heart author" faq


Dominique L Musselman / William McDonald / Charles B. Nemeroff

"And now here's my secret, a very simple secret: It is only with
the heart that one can see rightly; what is essential is invisible to
the eye.
(Antoine de Saint-Exupery, The Little Prince, 1943)"


The interactions of personality traits, psychiatric symptoms and syndromes, and environmental stressors with the cardiovascular system have long intrigued investigators interested in the factors that
contribute to the development and progression of atherosclerotic
heart disease. Differences in rates of ischemic heart disease (IHD)
remain substantially unexplained even after surveillance of the
well-established risk factors. Although the type A personality
pattern has been studied intensely as a risk factor for coronary artery
disease (CAD), lack of a consistent association between type A behavior and the subsequent development of IHD has stimulated questions about the
contributions of the psychological concept of hostility as well as the
syndrome of major depression. Increasing evidence is accumulating
suggesting that major depression (Table 1 below) a mood disorder, is
associated with drastically elevated morbidity and mortality after an index
myocardial infarction (MI) and also acts as an independent risk factor
in the development of atherosclerotic heart disease.
Depressive syndromes and major depression are exceedingly common.
The most recent comprehensive study done in the United States, the National Comorbidity Study, reported life-time prevalence rates of major depression and dysthymia of 13 percent and 5 percent, respectively.4 Point prevalence rates of major depression in primary care outpatients range from 2 to 16 percent and 9 to 20 percent for all depressive disorders and are even higher among medical inpatients: 8 percent for major depression and 15 to 36 percent for all depressive disorders.
Minor depressive disorder (depressive symptoms subthreshold in severity
compared with major depression and dysthymia) is also common in the
community and in primary care clinics. The Epidemiologic Catchment Area Study of over 18,500 individuals reported the lifetime prevalence rate of sub-threshold depressive symptoms to be 23 percent in comparison to 6 percent, the sum of the prevalence rates of major depression and dysthymia. Although depression in patients with CAD is diagnosed infrequently by primary care physicians and
cardiologists, recognition and treatment of major depression is crucial,
especially for patients after an MI. Not only do depressed patients experience great difficulties in problem solving and coping with challenges,
depression adversely effects compliance with medical therapy and
rehabilitation and increases medical comorbidity. Minor depressive disorder also is associated with significant functional impairment and substantial increases in health care utilization.
In patients with CAD, depression predicts future cardiac events and
hastens mortality. Since the 1960s, multiple cross-sectional and
longitudinal studies have scrutinized the association of cardiovascular
disease (CVD), especially CAD and congestive heart failure (CHF),
with depressive sympthms is well as major depression.

TABLE 1 DSM-IV Diagnostic Criteria tor Depressive Disorders


A. Five or more of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at
least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.
1. Depressed mood
2. Markedly diminished interest or pleasure
3. Significant weight loss or weight gain or decrease or increase in
4. Insomnia or hypersomnia
5. Psychomotor agitation or retardation (observable by others)
6. Fatigue or loss of energy nearly every day
7. Feelings of worthlessness or excessive or inappropriate guilt
8. Diminished concentration or indecisiveness
9. Recurrent thoughts of death (not just fear of dying) or suicide

B. The symptoms cause clinically significant distress or impairment in
social, occupation, or other important areas of functioning.
C. The symptoms are not due to the direct physiologic effects of a
substance or a general medical condition.
D. The symptoms are not better accounted for by bereavement.


A. Depressed mood for most of the day, for more days than not, for at
least 2 years

B. Presence, while depressed, of two or more of the following:

1. Poor appetite or overeating
2. Insomnia or hypersomnia
3. Low energy or fatigue
4. Low self-esteem
5. Poor concentration or difficulty making decisions
6. Feelings of hopelessness

C. The disturbance is not better accounted for by a chronic major
depressive disorder.

Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Copyright 1994, American Psychiatric Association.


Depression and CardiovascuLar Disease

Early studies reported the prevalence of depression to be 18 to 60
percent in patients with CAD. Later studies reported relatively
consistent prevalence rates of depression in patients with CVD
(patients with CAD) ranging from 16 to 23 percent (mean, 19 percent; median,18 percent) despite the potential methodologic weaknesses of some of the studies listed in Table
2 (such as the use of unmodified psychiatric diagnostic
instruments to determine the prevalence of depression, excluding patients
because of the severity of CVD, and measuring depressive symptoms at differenttimes after hospital admission) and methodologic differences among
the studies (dissimilar patient populations, different diagnostic instruments, different hospitalization status, unspecified type of heart
Although the prevalence of major depressive symptoms in patients
hospitalized for CHF has not been as well studied, preliminary
evidence indicates that these patients have equally high or even higher
rates of major depression.37'39 However, although severity of physical
illness is one of the most important variables associated with depression in
patients with other medical illnesses, studies of patients with CVD do
not always document a higher prevalence rate of depression in patients
with measures of more advanced CVD or a greater level of

Depression as a Risk Factor for Ischemic Heart Disease

The notion that having a psychiatric illness such as major
depression increases one's risk for developing ischemic heart disease remains controversial and often has been "explained" intuitively by the hypothesis that persons with psychiatric disorders generally have
other risk factors for the development of CAD. 1 Table 80-3 describes the
studies with the most rigorous methods:Those studies have been prospective in design, have used structured clinical interviews or diagnostic instruments, have included other risk factors for CVD in their analyses (such as hypertension,
hypercholesterolemia, nicotine and other substance abuse, and
physical inactivity), and have been controlled for demographic factors (such as age, sex, and socioeconomic status).Nearly all the recent studies in Table 3 document increased cardiovascular morbidity and mortality in patients with depressive symptoms or major depression, implicating depression as an independent risk factor in the pathophysiologic progression of CVD rather than merely as a secondary emotional response to cardiovascular illness.Such large epidemiologic studies may use self-report instruments ratherthan clinical interviews to evaluate the importance of psychological factors in predicting CVD. Assessments of this type typically are added to large, multiple-risk-factor studies in which population-based samples are followed up prospectively.' The advantage of using "dimensional" measures of depression (rather than a categorical diagnosis of major depression) lies in the increased statistical power that allowsthese studies to detect smaller "effects." However, such epidemiologic data are not equivalent to clinical data. A relatively large clinicalstudy supporting depression as an independent risk factor for CVD
observed hat patients with major depression experienced elevated mortality rates after an MI. Frasure-Smith and colleagues found depression to be a
significant predictor of mortality (p < .001) in 222 patients 6
months after an MI. Depression remained a significant predictor of
mortality (p = .01) even after multivariate statistical methodology was used to factor out the effects of left ventricular dysfunction and previous
MI. Multiple logistic regression analyses revealed that depression was
significantly related to 18-month cardiac mortality even after
controlling for other significant multivanate predictors of mortality
(previous MI,,Killip class frequency of permature ventricular

TABLE 2. Prevalence of Major Depression in Patients with
Cardiovascular Disease

CAD = coronary artery disease; MI = myocardial infarction; DIS = Diagnostic Interview Schedule, Version III; SADS = Schedule for Affective Disorders and Schizophrenia.

Adapted from and reprinted with permission from Archives of General Psychiatry 55:580--592, July 1998. Copyrighted 1998, American Medical Association.


Hypothalamic-Pituitary-Adrenocortical and SympathomeduLLary Hyperactivity

Recent advances in biological psychiatry have included the discovery of numerous neurochemical, neuroendocrine, and neuroanatomic alterations in unipolar depression. Often proposed as important adjuncts in the diagnosis of depressed subjects, some of these biological markers may reflect important pathophysiologic alterations that contribute to the increased vulnerability of depressed patients to CVD. These markers include sympathoadrenal hyperactivity, diminished heart rate variability (HRV), alterations in platelet receptors and/or reactivity, and ventricular instability and myocardial ischemia in reaction to mental stress (Fig. 208).

Two primary components that are central to the "fight or flight" stress response observed by Cannon in and the "general adaptation syndrome" described by Selye in 195663 are the hypothalamic-pituitary-adrenocortical axis and the sympathoadrenal system. In response to stress, hypothalamic neurons containing corticotropin-releasing factor (CRF) increase the synthesis and release of corticotropin (ACTH), /3-endorphin, and other
pro-opiomelanocortin (POMC) products from the anterior pituitary gland. Many studies have documented evidence of hypothalamic-pituitary-adrenocortical axis hyperactivity in medication-free patients with major depression,i.e., elevated CRF concentrations in cerebrospinal fluid, blunting of the ACTH response to CRF administration, nonsuppression of cortisol
secretion after dexamethasone administration, hypercortisolemia, and
pituitary and adrenal gland enlargement, as well as direct evidence of increased numbers of hypothalamic CRF neurons in postmortem brain tissue from depressed patients compared with controls. Administered corticosteroids have long been known to induce hyperdholesterolemia, hypertriglyceridemia, and hypertension. Other atherosclerosis-inducing actions of steroids include injury to vascular endothelial cells and intima and the inhibition of normal healing. Indeed, elevated morning plasma cortisol concentrations have been significantly correlated with moderate to severe coronary atherosclerosis in young and middle-aged men.

Many patients with major depression also exhibit dysregulation of
the sympathoadrenal system. The adrenal medulla and sympathetic nervous
system (SNS) together constitute the sympathoadrenal system.
Although central nervous system (CNS) regulation of the sympathoadrenal
system has been only partially characterized, hypothalamic CRF-containing
neurons provide stimulatory input to several autonomic centers that
are involved in regulating sympathetic activity. Nerve impulses from
regulatory centers in the CNS control catecholamine release from the
sympathoadrenal system. Physiologic and pathologic conditions
causing sympathoadrenal activation include physical activity, coronary
artery ischemia, heart failure, and mental stress. Epinephrine in plasma
is derived from the adrenal medulla, whereas plasma norepinephrine
(NE) concentrations reflect the secretion of NE largely from sympathetic
nerve terminals, with the remaining NE provided by the adrenal medulla
and extraadrenal chromaffin cells. Peripheral plasma NE concentrations
are determined not only by the rate of release from sympathetic
system nerve terminals but also by reuptake into presynaptic
terminals, local metabolic degradation, and redistribution into multiple
physiologic compartments. Hypersecretion of NE in unipolar
depression has been documented by elevated plasma NE and NE metabolite
concentrations and elevated urinary concentrations of NE and its
metabolites. Not only do depressed patients exhibit higher basal
plasma concentrations of NE. those with melancholia exhibit even greater
elevations in plasma NE concentrations when subjected to orthostatic
challenge than do normal control subjects and depressed patients
without melancholia.n Furthermore, depressed patients who are dexamethasone (DST) nonsuppressors exhibit significantly higher basal and
cold-stimulated plasma concentrations of NE than do depressed
patients who are DST suppressors. After treatment with tricyclic
antidepressants (TCAs), urinary excretion of NE and its metabolites diminishes together with plasma NEconcentrations,although Veith and colleagues reported that chronic treatment with desipramine increased plasma concentrations of NE.Thus,sympathoadrenal hyperactivityy seems to represents a state rather than a state rather than a state or trait marker of depression, possibly reflecting increased CRF release within the CNS.
Sympathoadrenal hyperactivity contributes to the development of CVD
through effects of catecholamines on the heart, blood vessels, and
platelets. Sympathoadrenal activation modifies the function of
circulating platelets through direct effects on platelets,
catecholamine-induced changes in hemodynamic factors (increased
shear stress), circulating lipids, and inhibition of vascular eicosanoid
synthesis Arachidonic acid metabolites such as prostaglandins and
leukotrienes contribute to diverse circulatory and hemostatic
functions,including inhibition of platelet aggregation, and vascular
contractility and permeability. Elevations of plasma NE levels are found most frequently in young hypertensive patients and in subjects with
high-cardiac-output borderline hypertension who later proceed to
established high-resistance hypertension.95 Even normotensive
depressed after orthostasis, and after exercise in comparison with normal controls.
These depressed patients also exhibited increased plasma
concentrations of NE and serotonin (5HT) at restThus the sympathoadrenal hvoeractivity observed in trait marker of depression, possibly reflecting increased CRF release > within the CNS.
Sympathoadrenal hyperactivity contributes to the development of CVD
through effects of catecholamines on the heart, blood vessels, and
platelets. Sympathoadrenal activation modifies the function of
circulating platelets through direct effects on platelets,
catecholamine-induced changes in hemodynamic factors (increased
shear stress), circulating lipids, and inhibition of vascular eicosanoid
synthesis Arachidonic acid metabolites such as prostaglandins and
leukotrienes contribute to diverse circulatory and hemostatic
functions, including inhibition of platelet aggregation, and vascular
contractility and permeability.93 Elevations of plasma NE levels are found most frequently in young hypertensive patients and in subjects with
high-cardiac-output borderline hypertension who later proceed to > established high-resistance hypertension.95 Even normotensive
depressed patients have been found to exhibit greater heart rates at rest,
after orthostasis, and after exercise in comparison with normal controls.
These depressed patients also exhibited increased plasma concentrations of NE and serotonin (5HT) at rest. Thus the sympathoadrenal hvoeractivity observed in many patients with major depression may contribute to the development of CVD through the effects of catecholamines on cardiac function and platelets.

Diminished Heart Rate Variability

Alterations in autonomic nervous system activity, as demonstrated
by reduced HRV, represent another mechanism that potentially
contributes to the diminished survival of depressed patients with CVD. It is
believed that the beat-to-beat fluctuations in hemodynamic parameters
reflect the dynamic response of cardiovascular control systems to a myriad of naturally occurring physiologic perturbations, such as fluctuations in heart rate associated with respiration. Therefore, HRV may providea sensitive measure of the functioning of the rapidly reacting sympathetic, parasympathetic, and renin-angiotensin systems.
Cardiovascular homeostasis is maintained by the parasympathetic and
sympathetic nervous systems through afferent pressor receptors and
chemoreceptors and efferents that alter heart receptors and efferents that alter heart rate,atrioventricular conduction,and contractility and impinge on the peripheral vasculature,altering arterial and venous vasomotor tone.HRV is the standard deviation of successive R-R intervals in sinus rhythm and reflects the interplay and balance between sympathetic and parasympathetic input on the cardiac pacemaker. Peripheral control of HRV occurs mainly through the parasympathetic cholinergic vagus nerve Central generation and control of heart rate are regulated by the hypothalamus, the limbic system, and the brainstem. Numerous CNS neurotransmitters are involved in modulating HRV, including acetylcholine, NE, 5HT, and dopamine.
A high degree of HRV is observed in normal hearts with good cardiac function, whereas HRV can be decreased significantly in patients with severe CAD or heart failure. Moreover, the relative risk of sudden death after an acute MI is significantly higher in patients with decreased HRV. Heart rate variability is one of many prognostic factors after an infarction age, left ventricular ejection fraction (LVEF), and frequency of arrythmias. Its positive predictive power, like that of other factors after an MI, is relatively modest when considered in isolation. Although positive predictive accuracy is not high when HRV is considered in combination with other prognostic factors, clinically useful levels of negative predictive accuracy can be achieved. Among the many arrhythmogenic factors, autonomic tone is the most difficult to measure, and therefore, interest in HRV continues. Power spectral analysis measurements of HRV often are used because certain frequency bands of the heart period power spectrum have been associated with autonomic nervous system control of the sinus node.The low-frequency power of the heart period power spectrum reflects modulation of sympathetic and vagal tone by baroreflex activity. while high-frequency power reflects modulation of vagal tone, primarily by respiratory frequency and depth, i.e., respiratory sinus arrhythmia. The physiologic mechanisms that contribute to ultralow-frequency and very low frequency power of the heart period spectrum (which account for more than 90 percent of the total power in a 24-h period) remain obscure. In a study of 715 patients after Ml, certain frequency bands (total, ultralow, and very low frequencies) of the heart period power spectrum were strongly associated with mortality during 4 years of follow-up even after adjustment for other major risk factors. Indeed, very low frequency power was most strongly associated with death secondary to arrhythmia.
Reduced high-frequency HRV has been observed in depressed patients in comparison with nondepressed groups, although discrepant reports exist. In patients with angiographicalI~ confirmed CAD, diminished HRV during 24-h Holter monitoring was significantly more common in depressed patients than in matched nondepressed patients)21 Diminished high-frequency HRV is thought to reflect decreased parasympathetic tone, possibly predisposing patients to ventricular arrhythmias and perhaps to the excessive cardiovascular mortality found in CVD patients with a comorhid major depressive disorder Diminished HRV in patients with major depression also may be contributed to by a deficiency of omega-3 fatty acids'23 in this patient population. Not only have multiple studies documented a deficiency of omega-3 fatty acids in patients with major depression) 1 these polyunsaturated lipids possess antiarrhvthmic properties and reduce the risk of ventricular arrhythmias.
One study (without a placebo control group) revealed normalization of reduced HRV in depressed patients after effective treatnient. The prognostic importance of antidepressant-in-duced improvement in diminished HRV in depressed patients remains an intriguing area of research. Subsequent investigations will seek to determine the processes that underlie ultralow and very low frequency bands of the heart power spectrum; whether these bands are altered in depressed patients (with or without CVD) remains obscure.

Alterations in Platelet Receptors and/or Reactivity

The adverse effects of depression on cardiovascular disease also may be mediated by platelet mechanisms. Markovitz and Matthews's' first proposed that enhanced platelet responses to psychologic stress may trigger adverse coronary artery ischemic events. This association between platelet activation and vascular disease is supported indirectly by studies linking cerebrovascular disease and depression. The Established Populations for Epidemiologic Studies of the Elderly prospectively studied 10,294 persons age 65 and older for 6 years and determined that rates of stroke (adjusted for age, physical disability, and other medical disorders) were 2.3 to 2.7 times higher in persons designated with 'high" versus 'Slow" levels of depressive symptoms. In another prospective study, 103 consecutive stroke patients were assessed for major depression or dysthymia approximately 2 weeks after a stroke. Patients with major depression or dysthymia were 3.4 times more likely to have died during the 10-year follow-up period than were nondepressed patients (p = .007) even after controlling for confounding variables (age, medical comorbidity, type of stroke, and lesion location) (p = .03).
Platelets play a central role in hemostasis, thrombosis, the development of atherosclerosis, and acute coronary syndromes'36 through their interactions with both subendothelial components of damaged vessel walls and plasma coagulation factors, primarily thrombin. Human platelets contain adrenergic, serotonergic, and dopaminergic receptors. Through activation of platelet alpha2 adrenoceptors, increases in circulating catecholamines (>4 nmol/L) potentiate the effects of other agonists and, at higher concentrations, initiate platelet thrombotic responses, including secretion, aggregation, and activation of the arachidonate pathway. After injury to vessel endothehum, platelets and circulating leukocytes attach to the newly exposed subendothelial layer. Platelets adhere to collagen (and other components of the subendothelial matrix) exposed within a denuded area of the vascular endothelium. Thrombin stimulates platelet activation, converting platelet membrane GPIIb/ lila complexes into functional receptors for fibrinogen. Activation also is accompanied by extrusion or secretion of platelet storage granule contents into the extracellular environment. Platelets activated at the site of an injury to the vessel wall accelerate the local formation of thrombin and release a variety of products from their storage granules, including chemotactic and mitogenic factors, inducing leukocyte migration from the bloodstream and vascular cell proliferation. These secreted platelet products, e.g., platelet factor 4, /3-thromboglobulin (f3-TG), and 5HT, stimulate and recruit other platelets and cause irreversible platelet-platelet aggregation, ultimately leading to the formation of a fused platelet thrombus. Platelets also contribute to vascular damage by stimulating lipoprotein uptake by macrophages and mediating vasoconstriction through the production and/or release of substances such as thromboxane A, platelet-activating factor, and 5HT. Clinical trials have conflrmecl the importance ot platelets in vascular damage ;antiaggregating medications are useful in secondary prevention, delay the progression of atherosclerotic lesions, and improve post-MI outcomes.

The authors sought to determine whether heightened susceptibility to platelet activation might be a mechanism by which depression in physically healthy young volunteers acts as a significant risk factor for cardiovascular and cerebrovascular disease and/or increased mortality after MI. Utilizing fluorescence- activated flow cytometric analysis, the authors discovered that in comparison with 8 normal controls, 12 depressed patients as
a group exhibited enhanced baseline platelet activation as well as increased platelet responsiveness.

In one study, 21 elderly patients suffering from comorbid s
CVD and major depression exhibited increased platelet activation as measured by markedly elevated plasma concentrations of the platelet secretion products PF4 and beta-TG compared with 17 healthy control subjects and 8 nondepressed age-matched patients with CVD. Although the mechanism or mechanisms responsible remain unknown, the authors believe that heightened susceptibility to platelet activation and secretion underlies, at least in part, the increased vulnerability of depressed patients to CVD and/or mortality after an MI.
Serotonin secreted by platelets induces both platelet aggregation and coronary vasoconstriction, both of which are mediated by 5HT2 receptors. Vasoconstriction occurs especially when normal endothelial cell counterregulatory mechanisms of vascular relaxation are defective, as often occurs in patients with CAD. Indeed, essential hypertension, elevated plasma ,cholesterol levels, older age, and smoking, which are well- known predisposing factors for the development of CVD, all contribute to 5HT-mediated platelet activation. Moreover, alterations in platelet 5HT-mediated activation also have been described in affective disorders, most notably major depression.
Considerable evidence has accrued in the last two decades that supports the hypothesis that alterations in CNS and platelet serotonergic function occur in depressed patients.

Serotonin-mediated platelet activation can contribute to the
development of atherosclerosis, thrombosis, and vasoconstriction. Even though 5HT is a weak platelet agonist, it markedly amplifies platelet reactions to a variety of other agonists such as adenosine diphosphate (ADP), thromboxane A2, catecholamines, and thrombin. Through an action on 5HT2 receptors,serotonin enhances platelet aggregation and the release of intragranular products and arachidonic acid metabolites in response to otherwise ineffective agonist concentrations. This 5HT induced platelet amplification occurs at the low concentrations attained when indoleamine is released from seeping platelets subjected to shear stresses and from platelet activation by contact with an arterial wall lesion. Several investigators have reported increases in platelet 5HT2 binding density in depressed patients. Moreover, the changes appear to be state-dependent in that 5HT2 binding-site density returned to control values only in patients who showed clinical improvement. Depressed patients have been found to exhibit significant reduction in the number of platelet and brain 5HT transporter sites as detected by [S3H] imipramine binding as well as by the more selective ligand (3H] paroxetine.The increased 5HT2 creceptor binding density and decreased 5HT transporter sites suggest that depressed patients may be particularly susceptible to 5HT-mediated platelet activation and coronary artery vaso-constriction. Decreased numbers of platelet 5HT transporters would potentially hinder the uptake and storage of periplatelet serotonin, exposing the increased numbers of 5HT2 receptors to 5HT.
Platelets from depressed patients exhibit significantly increased elevations of intracellular free calcium concentration, (Ca2+)i after 5HT-induced stimulation in comparison to controls. Even functionally trivial increases in intraplatelet calcium "prime" the platelet secretion and aggregation response to stimulation by even a "weak" agonist such as 5HT or in response to increased blood flow. Thus, platelets with elevated (Ca2+)i as are observed in depressed patients, probably would exhibit increased activation in comparison with normal comparison subjects under basal conditions or in response to shear-induced aggregation (e.g., after an orthostatic challenge). Future investigations will attempt to confirm and connect the pathophysiologic mechanisms of sympathoadrenal hyperactivity, exaggerated platelet reactivity, and alterations in the platelet 5HT system in depressed patients to the propensity of those patients for the development of CVD.

Myocardial lschemia and Ventricular
Instability in Reaction to Mental Stress

The combination of a vulnerable myocardium after MI, acute ischemia, and negative emotional arousal is thought to trigger fatal ventricular arrythmias. The interplay of these factors in patients with CAD is being scrutinized. Jiang and colleagues longitudinally assessed 126 patients with CAD over a 5-year period. Mental stress-induced myocardial ischemia at baseline in CAD patients was associated with significantly higher rates of subsequent fatal and nonfatal cardiac events independently of age, baseline LVEF, and previous Ml. This study proposed that the relation between psychological stress and adverse cardiac events is mediated by myocardial ischemia. Although myocardial ischemia probably is the most significant factor in predisposition to ventricular instability, other factors also contribute. CNS control mechanisms can significantly decrease the threshold for ventricular fibrillation. Ventricular fibrillation is believed to be the mechanism underlying sudden cardiac death, the most common cause of fatality among patients with CAD. Indeed, psychological stress predisposes to abnormal ventricular activity by lowering the ventricular vulnerable-period threshold even to the point of fibrillation. The vagus nerve, however, exerts antiarrthymic activity through a direct action on the ventricular myocardium and interference with sympathetic activity. Increased parasympathetic activity has a protective effect on myocardium electrically destabilized by increased adrenergic tone.
Psychological and physical events can elicit a stress response, which usually is defined as the reaction of an organism to deleterious forces that disturb physiologic homeostasis. Psychological stress in humans with CAD increases ventricular ectopic activity and increases the risk of ventricular fibrillation. There are several similarities between the stress response and major depression: both can be characterized by increased blood pressure and heart rate as well as increased arousal and increased mobilization of energy stores.Particularly relevant to both the stress response and depression are the criticalbrain structures the locus coeruleus and the central nucleus of the amuygdala,which both are innervated by CRF-containing nerve terminals. The stress response and major depression differ in some respects, however. In depression, some aspects of the normal stress response seem to escalate to a pathologic state'78 that fails to respond appropriately to usual counterregulatory responses, resulting in a sustained version of a usually transient phenomenon, i.e., hyperactivity of the hypothalamic-pituitaryadrenocortical (HPA) axis or the sympathoadrenal system. Although many studies have linked stressful life events to the onset of major depression, some depressions are clearly endogeneous-i.e., they have no obvious environmental precipitant-although in most of these studies the role of early adverse events that are now known to be of paramount importance was not assessed.

Frasure-Smith and colleagues proposed that depression worsens the prognosis after an MI through another mechanism:
PVCs. The risk of sudden cardiac death associated with significant depressive symptoms (Beck Depression Inventory score approximately 10) was greatest among patients with 10 or more PVCs per hour (60 percent of these patients died within 18 months), suggesting arrythymia as the link between depression and sudden cardiac death. Depressed patients with CAD are not more likely to have arrhythmias than are nondepressed patients with CAD, but the risk associated with depression is confined largely to patients with PVCs. Patients who were not depressed experienced little increase in risk associated with PVCs even in the presence of a low LVEF. Thus, the prognostic impact of PVCs may be related more to depression than to PVCs per se. In the Cardiac Arrhythmia Suppression Trial (CAST), suppression of PVC frequency in post-MI patients did not reduce but actually increased mortality even though PVCs are associated with increased mortality after an MI. Treatment of depression may be necessary to improve survival in depressed patients with PVCs.



Anxiety disorders are the most prevalent psychiatric disorders in the United States (Table 4), with simple phobias being the most common (9 percent) and social phobia (8 percent) being the most often observed (Tables -5 and -6). A survey of adult primary care patients (n = 637) enrolled in a health maintenance organization revealed that 10 percent had untreated anxiety disorders.

TABLE 4 12-Month Prevalence of DSM-IH-R Disorders in the National Comorbidity Survey
Disorder ---------------------------------------Percent

Any anxiety disorder --------------------------19.3
Any addictive disorder ------------------------11.3
Any mood disorder ----------------------------11.3
Nonaffective psychosis -----------------------0.3
Any National Cornorbidity, Survey disorder-30.9

TABLE 3 Antecedent Depression and Subsequent Risk of Cardiovascular Disease

RH = relative hazard; IHD = ischemic heart disease; MI = myocardial
infarction; hx = history; MDE = episode of major depression; OR = odds ratio; CI = confidence interval.

Adapted from and reprinted with permission from Archives of General Medical Association.

The Relationship Between Major Depression and Cardiovascular Disease

click to enlarge

Hypothetical schema of pathophysiologic findings is shown. CRF = corticotropin-releasing factor; ACTH = corticotropin; associated with depression that probably contribute to increased susceptibility TNF-a = tumor necrosis factor a; IL-i =interleukin-1;IL-6 = interleukin-6; to cardiovascular disease. Autonomic nervous system innervation of the heart HRV = heart rate variability; HPA =hypothalamic-pituitary-adrenocortical via the parasympathetic vagus (X) nerve and sympathetic (postgangtionic axis. efferents from the cervical and upper thoracic paravertebral ganglia) nerves

TABLE 6 Diagnostic Criteria for the Most Common DSM-IV Anxiety Disorders


Marked and persistent fear that is excessive or unreasonable, cued by the presence or anticipation of a specific object or situation (e.g., flying, heights, animals, receiving an injection, seeing blood).
Exposure to the phobic stimulus almost invariably provokes an immediate anxiety response, which may take the form of a situationally bound or situationally predisposed panic attack.
The person (adults only) recognizes that the feature is excessive or unreasonable.
The phobic situation is avoided or is endured with intense anxiety or distress.
The avoidance, anxious anticipation, or distress in the feared situations interferes significantly with the person's normal routine, occupational (or academic) functioning or social activities or relationships or there is marked distress about having the phobia.


Marked fear of being focus of attention; avoidance of meeting unfamiliar people and close scrutiny by others
Fear of behaving in embarassing or humiliating way
Extreme anticipatory anxiety which may manifest as a panic attack


Experience of a traumatic event
Reexperienced by intrusive and distressing recollection, dreams, flashbacks, distress in similar situations
Persistent avoidance of stimuli associated with trauma
Persistent symptoms of increased arousal
Duration of disturbance of at least 1 month


Recurrent and unexpected panic attacks plus one or more of the following:
Persistent concern about having additional attacks (anticipatory anxiety)
Worry about the consequences of the attacks
A significant change in behavior related to the attacks (phobic avoidance) Not due to a substance, medical condition, or mental illness
At least two unexpected panic attacks for diagnosis


A period of intense fear or discomfort in which at least four of the following symptoms develop suddenly
-Palpitations or increased heart rate -Chest pain or discomfort
-Sweating -Dizziness, light-headedness, or faintness
-Trembling or shaking -Derealization or depersonalization
-Sensations of shortness of breath or smothering -Fear of losing control or going crazy
-Feeling of choking -Chills or hot flashes
-Nausea or abdominal distress -Paresthesia (numbness or tingling)
-Fear of dying


Excessive anxiety and worry for more days than not for past 6 months
Difficulty controlling worry
Functional impairment and/or distress
Symptoms not attributable to other causes
Physical symptoms Psychological symptoms
Restlessness or feeling keyed up/on edge Excessive anxiety or worry
Fatigue Difficulty controlling worry
Muscle tension Irritability
Difficulty concentrating or mind going blank
Sleep disturbance

Source: Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Copyright 1994, American Psychiatric Association.