Studies reporting effects of chronic stressors on cardiovascular disease are more likely epidemiological than patho-physiological in nature. They usually focus on topics such as job stress, marital discord, or perceptions of being treated unfairly. However, there is a beginning interest in chronic every day hassles that vitiate one's morale and may have health consequences. These everyday niggling aggravations are certainly not benign in terms of morale. In addition, chronic hassles are associated with worsening health behaviors in terms of smoking and exercise (19
) and in terms of levels of inflammatory and procoagulant markers (20
). Although most of the chronic stressor research focuses on more virulent stressors, this study of day-to-day micro-stressors is likely to be a focus of increasing future research.
The paradigmatic studies of chronic stressors examine BP during wartime. For instance, during the siege of Leningrad, BP increased dramatically. What is more striking is that the effect of that siege combined with its starvation conditions cast a long shadow into the future. Even 50 years later, survivors of the Leningrad siege had increased BP and increased mortality from cardiovascular disease compared with Russians who had not been in the besieged city (21
The INTERHEART study (22
) investigated the relation of chronic stressors to incidence of MI in a sample of ~25,000 people from 52 countries. Stress was defined as “feeling irritable, filled with anxiety, or as having sleeping difficulties as a result of conditions at work or at home.” After adjusting for age, gender, geographic region, and smoking, those who reported “permanent stress” at work or at home had >2.1 times the risk for developing an MI.
Of course these reports of stress are subjective, but stress is, after all, subjective. The problem is that after sustaining a cardiac event, the patient strives harder to remember stressors, a kind of retrospective distortion of history that can introduce bias. The only way around that is to prospectively assess stress and wait for the onset of cardiac events. That kind of study requires large sample sizes in the general population or somewhat smaller sample sizes in high-risk patients. There are some such studies concerning chronic job stress.
One model for job stress views jobs that are highly demanding and that allow the employee relatively little control as “high stress.” An alternate model for job stress considers effort–reward imbalance, a mismatch between high efforts at work and low reward. There are many epidemiologic studies suggesting that individuals with such high-stress jobs are at increased cardiovascular risk. Studies from Stockholm (23
) found that initial MI patients were significantly more likely to have high work demands and low control. The Whitehall II study (24
) found a 2.15-fold increased risk for new coronary heart disease in men who experienced a mismatch between effort and reward at work. The high-risk subjects were those who were competitive, hostile, and overcommitted at work, in the face of poor promotion prospects and blocked careers.
Increasingly, studies are examining possible pathophysiological pathways of job stress. How does job stress increase risk? While the answer to that question is enormously complicated, tantalizing data are accumulating. Subjects who are in low control jobs have blunted baroreflex sensitivity; that is, when their BP increases, they fail to make the appropriate adjustments of HR (25
). Other studies have demonstrated that workers with low job control respond to stressors in the laboratory environment with increased fibrinogen (26
). Such studies seem to suggest that the job-stressed patient is primed to hyper-respond to stressors even outside of the work environment.
Freud said that happiness comes when one has pleasure in love and work. Orth-Gomer et al. (27
) studied the impact of work stress and marital stress on the subsequent incidence of CAD in a cohort of Stockholm women followed for ~5 years. Marital stress was associated with a 2.9-fold increased risk of recurrent events, whereas work stress did not predict subsequent coronary events in these women. Similar data are available for men in the MRFIT (Multiple Risk Factor Intervention Trial). That trial found that chronic work stress and marital dissolution increased the risk of cardiovascular mortality in men who were followed for 9 years (28
). As the late Dutch internist Johannes Groen (one of the original observers of the link between dietary cholesterol and heart disease) used to say, “What's a man to do, where can he go if he is unhappy at work and
at home?” The implied, if somewhat flamboyant, answer was always “to an early grave.”
There have been some interesting recent reports examining how chronic stress may relate to some of the physiological underpinnings of cardiac risk. Two unhappily prevalent chronic stressors (discrimination and caregiving) have provided informative data about how these risks operate.
Experience of ethnic discrimination is a lancinating event that echoes over a lifetime. While florid discrimination is less present in the U.S., subtle micro-aggressions based on race, religion, and so on are common. Other than being upsetting, does discrimination have a cardiac toll? In a recent study, Thomas et al. (29
) examined how perceived discrimination was related to pressor sensitivity in healthy subjects. Phenylephrine was infused intravenously, and the investigators examined the resulting increase in diastolic BP. Regardless of race, those subjects who reported experiencing more discrimination in their lives had a significantly increased pressor sensitivity in the face of equivalent amounts of SNS agonist infusion ().
Effect of Perceived Discrimination on Pressor Sensitivity
Millions of Americans provide caregiving for an ill family member. One of the most frequent and harrowing scenarios for caregiving involves taking care of a spouse with dementia. The unremitting downhill course of the patient is profoundly dispiriting for the caregiver. The Caregiver Health Effects study (30
) followed ~400 caregivers and ~400 matched control subjects. In a 4-year period, caregivers had a 63% higher mortality rate than noncaregiving control subjects. The increased mortality was particularly evident in caregivers who already had known cardiovascular disease. In a series of mechanistically oriented studies, the San Diego Caregiver study examined possible pathways between caregiving and cardiovascular disease. The investigators found that distressed caregivers had an increased risk for developing hypertension when followed over a 6-year period (31
). Other reports from this group have found that caregivers have increased levels of D-dimer, a circulating procoagulant factor (32
), more sleep disruption, and higher level of circulating plasma inflammatory cytokines (33
Vulnerability, Resilience, and Treatment Considerations
At this point certain tough questions about stress and heart disease need to be answered.
- Are the data unanimous about the effects of stress on cardiovascular disease? Obviously not. There are contradictory studies about all risks; not all studies, for instance, find that increased cholesterol is associated with angiographically-proven CAD. From the earliest days of cardiology, there has been a suspicion that stress has powerful adverse effects on the heart. In the first volume of Circulation, for instance, one finds the topic reviewed by Harold Wolff (34). Over the years, the empirical reports and reviews have proliferated, and this review tries to give a contemporary overview of the sorts of approaches being examined at the start of the 21st century. One would have to conclude that the overall data suggest that stress contributes to adverse clinical cardiac events and provides a milieu of increased vulnerability to the heart. That is not to say that “stress causes heart disease.” That simplistic notion is nonviable (as is a similar statement that “high cholesterol causes heart disease”) because heart disease is so heterogeneous and multiply-determined in terms of vulnerability and resilience.
- How important is stress in comparison with more traditional risk factors like elevated cholesterol? There are different ways of quantifying cholesterol's risks in populations with varying degrees of vulnerability. However, if one examines the risk of increased cholesterol in studies such as the Framingham study, relative risks of total cholesterol 200 to 239 mg/dl are 1.31; for total cholesterol levels >240 mg/dl, the risks are approximately 1.9 (35). Many of the stressor studies reviewed above show risk gradients comparable to or steeper than the risk gradient of elevated cholesterol.
- Is not all of the effect of stress on the heart due to other adverse behaviors such as smoking? Sure, smoking is poison. No argument. The problem is that once people are addicted, it becomes enormously difficult to get them off tobacco when their life stress and depression levels are elevated (36). In addition, many of the larger epidemiologic studies referenced in the preceding text controlled for risk-enhancing behaviors such as smoking and obesity. Thus, one way or another, stress has to be dealt with in modifying other health behaviors.
- Will considerations of stress lead to a flood of forensic cases? Yes. Extensive case law is accumulating concerning the role of stress and heart disease, and most physicians who do forensic work in psychiatry or cardiology can expect to be asked to testify in such cases. Short-term unusual severe stressors as well as job stress allegations are already heavily present on the court dockets, particularly in workmen's compensation cases. Courts are interested in whether stress “caused” or “contributed to” the development of a condition. Given the multiply-determined nature of cardiovascular disease, it is clear that psychological stressors contribute to cardiovascular disease, but “how much?” It is hard to assert that “stress caused this patient's disease,” just as one would be hard pressed to state that a “high fat diet caused this patient's disease.” Courts are also troubled about how to handle populations of extra vulnerability. Could a stressful stimulus be reasonably expected to elicit a fatal arrhythmia in the “average” patient with arrhythmias? Can one assign blame/causation/contribution when the stressor was relatively mild but the patient was singularly vulnerable (e.g., patients with long QT syndrome)? Thus, the answer to the question about forensic implications of stress is that our society has already been wrestling with this issue for a long time.
- Because stress is everywhere, what good does it do to identify a risk factor that cannot be modified? There are 2 replies to this question. Stress is no different from other background cardiac risk factors such as genetics or age. There is no reason to ignore such factors, just because they are not modifiable. However, stress can be modified through numerous approaches. It remains to be proven if such stress modifications consistently decrease the risk for MI and cardiac death (37). However, in terms of more modest goals, the interventions are certainly effective in addressing other end points such as patient well-being. Diverse and effective stress intervention programs have been tested in heart patients, programs that provide formal psychotherapy, psychotropic medications, time management training, progressive relaxation training, meditation, or regular exercise. The therapeutic nihilists are wrong. The majority of these intervention programs improve patients’ morale and functioning and decrease suffering. Increasingly, such programs are tracking markers of cardiovascular risk (such as endothelial function) as opposed to cardiac events and find that the psychosocial intervention programs have positive effects (38). The powerful effects of behavioral interventions sometimes become evident by serendipity. Years ago, we were infusing isoproterenol as a way of measuring in vivo beta-adrenergic receptor sensitivity. The average HR response to increasing doses of isoproterenol was admirably consistent until we happened to study a subject who got bored with the testing and started quietly meditating (39). No increased HR was detected! provides graphic detail of the potential powers of behavioral intervention to block even pharmacologic stress effects.
Effect of Meditation on HR Response to Infused Isoproterenol