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PNI and Cardiovascular Disease

The number one cause of death in the USA (and in most of Western society), and on its way to becoming number one in the developing countries worldwide, is atherothrombotic, coronary artery disease (CAD), also known as coronary heart disease (CHD), or ischemic heart disease (IHD) ()

Risk factors that have been identified include diet, age, sex, family history, smoking, hypertension, dyslipidemias, diabetes, HIV, stress, and lifestyles ().

Current research provides compelling evidence that in addition to the traditional biological risk factors, psychosocial elements can act independently in the pathogenesis and expression of coronary artery disease (, ).

Experts who have reviewed the extensive literature up to 2001 contend that there is convincing evidence for a psychological and social impact on CAD morbidity and mortality (). They analyzed clinical studies on the psychological and psychosocial factors on the development and outcome of coronary heart disease, especially studies employing verifiable outcomes of CAD morbidity or mortality. The researchers identified five key variables as possible psychosocial risk factors: acute and chronic stress, hostility, depression, social support, and socioeconomic status.

One way of looking at these risk factors is the following psychosocial constructs ():

hostility/over commitment,
depression, vital exhaustion,
social support and a stressful psychosocial work environment,
the demand–control model,
the effort-reward imbalance model

Another way to look at the psychosocial risk factors for CAD was presented by Rozanski et al. ():

depression
anxiety
personality
social isolation
chronic life style stress

Loss of control over one’s environment is perhaps a common link (). Indeed, evidence indicates that psychosocial stresses tend to occur as a group (e.g. depression, chronic life-style stress, anxiety), and when they occur as a group, their effect can be as significant for CAD as hypertension and elevation of cholesterol (, , ).

PNI Involvement in CAD

Relationships between CAD and the psychosocial factors are generally considered to be a combination of behavioral and direct influences (). Behavioral influences relate to increased bad health behaviors such as smoking, excessive alcohol consumption, poor diet, and lack of exercise (, ).

One hypothesis suggests a feedback between behavior, neuroendocrine changes, immunological responses, and the pathogenesis of CAD (). They propose a prolonged first stage in which there is chronic hostility, prolonged occupational over-exertion, and experiencing of other life stressors. This then passes into a shorter second phase of vital exhaustion. They believe that stressors provoke neuroendocrine changes which down regulate immune functions, which leads to reactivation of latent infections and possibly autoimmunity. Release of pro-inflammatory cytokines increases the fatigue associated with vital exhaustion and increases cytokine production in the brain. This in turn stimulates the chronically activated over-compensating limbic-hypothalamic-pituitary-adrenal axis. This lower-than-optimal response results in further fatigue and feeds into the whole cycle again. This ultimately results in atherosclerosis, coronary artery occlusion and myocardial infarction.

Another hypothesis proposes that chronic psychological risk factors such as hostility and low socioeconomic status are important at the beginning stages of the acute coronary syndrome (). Episodic factors such as depression and exhaustion are thought to be involved in transitioning from stable to unstable atherosclerotic plaques. Then acute psychological triggers such as mental stress and anger trigger myocardial ischemia and rupture of the atherosclerotic plaques.

An additional PNI model suggests that starting with an existing mild atherosclerotic plaque, and a dysfunctional endothelium, the acute cardiac syndrome will pass through 3 stages (). First is plaque instability. Second are extra-plaque factors promoting rupture. Third is superimposed thrombosis at a ruptured site. They postulate that this chain of events may persist if there is a deficiency of neuroendocrine-to-immune negative feedback resulting from cortisol resistance.

In stage one, proinflammatory cytokines (IL-1, IL-6, and TNF- á) and chemoattractants (MCP-1, IL-8) lure white blood cells to the site. Along with these, the costimulation system (CD40L-CD40) attracts monocytes/macrophages that produce matrix metalloproteinases that disintegrate the extra-cellular plaque matrix. The result is coronary instability. The PNI connection to this stage is the increase in proinflammatory cytokines associated with negative emotions: depression, anxiety, and anger.

In stage two, neuroendocrine factors (norepinephrine) and cytokines stimulate vasoconstriction and increased blood pressure, which causes a susceptible plaque to rupture. Acute stress, anger and hostility via stimulation of catecholamines may result in vasoconstriction and elevated blood pressure.

In stage three, inflammation induces coagulation factors to increase and anticoagulation factors (notably protein C) to decrease. This enhances platelet aggregation a key step in thrombosis, which can lead to severe coronary occlusion. Depression, hostility and vital exhaustion have been shown to be positively correlated to platelet aggregation.

Stress Management and CAD

Although empirical studies have shown that various psychosocial parameters are associated with increased cardiovascular morbidity and mortality, most of these studies are observational, not experimental. Although risks and trends can be identified with case-control studies, they can only go so far in examining possible causes for associations. In order to get evidence for the possible associations, experimental studies such as the gold standard randomized clinical trials (RCT) have been conducted.

The few RCT type of observational studies have provided results that at times seem to be at odds with each other. Some of this controversy arises from such things as comparing different parameters, experimental constructs such as intent to treat data, population and gender affects, and different control groups with differing benefits. A good debate reviewing the literature up to 2001 for evidence of the influence of psychosocial factors on both the incidence and amelioration of disease, including CAD, can be seen in () pro, and () con.. Perhaps because of that debate, since that time several illuminating studies have been published. Here are a couple of them.

The effects of stress management training on clinical events and medical expenses were assessed for 5 years in 94 men who had CAD and mental stress induced or ambulatory induced myocardial ischemia (). The exercise group received 16 weeks of aerobic exercise 3 times per week. The stress management group received 16 weeks of stress management (). Compared to the usual care group, the stress management group showed significant reduction in CAD events for the first two years and at the 5-year mark. Relative to usual care and exercise groups, the stress management group showed lower medical costs over the first two years, and relative to the treatment as usual group the medical costs were less at the 5-year mark.

Effects of exercise or stress management training on markers of cardiovascular risk were assessed in 134 (92 men and 42 women) patients who had stable ischemic heart disease and exercise-induced myocardial ischemia (). Three intervention groups were usual care, usual care plus 35 minutes of supervised aerobic exercise 3 times weekly for 16 weeks, and usual care plus 90 minutes of stress management training once a week for 16 weeks. Most patients were taking aspirin, most took lipid lowering medications or â-blockers, and about half took calcium channel blockers. The usual care group was not supposed to either exercise or undergo stress reduction therapy.

The stress management group usually had 8 folks per group. Three principle components of stress management were education, skills training, and social support (). Stress was defined as excessive demands balanced against inadequate coping skills.

Education included information about

IHD,
normal heart structure and function, and
traditional and psychological risk factors.

Skills training encompassed reducing affective, behavioral, cognitive, and physical aspects of stress. It made use of

graded tasks
being aware of irrational automatic thoughts
producing alternative interpretations of situations or unrealistic thoughts
problem solving
time management
assertiveness training
progressive muscle relaxation
guided imagery
role playing

After the 16 weeks, Beck Depression Inventory (BDI) scores for exercise and stress management were significantly better than the usual care and about equal with each other (p = 0.02). Stress as measured by the General Health Questionnaire (GHQ) was significantly and approximately equally reduced (p = 0.02). These measurements are quite important because distress measured on the BDI and GHQ has been independently associated with poorer prognosis among those who have IHD (, ). And, reported in 2002, the Psychophysiological Investigations of Myocardial Ischemia study demonstrated that in patients with CAD and subsequent exercise-induced ischemia, the occurrence of mental stress-induced ischemia predicted subsequent death ().

The following significant improvements were seen for cardiovascular markers for both interventions compared to the usual care: decreased left ventricular ejection fraction reduction during mental stress testing (p = 0.03); wall motion abnormalities (p = 0.02); flow mediated dilation (p = 0.03); and baroreflex sensitivity (p = 0.04).

Of considerable interest are the effects of stress management on cardiovascular functions. Usual care showed a 1% improvement in treadmill duration, aerobic exercise resulted in a 19% improvement, while stress management without exercise showed a 9% improvement. Peak oxygen consumption showed a 1% decrement in the usual care group, a 6% improvement in the aerobic group, and a 4% improvement in the stress management group. The mechanisms behind improvement in endothelial functions with stress management are unknown

The researchers concluded that exercise and stress management interventions decreased emotional distress and improved cardiovascular risk marker significantly more than the usual care. The clinical significance of these changes in the long term is unknown (, ). It is also unknown what the effects might be of combining stress management and exercise.

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