it. Other cognition concurrently increased production of IL6, generated and
deficits are related to damage of the frontal lobe neurons, sustained by many chronic life stressors as will be seen in the
which are highly sensitive to the effects of glucocorticoid following section. This situation contributes in an important
excess.49 It is also important to mention that in some manner to the age related diseases.53 Furthermore, under
depressive patients the hippocampal atrophy do not regress neuroendocrine stimulation, IL6 is released by activation of
completely after remission,50 justifying the speculation that b2 adrenergic receptors.54 This cytokine is comparatively
an early re-establishment of normal HPA activity in mood resistant to cortisol suppression, in contrast with other
disorders, before permanent deficits in neural functions proinflammatory cytokines, such as TNFa and IL1, which
occur, may be an important therapeutic goal. Finally, as the are down-regulated by glucocorticoids.

www.postgradmedj.com
432 Vale

SNS AXIS IN THE STRESS RESPONSE 3 9 – 4 4 Increased CRP consequences

Overview During the acute phase reaction, CRP is directly implicated in

Postgrad Med J: first published as 10.1136/pgmj.2004.028977 on 5 July 2005. Downloaded from http://pmj.bmj.com/ on April 29, 2020 by guest. Protected by copyright.
The second arm of the stress response is the ‘‘locus coeruleus/ CVD risk: (a) promoting secretion of inflammatory mediators
norepinephine system’’ within the central nervous system. Its by vascular endothelium, (b) increasing the expression of cell
activation causes central sympathetic discharge and periph- adhesion molecules, (c) facilitating the uptake of low density
eral sympathetic outflow. During stress, the CRF stimulates lipids into macrophages, a situation that decreases the
the production of tyrosine hydroxylase, the rate limiting endothelial nitric oxide synthase expression, (d) inhibiting
enzyme in the synthesis of norepinephrine, which is then endothelial progenitor cells differentiation, survival, and
synthesised centrally and secreted (while adrenaline (epi- function, and (e) activating vascular smooth cells. The acute
nephrine) is secreted in the adrenal medulla). During stress, phase reactants, because of the resultant low grade chronic
both molecules are invariably present in circulation. inflammation increase the risk of atherosclerotic complica-
Moreover, the primary (bone marrow, thymus) and second- tions.56–58 Moreover, CRP can be produced locally by the
ary (spleen, lymph nodes, etc) lymphoid tissues are inner- damaged endothelium, promoting inflammatory changes in
vated by SNS centrifugal pathways; hence, stress responses situ.57 59
are transmitted to lymphoid tissue also by neurogenical
channels. Inhibiting loop of the SNS activation
TNFa, IL1, and IL6, during its circulation and in a synergistic
manner, activate the HPA axis (despite block from the blood-
Rapid translocation of the NFkB molecule brain barrier).39 Then, the HPA will generate signals toward
During stress, the cardiovascular and cerebrovascular systems the SNS, down-regulating it. Inflammatory molecules may
are the immediate targets of catecholamines. However, also activate the HPA axis indirectly, by brain noradrenergic
among the plethora of the adrenergic biological effects, the pathways.
SNS starts some proinflammatory molecular cascades, which
are more evident during chronic stress. For example, in
circulating monocytes starts the norepinephrine dependent DEREGULATION OF THE HPA AND SNS
adrenergic activation of the transcription factor NFkB55 The stress response is tightly autocontrolled for: (a) preser-
which, in turn, activates the nuclear transcription of several ving the equilibrium between immunosuppression and
proinflammatory cytokines such as TNFa, IL1, IL6, among inflammation, (b) obtaining the appropriate and opportune
suppression of both arms after the tissular injury has been
others (see the NFkB section, below). Finally, during chronic
resolved, and (c) returning to the physiological levels from
stress the proinflammatory reactivity from the SNS can
the previously increased concentrations of cortisol and
surpass the immunosuppressant effects of the HPA axis
catecholamines. However, during chronic PSS, the tissular
activity.
damage required for the classic stress response does not exist
and the reaction is orchestrated in the brain without physical
Th2 subset activation and ‘‘natural killer’’ cells down- injury. This situation results that the equilibrium of the
regulation response sometimes does not regress. Consequently, the
SNS activates immune responsive cells: (a) from the innate immunosuppressant or the inflammatory sides of the
immune system such as monocytes/macrophages and den- response may dominate the scenery. How and when exactly
dritic cells, and (b) a T helper lymphocytes subset from the this deregulation presents itself, is still a poorly understood
adaptive immune system. In this T helper compartment, matter.
there is a shift toward the T helper 2 (Th2) subclass derived On the one hand, an excessive HPA response during
from the inhibitory activity of catecholamines on the T helper chronic PSS can imitate the hypercortisolaemic state,
1 (Th1) cells (as b adrenoceptors are expressed on Th1 cells increasing the susceptibility to certain infectious agents,
but not on Th2 cells). However, because the response to b neoplasms, and increasing the resistance to autoimmune or
adrenoceptors wanes during monocyte maturation, in some inflammatory diseases. This HPA hyperreactivity can be
compartments of the body the a adrenoceptor mediated present in: (a) the visceral obesity and the associated
effect of catecholamines may become transiently dominant, syndrome of insulin resistance, and (b) the response to HIV
increasing Th1 cellular immune responses. infection (during acute and subacute stages). The hippocam-
In the short term, catecholamines mobilise the natural pal atrophy occurring late in the depressive disease is also
killer cells from storage areas, whereas in the long term they considered as a consequence of glucocorticoid excess.
reduce their circulating amounts. As CRF also decreases the On the other hand, the stress induced hypoactivity of the
natural killer activity independently of the adrenocortical HPA (acquired glucocorticoid resistance) can be present as
activation, the result is a drastic diminution of these cells the resultant of the intense or repetitive action of the
responses. proinflammatory molecules, or during the severe activation
of the innate and adaptive immunity surpassing the
inhibitory loops, similar to that which occurs during the
Generation of the sickness syndrome and the acute acute respiratory distress syndrome60; only on rare occasions
phase reaction is it produced by glucocorticoid receptors that are genetically
Circulating TNFa, IL1, and IL6 (and the family of other defective. Other stress independent human diseases are
proinflammatory cytokines such as interferon gamma, etc) facilitated by a decreased HPA sensitivity: (a) rheumatoid
also cause a systemic syndrome: anorexia, fatigue, asthenia, arthritis, (b) corticosteroid resistant asthma, (c) acquired
somnolence, and fever, collectively identified as the sickness immunodeficiency syndrome in terminal stages, (d) degen-
syndrome. Moreover, these cytokines activate the synthesis erative osteoarthritis, (e) Crohn’s disease, (f) systemic lupus
(in the hepatic and other tissues) of the acute phase proteins erythematosus, among others.61 In all diseases mentioned
(C reactive protein (CRP), cell adhesion molecules, fibrino- above, a sustained PSS has severe deleterious effects.
gen, etc). These molecules will cause another adaptive Conversely, a hypernoradrenergic function (although
phenomenon referred as the acute phase reaction. These coupled to hypercortisolism) has been described in the
biological responses are commonly seen when stress is the melancholic depression (also called atypical depression, with
consequence of an inflammatory or an infectious disease, hypersomnia, hyperphagia, letargy, and fatigue).62 In the case
although also appear during PSS. of the metabolic syndrome, there is also hyperactivity in both

www.postgradmedj.com
Markers of CVD fragility during PSS are needed 433

arms of the stress response, but with a clear (indirect) QUANTIFYING PROBLEMS IN PSS
sympathetic predominance.63 Specific pathological situations The construction of a comprehensive instrument that may

Postgrad Med J: first published as 10.1136/pgmj.2004.028977 on 5 July 2005. Downloaded from http://pmj.bmj.com/ on April 29, 2020 by guest. Protected by copyright.
where the SNS response to PSS can be hypoactive have not quantify the PSS should range from emotion perceptions to
been described; however, it is reasonable to speculate that behaviour in response to these stimuli. As not all people
patients with poor SNS sensitivity behave, under stress under PSS have the same somatic response and the causes of
conditions, like HPA hyper-reactors. the PSS are heterogeneous, it has been difficult to design any
psychological scale that may reflect the overall facets of this
NFKB SYSTEM IN PSS RESPONSE problem. Moreover, multiple factors influence response to
Overview stress. These include features such as duration of the
During the past decade, the transcription factor NFkB has emotional response, timing and causation, and features of
been shown crucial for the induction of genes involved in the sufferers, such as age, intelligence, prior exposure to
inflammation and in diseases originated from chronic traumas, and pre-existing psychiatric disorders. Expected
activation of the immune system. Most immunoregulatory responses to PSS must be also outlined for each develop-
genes that code for proinflammatory molecules contain NFkB mental stage. To exemplify this complexity, the comprehen-
sites in their regulatory or promoter regions. Examples of sive series on scales of Myers and colleagues, (related to
some NFkB regulated genes are: vascular cell adhesion emotional perceptions/reactions) can be reviewed.69–72
molecule (VCAM)1, E-selectin, tissue factor, plasminogen Therefore, for the moment, a unifying tool that may detect
activator inhibitor (PAI)1, cyclooxygenase 2 (COX2), and those people who are being damaged by PSS awaits the
inducible nitric oxide synthase (iNOS), plus several proin- identification and validation of some biological variables
flammatory cytokines (such as interferon gamma, IL1a, IL1b, (biomarkers) that can point out people with CVD fragility
IL2, IL11, transforming growth factor b, and RANTES. during PSS.
Importantly, IL1, a master regulator cytokine, is often
produced at the site of inflammation and then activates DEPRESSION AS AN EXAMPLE OF CHRONIC PSS
other cytokines including some chemokines). Few human diseases are as painful as depression. Reasons go
In unstimulated cells, NFkB molecules are present in the from its inherent subjective suffering to its chronicity and
cytoplasm in an inactive form, associated with members of insufficient recognition and treatment. Fortunately, success-
other family of proteins called inhibitors of kB (IkB). Under ful therapeutic regimens exist (psychotherapy, drugs, or
stimulation, IkB is degraded and allows the NFkB to migrate both) and when properly applied, most patients improve,
to the nucleus to exert its effects on gene regulation. although they are frequently forced to take drugs indefinitely
Activation of the NFkB is a transient phenomenon because so as to prevent relapses. However, this picture is not always
it is up-regulated on demand for a limited period of time and true. Many depressed patients continue aging with cognitive
then shut down. Prolonged activation may occur through damage or vascular damage in their brains related to their
persistence of their stimulator agents, or through impairment chronic depressive states. Depression also increases the
of the mechanisms for down-regulation.64 65 mortality derived from CVDs.73 Hence, we know that
depression is a silent killer, but how and why? Can a
NFkB activation and endothelial dysfunction deregulated stress response be one of the culprits?
During mental stress, noradrenergic signalling on peripheral The most conservative answer is affirmative. There are
blood mononuclear cells (through the b1 adrenergic recep- enough data to include depression among other chronic
tors) begins a rapid but brief activation of the transcription diseases with inflammatory components, as we do now with
factor NFkB (activation that terminates itself by inducting obesity or diabetes. On the one hand, many research articles
the inhibitory molecule IkBa by the b2 receptors among other prove the existence of molecular markers relating depression
mechanisms), changing the immune state of monocytes to atherosclerosis: (a) chronic endothelial activation,73
towards activation.55 58 It is probable but not yet proved that monocyte activation,74 high CRP levels, and increased
endothelial cells also react rapidly with the NFkB activity inflammatory responses after a depressive episode, among
during mental stress, as occurs with the NFkB system in the others.47 75 On the other hand, about 50% of depressed
brain cortex as a result of acute and/or chronic stress.66 patients are hypercortisolaemic, a situation that also may
culminate in atherosclerosis. Why then, despite the weight of
NFkB autoregulatory loop accumulated evidence, have some recent reports76 77 not
On the one hand, activation of NFkB occurs under the found an association between depression and mortality?
following circumstances (among others): (a) increased Intensity of immune responses to stress can be of different
oxidative stress, (b) dyslipidaemia, (c) hyperhomocysteinae- magnitude among different patients. It has been shown that
mia, (d) by the action of several infectious agents (Chlamydia early attacks to the immune system led to immune hyper-
pneumoniae, or cytomegalovirus for example). On the other reactivity thereafter.47 78 Thereby, it is reasonable to suppose
hand, there are several types of inhibitors of NFkB such as that there are subgroups of depressed patients with intense
the antioxidants and radical scavengers (N-acetylcysteine immune activation. These patients may have a high set point
and analogues) or resveratrol (a polyphenolic compound for shutting down the stress response (or a deregulated stress
identified as a constituent of the red wine). Also, the fatty response) forming an arteriosclerosis prone subgroup.
acids of the omega-3 family inhibit NFkB activation via a Therefore, if we continue studying un-stratified depressed
peroxisome proliferators activated receptor a dependent patients to disclose the effects of depressive related stress on
pathway. There are also molecules that increase the activity CVD, many investigations will show inconclusive or negative
of the NFkB specific inhibitory factor, IkBa.64 67 For instance, results. Perhaps the already cited markers of inflammation in
the induced COX2 generates substances called cyclopente- depressive patients may be used in future studies for a better
nones, preserving the integrity of the IkBa; also curcumin or selection of the high risk atherosclerotic prone depressive
the epoxyeicosatrienoic acids have this property. The salicy- patients.73–75
lates (in very high doses), binding to some kinases (IKK2),
up-regulate the IkBa.64 67 The statin family can also stabilise PSS AND CVD: THE PROBLEM OF THE NEGATIVE
IkBa.68 Also the aminosalicylate drug mesalamine down- REPORTS
regulates NFkB by other unknown mechanism besides the This review summarises the scientific basis underlying the
upregulation of the IkBa inhibitory molecule. relation between PSS and CVD. Its limitations are

www.postgradmedj.com
434 Vale

represented by the selective review of a complex area of endothelial dysfunction. (3) Should we still prescribe drugs
human behaviour and biology. Nevertheless, we have now such as the non-steroidal anti-inflammatory agents or

Postgrad Med J: first published as 10.1136/pgmj.2004.028977 on 5 July 2005. Downloaded from http://pmj.bmj.com/ on April 29, 2020 by guest. Protected by copyright.
enough hard data to accept that the PSS is associated to statins? Although these substances may be beneficial for
CVD; but, what percentage of patients with PSS will have some stressed people, because of the uncertain knowledge
an important or fatal CVD problem? In the case of acute about patients that can be undoubtedly helped, we are not
PSS, authors do not disagree, probably because outcomes yet in the possibility of advising their general use. (4)
take place in people already damaged by arteriosclerosis. Patients with other risk factors for CVD (diabetes, hyperten-
The problem exists during chronic PSS, where negative sion, obesity, etc) in addition to PSS, should be advised not
reports should be understood before proper clinical only to take the best lifestyles to promote their health, but to
decisions can be adopted. Hence, I propose the following receive the secondary prevention measures for treating their
theoretical approaches: overlapping risk factors for CVD. (5) The PSS is probably a
(1) Rejecting the PSS effects on atherosclerosis because not mediator or moderator risk factor (an intervening causal
all stressed people have deleterious consequences is equiva- variable) among the chain of causal risk factors for CVD.
lent to discarding the risk that being overweight has on CVD, Consequently, specific biological markers to stratify ade-
because some people do not suffer the related consequences. quately PSS patients who are prone to suffering a severe CVD
Unfortunately, this is exposed in conclusions like ‘‘… there is are needed with urgency.
no association between psychological stress and the CVD Funding: none
…’’.76 We can hypothesise that PSS does not predict CVD
Competing interests: none declared
fatalities, but not that there is no association between mental
stress and CVD.
(2) CVD risk factors may cause fatal atherothrombotic REFERENCES
accidents in some diseases, while other risk factors can act as 1 Malzberg B. Mortality among patients with involutional melancholia.
moderators or mediators.79 The unremitting PSS may be Am J Psychiatry 1937;93:1231–8.
2 Yan LL, Liu K, Matthews KA, et al. Psychosocial factors and risk of
located in the second category. hypertension: the coronary artery risk development in young adults (CARDIA)
(3) Fatal outcomes in CVD patients with PSS may be study. JAMA 2003;290:2138–48.
selectively related to the presence of un-modifiable factors 3 Lampert R, Jain D, Burg MM, et al. Destabilizing effects of mental stress on
ventricular arrhythmias in patients with implantable cardioverter-defibrillators.
(as occurs in common inherited abnormalities in blood Circulation 2000;101:158–64.
coagulation). Additionally, there exist subgroups of athero- 4 Eaker ED, Sullivan LM, Kelly-Hayes M, et al. Anger and hostility predict the
sclerotic prone people that can react severely during PSS, development of atrial fibrillation in men in the Framingham offspring study.
such as those with vascular vulnerability acquired by a long Circulation 2004;109:1267–71.
5 Chang PP, Ford DE, Meoni LA, et al. Anger in young men and subsequent
term effect of early prenatal events (programming).80 premature cardiovascular disease: the precursors study. Arch Intern Med
Postnatal growth acceleration can also have a programming 2002;162:901–6.
effect that, interacting with adverse life events situates the 6 Williams JE, Paton CC, Siegler IC, et al. Anger proneness predicts coronary
heart disease risk: prospective analysis from the atherosclerosis risk in
patients in risk for CVD.81 Also, early attacks to the immune communities (ARIC) study. Circulation 2000;101:2034–9.
system lead to immune hyper-reactivity thereafter.47 7 Knox SS, Adelman A, Ellison RC, et al. Hostility, social support, and carotid
artery atherosclerosis in the National Heart, Lung, and Blood Institute family
heart study. Am J Cardiol 2000;86:1086–9.
WHERE DO WE STAND NOW? 8 Williams JE, Nieto FJ, Sanford CP, et al. The association between trait anger
The theme of PSS and CVD is a goal actively pursued in the and incident stroke risk: the atherosclerosis risk in communities (ARIC) study.
Stroke 2002;33:13–20.
scientific literature from past decades until now. However, as 9 Suarez EC. Joint effect of hostility and severity of depressive symptoms on
not all prospective studies have reported a significant relation plasma interleukin-6 concentration. Psychosom Med 2003;65:523–7.
between psychological stress and ischaemic heart disease, a 10 Phillips ML. Understanding the neurobiology of emotion perception:
implications for psychiatry. Br J Psychiatry 2003;182:190–2.
definite direction towards the search of biological markers
11 Lucini D, Norbiato G, Clerici M, et al. Hemodynamic and autonomic
has not been outlined yet. Most international ongoing adjustments to real life stress conditions in humans. Hypertension
researches are still dealing with the demonstration of good 2002;39:184–8.
evidence for the association. This is the case of: (a) the 12 Becker LC, Pepine CJ, Bonsall R, et al. Left ventricular, peripheral vascular,
and neurohumoral responses to mental stress in normal middle-aged men and
INTERHEART study group, or (b) the respective section of women. Reference group for the psychophysiological investigations of
the Framingham study, or the works in different countries: myocardial ischemia (PIMI) study. Circulation 1996;94:2768–77.
(c) Ismail, (d) Bluzhas, (e) Wamala, and many others.82–86 13 Harris CW, Edwards JL, Baruch A, et al. Effects of mental stress on brachial
artery flow-mediated vasodilatation in healthy normal individuals. Am Heart J
2000;139:405–11.
CONCLUSIONS 14 Nabel EG, Ganz P, Gordon JB, et al. Dilation of normal and constriction of
atherosclerotic coronary arteries caused by the cold pressor test. Circulation
Nowadays, we do not know what percentage of patients can 1988;77:43–52.
sustain, despite persistent PSS, a low set point for stopping 15 Feigle EO. The paradox of adrenergic coronary vasoconstriction. Circulation
their immune suppressive/immune activating response. 1987;76:737–45.
16 Wallen NH, Goodall AH, Li N, et al. Activation of haemostasis by exercise,
These people will have few complications derived directly mental stress and adrenaline: effects on platelet sensitivity to thrombin and
from their mental stress. For the others, a deregulated thrombin generation. Clin Sci (Lond) 1999;97:27–35.
response will result. Their consequent disease can be skewed 17 von Kanel R, Bardwell WA, Berry CC, et al. Effect of Beta2-adrenergic
towards immunosuppression or towards the inflammatory receptor functioning and increased norepinephrine on the hypercoagulable
state with mental stress. Am Heart J 2002;144:68–72.
side. Finally, some patients may conserve the equilibrium 18 von Kanel R, Mills PJ, Fainman C, et al. Effects of psychological stress and
between both arms of the stress response, but with an psychiatric disorders on blood coagulation and fibrinolysis: a biobehavioral
abnormally high set point for stopping the response, a pro- pathway to coronary artery disease? Psychosom Med 2001;63:531–44.
19 Behrendt D, Ganz P. Endothelial function: from vascular biology to clinical
atherosclerotic process also (see fig 1). So, several suggestions applications. Am J Cardiol 2002;90:40–8L.
to patients with PSS can be advanced (besides intending to 20 Ganz P, Vita JA. Testing endotelial vasomotor function: nitric oxide, a
help them in reducing it when possible). multipotent molecule. Circulation 2003;108:2049–53.
21 Spieker LE, Hurlimann D, Ruschitzka F, et al. Mental stress induces prolonged
(1) As it is well reported that healthier lifestyle delays or endothelial dysfunction via endothelin-A receptors. Circulation
reduce the atherosclerotic risks, the emphasis on modifying 2002;105:2817–20.
unhealthy habits like smoking, alcoholism, overweight, high 22 Yang Y, Loscalzo J. Regulation of tissue factor expresión in human
fat diet, sedentary life, etc, is of paramount importance for microvascular endotelial cells by nitric oxide. Circulation 2000;101:2144–8.
23 Ferri C, Bellini C, Desideri G, et al. Elevated plasma endothelin-1 levels as an
these patients. (2) Addition of appropriate doses of fish or additional risk factor in non-obese essential hypertensive patients with
omega-3 fatty acids in diet is not harmful and may delay metabolic abnormalities. Diabetologia 1997;40:100–2.

www.postgradmedj.com
Markers of CVD fragility during PSS are needed 435

24 Stern SL, Dhanda R, Hazuda HP. Hopelessness predicts mortality in older middle-aged and elderly subjects with no apparent heart disease. Eur Heart J
Mexican and European Americans. Psychosom Med 2001;63:344–51. 2004;25:363–70.
25 Strike PC, Steptoe A. Psychosocial factors in the development of coronary 57 Blake GJ, Ridker PM. Inflammatory bio-markers and cardiovascular risk

Postgrad Med J: first published as 10.1136/pgmj.2004.028977 on 5 July 2005. Downloaded from http://pmj.bmj.com/ on April 29, 2020 by guest. Protected by copyright.
artery disease. Prog Cardiovasc Dis 2004;46:337–47. prediction. J Intern Med 2002;252:283–94.
26 Kuper H, Singh-Manoux A, Siegrist J, et al. When reciprocity fails: effort– 58 Blake GJ, Rifai N, Buring JE, et al. Blood pressure, C-reactive protein, and risk
reward imbalance in relation to coronary heart disease and health functioning of future cardiovascular events. Circulation 2003;108:2993–9.
within the Whitehall II study. Occup Environ Med 2002;59:777–84. 59 Verma S, Szmitko PE, Yeh ETH. C-reactive protein: structure affects function.
27 Kivimäki M, Leino-Arjas P, Luukkonen R, et al. Work stress and risk of Circulation 2004;109:1914–17.
cardiovascular mortality: prospective cohort study of industrial employees. 60 Meduri GU, Tolley EA, Chrousos GP, et al. Prolonged methylprednisolone
BMJ 2002;325:857–9. treatment suppresses systemic inflammation in patients with unresolving acute
28 Vrijkotte TG, van Doornen LJ, de Geus EJ. Work stress and metabolic and respiratory distress syndrome: evidence for inadequate endogenous
hemostatic risk factors. Psychosom Med 1999;61:796–805. glucocorticoid secretion and inflammation-induced immune cell resistance to
29 Orth-Gomer K, Wamala SP, Horsten M, et al. Marital stress worsens glucocorticoids. Am J Respir Crit Care Med 2002;165:983–91.
prognosis in women with coronary heart disease: the Stockholm female 61 Kino T, Chrousos GP. Tissue-specific glucocorticoid resistance-hypersensitivity
coronary risk study. JAMA 2000;284:3008–14. syndromes: multifactorial states of clinical importance. J Allergy Clin Immunol
30 Lee S, Colditz GA, Berkman LF, et al. Caregiving and risk of coronary heart 2002;109:609–13.
disease in U.S. women: a prospective study, Am J Prev Med 62 Wong ML, Kling MA, Munson PJ, et al. Pronounced and sustained central
2003;24:113–19. hypernoradrenergic function in major depression with melancholic features:
31 Brummett BH, Barefoot JC, Siegler IC, et al. Characteristics of socially isolated relation to hypercortisolism and corticotropin-releasing hormone. Proc Natl
patients with coronary artery disease who are at elevated risk for mortality. Acad Sci U S A 2000;97:325–30.
Psychosom Med 2001;63:267–72. 63 Brunner EJ, Hemingway H, Walker BR, et al. Adrenocortical, autonomic, and
32 Steptoe A, Owen N, Kunz-Ebrecht SR, et al. Loneliness and neuroendocrine, inflammatory causes of the metabolic syndrome: nested case-control study.
cardiovascular, and inflammatory stress responses in middle-aged men and Circulation 2002;106:2659–65.
women. Psychoneuroendocrinology 2004;29:593–611. 64 Collins T, Cybulsky MI. NF-kB: pivotal mediator or innocent bystander in
33 House JS. Social isolation kills, but how and why? Psychosom Med atherogenesis? J Clin Invest 2001;107:255–63.
2001;63:273–4. 65 De Martin R, Hoeth M, Hofer-Warbinek R, et al. The transcription factor NF-
34 Matthews KA, Flory JD, Muldoon MF, et al. Does socioeconomic status relate kappa B and the regulation of vascular cell function. Arterioscler Thromb Vasc
to central serotonergic responsivity in healthy adults? Psychosom Med Biol 2000;20:E83–8.
2000;62:231–7. 66 Madrigal JL, Hurtado O, Moro MA, et al. The increase in TNF-alpha levels is
35 Woodward M, Oliphant J, Lowe G, et al. Contribution of contemporaneous implicated in NF-kappaB activation and inducible nitric oxide synthase
risk factors to social inequality in coronary heart disease and all causes expression in brain cortex after immobilization stress.
mortality. Prev Med 2003;36:561–8. Neuropsychopharmacology 2002;26:155–63.
36 Schwarz AM, Schachinger HH, Adler RH, et al. Hopelessness is associated 67 Yuan M, Konstantopoulos N, Lee J, Hansen L, et al. Reversal of obesity- and
with decreased heart rate variability during championship chess games. diet-induced insulin resistance with salicylates or targeted disruption of Ikk-
Psychosom Med 2003;65:658–61. beta. [Erratum in Science 2002;295:277]. Science 2001;293:1673–77.
37 Bottiglieri T, Laundy M, Crellin R, et al. Homocysteine, folate, methylation, and 68 Wolfrum S, Jensen KS, Liao JK. Endothelium-dependent effects of statins.
monoamine metabolism in depression. J Neurol Neurosurg Psychiatry Arterioscler Thromb Vasc Biol 2003;23:729–36.
2000;69:228–32. 69 Myers KM, Winters NC. Ten-year review of rating scales, I: overview of scale
38 Corwin EJ, Murray-Kolb LE, Beard JL. Low hemoglobin level is a risk factor for functioning, psychometric properties, and selection. J Am Acad Child Adolesc
postpartum depression. J Nutr 2003;133:4139–42. Psychiatry 2002;41:114–122.
39 Chrousos GP. Stress, chronic inflammation, and emotional and well-being: 70 Myers KM, Winters NC. Ten-year review of rating scales, II: scales for
concurrent effects and chronic sequelae. J Allergy Clin Immunol internalizing disorders. J Am Acad Child Adolesc Psychiatry
2000;106:S275–91. 2002;41:634–59.
40 Black PH. Central nervous system-immune system interactions: 71 Winters NC, Myers K, Proud L. Ten-year review of rating scales, III: scales
psychoneuroendocrinology of stress and its immune consequences. assessing suicidality, cognitive style, and self-esteem. J Am Acad Child
Antimicrob Agents Chemother 1994;38:1–6. Adolesc Psychiatry 2002;41:1050–181.
41 Black PH. Immune system-central nervous system interactions: effect and 72 Ohan JL, Myers K, Collett BR. Ten-year review of rating scales. IV: scales
immunomodulatory consequences of immune system mediators on the brain. assessing trauma and its effects, J Am Acad Child Adolesc Psychiatr
Antimicrob Agents Chemother 1994;38:7–12. 2002;41:1401–22.
42 Chesnokova V, Melmed S. Neuro-immuno-endocrine modulation of the 73 Lesperance F, Frasure-Smith N, Theroux P, et al. The association between
hypothalamic-pituitary-adrenal (HPA) axis by gp 130 signaling molecules. major depression and levels of soluble intercellular adhesion molecule 1,
Endocrinology 2002;143:1571–4. interleukin-6, and C-reactive protein in patients with recent acute coronary
43 McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med syndromes. Am J Psychiatry 2004;161:271–7.
1998;338:171–9. 74 Suarez EC, Krishnan RR, Lewis JG. The relation of severity of depressive
44 Elenkov IJ, Wilder RL, Chrousos GP, et al. The sympathetic nerve--an symptoms to monocyte-associated proinflammatory cytokines and chemokines
integrative interface between two supersystems: the brain and the immune in apparently healthy men. Psychosom Med 2003;65:362–8.
system. Pharmacol Rev 2000;52:595–638. 75 Danner M, Kasl SV, Abramson JL, et al. Association between depression and
45 DeRijk RH, Schaaf M, de Kloet ER. Glucocorticoid receptor variants: clinical elevated C-reactive protein. Psychosom Med 2003;65:347–56.
implications. J Steroid Biochem Mol Biol 2002;81:103–22. 76 O’Malley PG, Jones DL, Feuerstein IM, et al. Lack of correlation between
46 Leung DY, Bloom JW. Update on glucocorticoid action and resistance. psychological factors and subclinical coronary artery disease. N Engl J Med
J Allergy Clin Immunol 2003;111:3–22. 2000;343:1298–304.
47 Maes M, Ombelet W, De Jongh R, et al. The inflammatory response following 77 Lauzon C, Beck CA, Huynh T, et al. Depression and prognosis following
delivery is amplified in women who previously suffered from major hospital admission because of acute myocardial infarction. Can Med Assoc J
depression, suggesting that major depression is accompanied by a 2003;168:547–52.
sensitization of the inflammatory response system. J Affect Disord 78 Llabre MM, Spitzer S, Siegel S, et al. Applying latent growth curve modeling
2001;63:85–92. to the investigation of individual differences in cardiovascular recovery from
48 Czeh B, Michaelis T, Watanabe T, et al. Stress-induced changes in cerebral stress. Psychosom Med 2004;66:29–41.
metabolites, hippocampal volume, and cell proliferation are prevented by 79 Kraemer HC, Stice E, Kazdin A, et al. How do risk factors work together?
antidepressant treatment with tianeptine. Proc Natl Acad Sci U S A Mediators, moderators, and independent, overlapping, and proxy risk
2001;98:12796–801. factors. Am J Psychiatry 2001;158:848–56.
49 Young AH, Sahakian BJ, Robbins TW, et al. The effects of chronic 80 Singhal A, Lucas A. Early origins of cardiovascular disease: is there a unifying
administration of hydrocortisone on cognitive function in normal male hypothesis? Lancet 2004;363:1642–4.
volunteers. Psychopharmacology (Berl) 1999;145:260–6. 81 Eriksson JG, Forsen T, Tuomilehto J, et al. Catch-up growth in childhood and
50 Gildengers AG, Butters MA, Seligman K, et al. Cognitive functioning in late- death from coronary heart disease: longitudinal study. BMJ
life bipolar disorder. Am J Psychiatry 2004;161:736–8. 1999;318:427–31.
51 Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose 82 Rosengren A, Hawken S, Ounpuu S, et al. Association of psychosocial risk
tissues of obese subjects release interleukin-6: adipose tissue difference and factors with risk of acute myocardial infarction in 11119 cases and 13648
regulation by glucocorticoid. J Clin Endocrinol Metab 1998;83:847–50. controls from 52 countries (the INTERHEART study): case-control study. Lancet
52 Chrousos GP, Gold PW. A healthy body in a healthy mind— and vice versa— 2004;364:953–62.
the damaging power of ‘‘uncontrollable stress’’. J Clin Endocrinol Metab 83 Eaker ED, Pinsky J, Castelli WP. Myocardial infarction and coronary death
1998;83:1842–5. among women: psychosocial predictors from a 20-year follow-up of women
53 Kiecolt-Glaser JK, Preacher KJ, MacCallum RC, et al. Chronic stress and age- in the Framingham study. Am J Epidemiol 1992;135:854–64.
related increases in the proinflammatory cytokine IL-6. Proc Natl Acad Sci U S A 84 Ismail J, Jafar TH, Jafary FH, et al. Risk factors for non-fatal myocardial
2003;100:9090–5. infarction in young South Asian adults. Heart 2004;90:259–63.
54 Sternberg EM. Neuroendocrine regulation of autoimmune/inflammatory 85 Bluzhas JN, Malinauskiene VA, Azaraviciene AP, et al. [The effect of risk
disease. J Endocrinol 2001;169:429–35. factors on development of myocardial infarction among professional drivers in
55 Bierhaus A, Wolf J, Andrassy M, et al. A mechanism converting psychosocial Kaunas]. (Abstract in Russian). Kardiologiia 2003;43:37–41.
stress into mononuclear cell activation. Proc Natl Acad Sci U S A 86 Wamala SP, Mittleman MA, Schenck-Gustafsson K, et al. Potential
2003;100:1920–5. explanations for the educational gradient in coronary heart disease: a
56 Sajadieh A, Nielsen OW, Rasmussen V, et al. Increased heart rate and population-based case-control study of Swedish women. [Erratum in Am J
reduced heart-rate variability are associated with subclinical inflammation in Public Health 1999;89:785]. Am J Public Health 1999;89:315–21.

www.postgradmedj.com