Download New insights into the link between cardiovascular disease and

doi: 10.1111/j.1742-1241.2007.01640.x
REVIEW ARTICLE
New insights into the link between cardiovascular
disease and depression
S. A. Mosovich,1 R. T. Boone,2 A. Reichenberg,1 S. Bansilal,1 J. Shaffer,3 K. Dahlman,1 P. D. Harvey,4
M. E. Farkouh5
Linked Comment: Puri. Int J Clin Pract 2008; 62: 355–7.
1
SUMMARY
Review Criteria
Introduction: Although the association between depression and cardiovascular
disease (CVD) is well documented, the underlying mechanisms for this relationship
remain unclear. In this paper, we present three possible models which account for
the comorbidity between depression and cardiovascular disease. Models: The first
model outlines depression as a risk factor for CVD and the second model presents
CVD as a risk factor for depression. The third model proposes a common underlying pathway related to the effects of chronic stress on the body in manifesting as
depression or cardiovascular disease. Conclusions: If the proposed model holds
true, it may be possible that an intervention initiated before overt manifestations
of CVD or depression become apparent, may delay or prevent the onset of these
serious clinical entities.
Introduction
The association between depression and vascular disease is well documented. Meta-analyses have indicated that depression is associated with an increased
risk of developing coronary heart disease (CHD) in
healthy individuals (1,2). Early longitudinal studies
of CHD mortality found that, in many patients,
depression or other mood disorders preceded death
from myocardial infarction (MI) (3–5). Forty-five
per cent of postmyocardial patients suffered from
either minor or major depression symptoms (6,7),
and it has been estimated that between 17% and
27% of patients with coronary artery disease (CAD)
suffer from major depression, and a significantly larger percentage has subsyndromal symptoms of
depression.
The precise mechanisms by which depression and
vascular disease are linked remain largely unknown.
In particular, the direction of causation is not understood, and numerous studies conducted in recent
years have suggested both that depression is a risk
factor for cardiovascular disease (CVD) and that
CVD is a risk factor for depression. Such a reciprocal
relationship allows for three possibilities: (i) CVD
causes depression (Figure 1A); (ii) depression causes
CVD (Figure 1B) or (iii) both CVD and depression
are caused by a common underlying factor
(Figure 1C). Statistically, it is impossible to disentan-
Our theory emerged from authors’ extensive clinical
practice, reading of recent journals and feedback
from reviewers.
Message for the Clinic
Cardiovascular disease and depression may be
linked via a common underlying process.
Specifically, pro-inflammatory cytokines may disrupt
serotonin levels and subsequent platelet
aggregation, causing both depression and
arteriosclerosis.
gle the first two models as the correlation between
CVD and depression is bi-directional in cross-sectional research. Further, the picture can be further
clouded as the relationship between depression and
vascular disease is likely to be influenced by lifestyle
choices that affect each independently. For example,
behaviours such as smoking, sedentarism or poor
diet can contribute, either directly or indirectly,
to the development of both vascular disease and
depression (8–10).
Nevertheless, the robust comorbidity of vascular
disease and depression invites conceptual models to
explain the pathophysiological processes underlying
both illnesses. A common underlying factor that
leads to both CVD and depression, if the appropriate
mechanism is identified, provides a more comprehensive and parsimonious explanation than trying to
determine whether CVD causes depression or vice
versa. Indeed, if common biological mechanisms for
both disorders can be demonstrated, then their interrelationship may be better understood, leading to
more effective prevention and treatment of these
conditions. Further, such a model also offers new
theoretical directions for understanding individual
differences in the manifestation of these disorders.
In this paper, we present three possible models
that account for the comorbidity between depression
and cardiovascular disease. The first model which
outlines depression as a risk factor for CVD; the
ª 2007 The Authors
Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, March 2008, 62, 3, 423–432
Department of Psychiatry,
Mount Sinai School of
Medicine, New York, NY, USA
2
Department of Psychology,
University of Massachusetts,
Dartmouth, MA, USA
3
Department of Psychology, St.
Johns University, Jamaica, NY,
USA
4
Department of Psychiatry,
Emory University, Atlanta, GA,
USA
5
Department of Cardiology,
Mount Sinai School of
Medicine, New York, NY, USA
Correspondence to:
R. Thomas Boone, PhD,
Department of Psychology,
University of Massachusetts,
Dartmouth, 285 Old Westport
Road, North Dartmouth, MA
02747, USA
Tel.: + 1 508 999 8440
Fax: + 1 508 999 9169
Email: [email protected]
Disclosure
The authors have no conflicts
of interest to declare as regards
this manuscript.
423
424
Link between cardiovascular disease and depression
A
CVD
Depression
B
Depression
CVD
C
Depression
It seems that depression may not only contribute
to the onset of CVD, but also heighten its severity
(14). Patients with a depressive episode in the month
before the first MI have been shown to have a twofold higher risk of cardiac failure compared with
non-depressed subjects (19). Even mild depressive
symptoms of depression increase mortality risk after
acute MI (20).
CVD
Model no. 2: CVD as a risk factor
for depression
Common underlying
factor
(Cytokine and
inflammatory response to
stress)
Figure 1 Three models for comorbidity of cardiovascular
disease (CVD) and depression
second model which presents CVD as a risk factor
for depression and finally a third model which proposes a common underlying factor which leads to
depression and CVD. We critically discuss the
strengths and limitations and present potential biological correlates for each model.
Model no. 1: Depression as a risk
factor for CVD
Several studies have suggested that a prior history of
depression or depressive symptoms is strongly associated with subsequent development of ischaemic heart
disease and MI (11–14). Frasure-Smith and Lesperance (15) performed a review of 143 articles on this
topic and concluded that depression is a likely cardiac risk factor, although their conclusions were
somewhat qualified as they were unable to systematically control for other risk factors, as covariates
across the studies included in their analyses. Risk of
MI is significantly elevated for up to 10 years after
the onset of the first depressive episode (16). Community-based studies have found that pre-existing
depressive symptoms predicted not only CHD but
also stroke. In a 10-year prospective study, subjects
with baseline depressive symptoms were almost three
times more likely to suffer an ischaemic stroke during the follow-up period than non-depressed subjects, even after controlling for other cardiovascular
risk factors including systolic blood pressure, diabetes, cholesterol level and smoking status (17).
Another study with a 16-year average follow-up period reported similar results (18).
Research has also suggested that CVD precedes the
onset of depression. A study of 222 patients who had
experienced MI found that 16% tested for major
depression between 5 and 10 days after their initial
hospitalisation (21). Hance et al. (22) found that
17% patients who were receiving catheterisation and
angiography had major depression and another 17%
qualified for minor depression. While the effect was
only true for males, Hippisley-Cox et al. (13) found
using a community sample in an ambulatory setting
that 20% of the CAD subjects had depression, compared with 12% of matched controls with an odds
ratio of two, even after controlling for smoking, diabetes, hypertension and socioeconomic status (SES).
Several studies have also found increased rates of
depression following a stroke event. Robinson et al.
(23,24) studied both the short (postevent) and longterm (1–2 years) effect of stroke on depression. They
found that 27% of 103 patients qualified for major
depression after the stroke event, while follow-up
tests of 65 patients showed that 14% continued to
have major depression up to 2 years later, although,
interestingly, levels of depressed symptoms for diagnosed depression seemed stable while levels of
depressed symptoms for the subclinical group
appeared to increase. Indeed, another 18% of
patients followed over time met criteria for minor
depression.
Other studies have examined depression in the
interim duration (2–6 months) after a stroke.
Pohjasvaara et al. (25) evaluated 277 patients for
major depression and found that 4 months after
stroke, 27% had major depression and 14% had
minor depression. In another study, Gainotti et al.
(26) found that an increase in the incidence of
depressive symptoms as more time elapsed after the
stroke. Other studies, which compared poststroke
subjects to controls, found that there were significantly higher rates of depression in the stroke group
(27–31).
Models explaining the mechanism underlying
this association have emerged from the imaging
literature. Based on imaging studies in geriatric
ª 2007 The Authors
Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, March 2008, 62, 3, 423–432
Link between cardiovascular disease and depression
populations, it has been hypothesised that depression
is a direct outcome of subcortical brain lesions on
strategic brain areas caused by cerebral atherosclerosis. Specifically, the lesions may disrupt the striatopallido-thalamo-cortical pathways (32,33). Thus, a
possible mechanism linking vascular disease and
depression may lie in structural changes resulting
from vascular lesions in the prefrontal cortex, subcortical regions, the hippocampus and amygdala – all
have been linked to the pathophysiology of depression (32). However, relating CVD to depression
using the localisation of lesions in the brain offers no
explanation for cases where depression has been
shown to precede vascular diseases (34).
Another model posits that the relationship
between vascular disease and depression results from
the way in which blood-borne mediators, activated
by stress, profoundly influence mood through effects
on brain targets (35). This model takes into consideration a series of events initiated by an initial insult
(stress) with systemic implications.
Model no. 3: Integrated model,
a common underlying factor for
cardiovascular disease and depression
We have described above evidence for the association
between depression and vascular disease. Given the
nature of this research, namely correlational, it is statistically impossible to infer the direction of causality.
What is needed is a better understanding of the biochemical processes that link these two diseases. However, attempts to pinpoint the biochemical
explanation for this association have thus far proved
unsatisfactory. Rather than limiting ourselves to the
causal, bi-directional relationships described above,
we propose a new model; that depression and CVD
share a common underlying cause; the two illnesses
are two possible outcomes that result from prior
stress related insult to the body (36). This third possibility has not been explored in CVD and depression
despite the abundant examples for such relationships
in medicine. For instance, craniofacial abnormalities
are comorbid with mental retardation; however, we
do not talk about craniofacial abnormalities causing
mental retardation, or vice-versa. As recently uncovered in 1970s, when this coupling occurs, it is often
the result of fetal alcohol syndrome. A more classic
example is the work of Koch who in 1882 recognised
that the four disparate symptoms of pyrexiae, locales,
neuroses and cachexiae described by Cullen were
caused in their entirety by tuberculosis (37).
Platelet activation, in its critical role in generating
atherosclerotic plaque, is clearly related to CVD. A
reduction in the baseline level of serotonin is a chem-
ical marker of depression. Both phenomena can
result from a cascade of pathways initiated by a stressor. We would like to propose that the specific mechanism that underlies CVD and depression rests on
the presence of an initial stressor that sets off a chain
of local and systemic events, mediated by immune
intercellular messengers, which lead to neurotoxicity
and decreased production of serotonin.
Stress
Stress is a general term that refers to any demand on
the body which is, leads to a disruption of the
homeostatic systems and signals, a disparity between
what is optimal for the body and what actually exists
(37). Stress can take many shapes and can have drastically different magnitudes: it can be psychological,
such as exam stress or the death of a spouse; inflammatory, such as rheumatoid arthritis; infectious, such
as influenza; traumatic, such as brain injury; metabolic, such as diabetes; or cancerous. Individuals’
proclivity to express a pathological response to these
commonplace stressors is a result of their genetic
vulnerability and their behaviours combined. When
there is stress, the body recognises, evaluates and
adapts to the adverse events by initiating an immune
reaction meant to both eradicate the stressor and to
return the body to homeostatic balance.
One level of defense in the immune reaction
comes from macrophages, which circulate in the
bloodstream and in the glial cells of the brain as
shown in Figure 2. When they encounter stress,
macrophages induce the production of cytokines as
part of an attempt to summon other immune
defenses against that stressor.
Cytokines
Cytokines are hormone-like messengers that facilitate
communication between different parts of the
immune system. They have been implicated [interleukin (IL)-1, IL-6, tumour necrosis factor-(TNF)alpha] in the central control of response to systemic
disease and other stressors and in the activation of
neuroendocrine, immune and behavioural responses
(38–40). Some cytokines and their receptors are also
expressed in neuronal glial cells even under noninflammatory conditions. After infection or trauma,
cytokines are expressed in much larger quantities,
and excessive secretion of cytokines is thought to be
involved in many pathological processes within the
brain, possibly contributing the development of
various neuropsychiatric conditions (14,41–43).
Cytokines and the brain response
During stress, the body secretes cortisol excessively,
which is associated with the ‘fight or flight’ response.
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Link between cardiovascular disease and depression
Figure 2 Stress-immunochallenge-functional disruption of a neuron acting on susceptible individuals
Hypothalamus
Corticotrophin releasing
hormone
Pituitary
Suppresses immune
system
cytokines
Activates immune
system,
more cytokine induction
Adrenocorticotrophin
hormone
Glucocorticoids
Adrenal glands
Epinephrine
Norepinephrine
Alters metabolism
Figure 3 Regulation of homeostasis via hypothalamopituitary axis
Cytokines have receptors in the hypothalamus, which
in turn produces cortisol releasing factor (CRF),
which then stimulates cortisol adrenocorticotropic
hormone (ACTH) and cortisol production from the
adrenal gland (44). Under normal circumstances, this
secretion of corticosteroids works to suppress the
cytokine response that initiated the cycle (45), thus
returning the system to a homeostatic balance (Figure 3). However, when stress persists for a longer
duration, the cytokine response becomes maladaptive, diminishing the immune system’s sensitivity to
glucocorticoid hormones that normally terminate the
inflammatory cascade (46). When the negative feedback loop is disrupted, the central action of cytokines may also account for the hypothalamic–
pituitary axis hyperactivity that is frequently seen in
depressive patients (14,47,48).
This excess cortisol, in conjunction with
unchecked cytokine production because of cortisol,
changes the normal pathway of serotonin synthesis.
Normally, tryptophan, an essential amino acid, is
converted to 5-hydroxy tryptamine (5-HTP) and
serotonin (5HT) in the brain (Figure 4). However,
the metabolism of tryptophan can be switched to the
kynurenine pathway in the presence of elevated levels
of the glucocorticoids and cytokines, which are both
produced as a result of stress. This alternate pathway,
the kynurenine pathway, results in quinolinic acid,
which has neurotoxic effects on neuronal targets
(49). In addition, the production of serotonin is also
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Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, March 2008, 62, 3, 423–432
Link between cardiovascular disease and depression
Figure 4 Alteration of tryptyophan synthesis by immune challenge (acting on susceptible individuals)
diminished, as the system is lacking the tryptophan
that would have produced under normal circumstances. Because of the pathway switch, the reduced
tryptophan limits the biosynthesis of serotonin and
consequently may relate to an increased susceptibility
for depressive mood (50). The products of the tryptophan–kynurenine pathway display various functions in the brain. For example, high doses of a form
of kynurenine act as cytotoxic on cultures of neuronal cells (51).
Thus, excess cortisol and a cytokine response that
is not ‘turned’ off can lead to depression by affecting
serotonin levels through a disruption of the serotonin precursor tryptophan. However, the impact of
the disregulated cytokine response has other dramatic effects. Specifically, in addition to effects on
the brain, cytokines play four important roles in the
body.
Cytokines and the systemic response
Oxidative stress and cell death. In the body, cytokines
initiate a series of events that eventually lead to the
death of cells, including serotonin-producing cells.
Blood-borne cytokines stimulate the activity of cyclooxygenase within cells, leading to the synthesis of
thromboxane A2 (TXA2), prostacyclin and prostaglandins (PGE2) as shown in Figure 5. An increase
in plasma and cerebrospinal fluid concentrations of
PGE2 has been reported in patients with depression
and may contribute to the decrease in brain biogenic
amine function by affecting the synthesis of the
amines (52). Some evidence has shown that PGE2
formed as a result of the cyclo-oxygenase pathway
are potential inducers of intracellular oxidative stress
– composed of nitric oxide and free radicals – which
leads to cell degeneration and death (53). Nitric
oxide can have toxic effects on neurons and other
cells (54,55), leading to the death of cells that specialise in the synthesis neurotransmitters such as
serotonin. Thus, cytokines’ impact and resultant oxidative stress has been directly linked to CVD and
depression.
Acute phase reactants. Cytokines also travel to the
liver and induce increased production of acute phase
reactants (APRs), a response of the organism to
disturbances of its homeostasis because of stressors
(56) as shown in Figure 6. Black and Garbutt (57)
hypothesise that repeated episodes of stress, may lead
to chronic inflammatory process or progression of
atherosclerosis. The APRs produced include coagulation factors such as fibrinogen and prothrombin,
which when converted, respectively, to the forms of
fibrin and thrombin, provide a structurally sound
meshwork for thrombus formation (58).
Neopterin. On activation by cytokines, neopterin is
released by macrophages and monocytes. Increased
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Figure 5 Prostaglandin synthesis as mediator of neurotoxicity leading to depression
levels of neopterin are found when individuals have
infections, inflammatory disease and surgical stress
(59). Neopterin may enhance oxidative stress and
induce apoptosis in neuronal, astrocytic and microglial cells (60). Neopterin derivatives, combined with
the immune stimuli and cortisol referenced in the
section on cytokines and the brain response, are
involved in the degradation of tryptophan, thereby
restricting the biosynthesis of serotonin (61) as
shown in Figure 4.
Infections in the vascular bed. Many investigations
have demonstrated that pre-existing infectious
agents, such as viral and bacterial pathogens, embedded in vascular tissue may act as inflammatory stressors, evoking immune changes similar to the ones we
have already described (62,63). In brief, these agents
initiate cytokine-mediated cascade of events leading
to the attenuation of serotonin synthesis in one case
as well as to neuronal degeneration and cell death.
The vascular bed and platelet aggregation. Research
has shown that stress, including the psychosocial
variety, can induce structural changes in healthy
blood vessels. Stressors also activate the sympathetic
nervous system, which increases blood pressure and
heart rate, which in turn puts pressure on parts of
the endothelial wall, leaving them vulnerable to
atheromatous plaques. Stress may also play a role in
endothelial cell synthesis of molecules important
in promoting atherosclerosis, such as adhesion
molecules and clotting factors.
Under conditions of chronic stress, the overexpression of adhesion molecules, which were initially
intended to stem an acute condition by attracting
white blood cells, leads to an increased adhesiveness
of the vascular wall, culminating in the accumulation
of a pathological number of macrophages and lymphocytes. Even in individuals with no symptoms of
disease, the presence of adhesions in the blood indicate an ongoing or intermittent inflammatory process that may consist of repetitive or chronic stress
and repetitive endothelial damage (64,65).
As stress contributes to modifications in the vascular bed, decreased serotonin levels, which, in this
case, resulted from the brain response to cytokines,
increase platelet activation. Platelets both store and
release serotonin, and serotonin plays an important
role in platelet activation (66,67). A weak platelet
agonist itself, serotonin increases the effects of several
other platelet agonists, such as adenosine diphosphate, TXA2, thrombin and catecholamines (68).
ª 2007 The Authors
Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, March 2008, 62, 3, 423–432
Link between cardiovascular disease and depression
Figure 6 Central and systemic response to stress induced immune challenge
Platelets are also embryologically related to serotonin
neurons (69).
There is evidence that lower levels of serotonin are
associated with factors in the determination of vascular disease and acute coronary syndromes. The exact
mechanisms are still debated, but it is possible that
lower levels of plasma-bound 5-HT induce platelet
receptor upregulation, which in turn increases platelet reactivity and the aggregation response (69–71).
In addition, selective serotonin reuptake inhibitors
(SSRIs), which increase the amount of plasma-bound
serotonin, have been shown to decrease platelet aggregability and reduce risk of acute coronary syndromes, further connecting serotonin to vascular
disease processes (72).
Thromboxane A2, which is derived from the
cyclo-oxygenase pathway, plays vasoconstrictive role
by promoting platelet aggregation, which in pathological states leads to thrombosis (73). Among many
other effects, chronic stress has been shown to
increase intracellular calcium, which, in conjunction
with platelet agonists like TXA2, causes further platelet aggregation. In addition, a greater resting level of
calcium has been found in the platelets of both
depressed and hypertensive patients in comparison
with controls (74–76).
Cytokines can also lead to other cellular imbalances. When induced by stress, cytokines increase the
concentration of various lipids such as triglycerides,
cholesterol and free fatty acids. Certain cytokines,
such as TNF-alpha and interferon-gamma, stimulate
lipolysis in animals, which contribute to the free fatty
acid pool (77). These lipid changes generally occur
quickly after the onset of stress and last as long as
the stress. If conditions such as high blood pressure
and/or endothelial damage resulting from acute stress
exist simultaneously to the short-term elevation atherogenic lipids, then the effects may be of clinical relevance. During stress, increases in corticosteroids
(see section above) sensitise adipose tissue, causing a
subsequent increase in fatty acids, which become part
of the fatty acid pool (78).
An injured endothelium (which can be caused by
hypertension or other factors in addition to stress)
reacts by releasing molecules that attract white blood
cells that adhere to adhesion molecules on the endothelial wall, so that they can attend to the source of
the immune distress. In addition, cytokines and the
glucocorticoids they cause (see above) may induce
adhesion molecules on the damaged endothelium.
Blood vessels that are already compromised by atherosclerosis can have an even greater response to
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stress, which, if chronic, can lead to further endothelial injury in those vessels.
These combined effects of stressors and cytokines
on endothelial cells, adhesion molecules, platelets
and plasma lipid concentration will, under conditions of chronic stress, lead to vascular disease, such
as plaque buildup leading to atherosclerosis.
Evidence for cytokine
and inflammatory response as
underlying factor
The proposed integrative model that cytokines and
inflammatory response might be the common underlying factor that connects CVD and depression has
only recently been getting attention from researchers
(36). To date, our proposed model is the one that
offers the most detailed description of the process,
identifying the specific role of cytokines and serotonin de-regulation. The connections detailed in the
model above are based upon correlations and an
attempt to integrate a pattern of findings. Collectively, these relationships are consistent with our
model, but are not definitive proof. To fully support
our model, a prospective study in which data on
cytokines, serotonin, atherosclerosis, depression and
CVD are monitored over a period of time would be
required. Such a study will simultaneously allow for
testing our integrated model vs. the other models,
CVD causes depression and depression causes CVD.
In lieu of this study, there is some indirect evidence that the common underlying factor model is
the best explanation. Our integrated model identifies
the effects of cytokines and serotonin de-regulation
as part of an inflammatory process. As there are
other illnesses that also fall under inflammatory processes, notably asthma and rheumatoid arthritis, our
model would predict that depression should also be
comorbid with these inflammatory diseases. A recent
meta-analysis (J. S. Shaffer, R. T. Boone, S. A.
Mosovich, A. Riechenberg, M. Farkouh, St. John’s
University, Manuscript submitted for publication)
demonstrates just that.
Finally, the role of parsimony must be considered.
CVD and depression are clearly related to one
another. In detailing our integrated model, we have
also shown that inflammatory processes related to
cytokines and serotonin brought on as a reaction to
stress are also related to both depression and CVD.
While the directionality of depression and CVD is
logically ambiguous, it is less likely that CVD or
depression cause a stress-produced inflammatory
process. Thus, our integrated model captures the
inter-relatedness of all three of these processes and
offers a logical time sequence that makes sense.
Clinical implications
If our proposed integrative model holds true, it may
be possible that an intervention initiated when cytokine levels are elevated and before overt manifestations of CVD or depression become apparent in
individuals at risk, may delay or prevent the onset of
these serious clinical entities. Therapies targeted at
this common underlying mechanism for depression
and CVD require further evaluation in randomised
clinical trials. Use of anti-depressants for treating
cardiac patients, particularly those that target serotonin, has already demonstrated clinical efficacy (79).
The common underlying factor model also offers
some interesting theoretical directions for further
research, most notably on individual differences in
susceptibility to specific disease. In short, our model
offers a mechanism for how stress can cause a broad
range of illnesses. The higher than chance levels of
comorbidity across these illnesses supports our
model, but the failure to see higher rates of comorbidity suggests that there are mediators that operate
on an individual level. Future research can be directed to identify the biological markers for who is
likely to develop CVD alone, who is likely to develop
depression alone and who is likely to develop both
illnesses.
In addition to looking for biological markers, future
research could also consider the effects of different
types of stress. Specifically, some stressors may be
more likely to lead to some illnesses more than others.
There may also be a threshold level of stress required,
along with individual differences for such a threshold,
before the inflammatory processes can have pathogenic effects. Finally, while stress, even chronic stress,
is fairly ubiquitous, there may be specific processes,
such as a learned helplessness reaction, that yields
activation of the damaging inflammatory process.
Summary
In summary, a cytokine-mediated chain of events initiated by chronic stress leads to biodynamic outcomes
(e.g. serotonin dysfunction, platelet hyper-reactivity)
that, over time, can manifest themselves in severe
clinical outcomes: depression, and /or CVD. The
chain of events described in Model no. 3 is not a series of staggered occurrences that take place sequentially, but rather a simultaneous collection of wellestablished biological events, which, once they are initiated, overwhelm the body’s defenses and lead to
effects throughout the body. The results of the various cytokine-mediated pathways described in this
paper do not exist in isolation; instead, the total effect
of the stressor on the body is the cumulative result of
ª 2007 The Authors
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Link between cardiovascular disease and depression
all of these established steps. In this way, via a series
of biochemical events, a systemic response to a stressor leads to an expression of vascular disease on the
endothelial wall. Conversely, the local site of disease
in itself, as we mentioned, can set off a systemic
response, thus perpetuating these events.
If we follow this framework, how does a person
who experiences stress fail to develop CVD or
depression? The full execution of the pathways
described above hinge on an individual’s susceptibility to pathological processes, which is associated with
his genetic endowment and/or to prenatal/perinatal
environmental exposure such as low birth weight or
hypoxia (80,81). However, our hypothesis is useful
because it provides a framework for future research
that may lead to a better understanding of the
explicit mechanisms connecting vascular disease and
depression that have so far eluded cardiovascular
researchers and psychiatrists.
Acknowledgements
The authors wish to thank Hanna Alberts and Josephine Barbiere for their assistance with the preparation of this manuscript.
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Paper received August 2007, accepted October 2007
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