Introduction
Gary Carlson / Photo Researchers, Inc.
The way Hollywood tells it, heart attacks typically strike after fights with spouses or in the wake of sudden, shocking events. With fists clutched to the chest, the lead character struggles as emotion literally overwhelms the heart and stops it from beating. Researchers now believe there may be a shred of truth in this Hollywood cliché. However, although cardiac events are sometimes linked to sudden emotional stressors, the researchers suspect the culprits are more often the long-term, chronic forms of depression and anxiety.
"The link between depression and heart disease has been explored from every angle, and there is a strong relationship here," says Nancy Frasure-Smith of McGill University in Montreal, Canada.
Along with her colleagues from the Montreal Heart Institute, Frasure-Smith spent two years following more than 800 people with stable heart disease, including about 100 individuals who also suffered from depression or anxiety. During the course of the study, 26% of the group with depression experienced a major repeat cardiac event, including an emergency bypass surgery or sudden death from a heart attack. By comparison, 13% of the subjects who did not suffer from these psychiatric conditions experienced such cardiac events1.
"The evidence keeps growing stronger. It's no surprise that anxiety factors in, as well," says Frasure-Smith, who also conducts research at the University of Montreal.
The study bolsters a growing body of evidence that suggests depression has a role in heart disease.
In the mid-1990s, a groundbreaking study compared approximately 450 depressed individuals to a reference group with more than 1,000 members. The investigators found that people with major depressive disorder were twice as likely as those in the control group to suffer a first-time heart attack over the course of the 13-year study. What's more, even those participants who said they had experienced a blue streak lasting longer than two weeks, but didn't suffer from clinical depression, still had a 74% higher risk of heart attack than the control group2.
"People said [the extra heart risk] was due to the smoking and irregular sleeping schedules that depressed people sometimes fall prone to," says Laura Pratt, an epidemiologist at the US Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, who helped conduct the study. "But we were able to show the relationship was with the depression itself. These other lifestyle factors don't play a significant role."
The study offered the first sizable glimpse into the connection between depression and heart disease, according to Pratt, who was a graduate student at the Johns Hopkins University Bloomberg School of Public Health when it was published. "I was surprised we saw such a clear risk factor," she says, referring to mood. "The findings made people reconsider their views of depression and start taking it more seriously."
Of all the research indicating that our emotions affect our health, examples of heart disease are perhaps the best documented. "Depression, stress and anxiety are easier to study because they can be clinically diagnosed, and it's something that impacts a lot of people," says Michael Irwin, an immunologist at the University of California, Los Angeles.
Real heartache: Can feelings influence inflammation?
The part distress plays in cardiac diseases has historically been a primary focus of 'psychoneuroimmunology'—the study of how emotions can influence immune and nervous system function and related health problems.
The field gained attention in the 1970s when laboratory animal studies began to show that biological stressors such as noise, overcrowding and restraint disrupt the immune system3, 4, 5. Around the same time that animal studies were sparking interest, researchers noticed that people who lose a job, declare bankruptcy or lose a spouse are more likely to suffer a heart attack6.
Whereas these early studies focused on nonspecific forms of distress, nowadays studies involve a strict diagnosis of depression and anxiety—sometimes limiting samples to severe cases of clinical depression and phobic disorders.
One study found that in comparison to control groups, people with phobic, panic-like anxiety had a nearly three-fold higher chance for developing fatal coronary heart disease when evaluated at a seven-year follow-up7. A separate study of 34,000 male health professionals revealed that those with phobic anxiety were 150% more likely to develop fatal heart disease than those with few or no psychological symptoms8. Similarly, female homemakers who suffered a heart attack or fatal cardiac event scored 50% higher on an anxiety test than those who did not experience this type of incident9. Hostility and anger have also been shown to predict the development of coronary heart disease, although the evidence is more limited.
Totally inflamed
Over the past 15 years, researchers have also shown that depression, anxiety and loneliness are linked to inflammation—an important factor in heart disease. At the molecular level, this connection can be traced back to cytokines—proteins produced by immune cells that invoke an inflammatory response. Researchers have found levels of certain cytokines are much higher in people experiencing distress, grief, depression and other difficult emotions10, 11.
Although scientists don't know why cytokine expression is higher in depressed and anxious people, they speculate that it might be because psychological stress can alter blood pressure and heart rate. Experts suggest these basic physiological changes can cause the release of cell signaling molecules that in turn boost cytokine production. Psychological stress can, for example, increase the abundance of a cell signaling molecule named NF-
B, which stimulates cytokine production.
"We are still at the descriptive phase," emphasizes Irwin. "There is a lot of interest here, but no one has clearly defined how depression and stress might cause increases in cytokines."
The link between cytokines and heart disease, on the other hand, is much better established. "Many cytokines are known to cause inflammation, and heart disease has a strong inflammatory component," explains Nick Cohen, emeritus professor of immunology at the University of Rochester, New York.
Evidence from animal and in vitro studies has implicated inflammation caused by cytokines in the development of arterial plaques12. Cytokines summon disease-fighting macrophages, which try to eat up the 'bad cholesterol' low-density lipoproteins that coat the arteries of people with heart disease. As overactive macrophages fill up with the frothy, fatty droplets, they lose their ability to move around. A fatty scar begins to form, eventually growing into plaque that hardens and clogs the arteries.
Although negative emotions have not been shown to increase the risk of developing diabetes or cancer, they are widely believed to exacerbate the progression of these illnesses. "There is evidence that once you have cancer, psychological distress and depression can exacerbate it," says Miller, "and these emotions have been linked to high levels of proinflammatory cytokines."
Diabetes is strongly linked with raised levels of interleukin-6 (IL-6)—a cytokine also affiliated with stress, depression and grief13. And although IL-6 is a crucial part of the body's disease-fighting system, it seems that this molecule can also cause disease when levels remain chronically high.
Research has also implicated cytokines in contributing to chemotherapy resistance and the transition of tumor cells into full-blown cancer. Some cytokines seem to induce angiogenesis—the formation of blood cells that feed tumors14, 15.
For all this, though, researchers warn that the relationship between negative emotions and ill health remains a mystery for the most part.
"Many years ago I got a phone call from an attorney whose client had developed cancer after being divorced and fired," says Cohen. "He wanted to know if there was evidence to hold the employer liable for causing stress, and potentially illness. Of course there is no way to prove that a single event caused a tumor to develop." And although negative emotions can play a part in illness, it is still thought to be more directly affected by environmental and genetic factors, say scientists.
Laughter, the best medicine?
People possess coping skills—we can forgive and forget, develop networks of social support, or practice meditation. The existence of these coping strategies makes it hard to pin all of the blame on psychological stressors for causing illness, even if they can potentially have a biochemical role. "Our ability to buffer stress and negative experiences is often overlooked during conversations about disease," says Cohen.
Laughter, happiness and self-esteem have been shown to lower the expression of certain cytokines that cause inflammation, such as IL-6. For example, researchers observed a 16% drop in IL-6 in subjects with rheumatoid arthritis—a group in which it is usually very difficult to reduce inflammation—after the subjects had watched an hour of rakugo, a traditional form of Japanese comedic storytelling16. And, in another experiment that involved showing participants clips of the slapstick movie There's Something About Mary, researchers linked laughter with boosted blood flow to the heart and relaxed arteries17.
An investigation involving 3,000 healthy British adults found that, among the female participants, those who reported feeling happy had much lower levels of IL-6. This held true even after researchers took into account the women's weight, smoking habits, income and employment—factors that can influence stress and well-being. The study did not find the same association in men, however18.
Meanwhile, a study of elderly Mexican-Americans found that optimistic adults with healthy self-esteem were half as likely to die during the course of a two-year study, even after the researchers controlled for body mass, smoking, drinking and age19.
Yet despite these findings, Cohen also warns that the data on happiness remains comparatively scant. "We simply don't know how much of an impact positive emotions really have," he says, "because most of the research has focused on depression and anxiety."
A change of heart
Good humor: Preliminary findings suggest health benefits from funny films.
On the basis of the preliminary evidence linking happiness to good health, a handful of trials have tried to treat depression in people with heart disease. Doctors running the trials reason that if depression can exacerbate inflammation, then patients might benefit from personalized treatment that addresses their psychological needs.
One preliminary study found that antidepressants lowered the incidence of severe cardiovascular events among depressed subjects. After following 369 people with heart disease and major depressive disorder for four years, researchers found that the incidence of severe cardiovascular events was only 14.5% in the group given the antidepressant sertraline (Zoloft), in comparison to 22.4% in the group given a placebo20. Experts say that they observed virtually no change in the level of depression experienced by patients over the course of the trial, and that this raises questions about whether lowering depression directly helps heart patients.
In another case, one of Frasure-Smith's early experiments monitored heart patients by phone for a year and provided stress-reduction interventions whenever they seemed depressed or anxious. Although the results showed that the treated group experienced fewer deaths, later attempts to repeat the study failed21, 22, 23.
So far, no trial has definitively shown that reducing depression helps reverse disease, perhaps indicating that the emotional link to the heart is more complex than predicted. "Right now, people are happy with the idea that that depression causes inflammation and thus heart disease," says Miller, "but the human body is much more complex than this."
It may be, for example, that depression and coronary problems share a common basis. "It's possible that depression is also exacerbated by the body's attempts to fight heart disease," says Cohen. "We simply don't know yet." Moreover, the sizes of trials to study the link are often too small to entirely rule out the lifestyle factors that affect depressed populations.
Cohen is quick to add, however, that future research must continue to flesh out the cytokine connection that seems to link the heart and mind: "There should be no question in any scientist's mind that behavioral and psychological factors impact the inflammatory response."
In the meantime, an increasing amount of molecular, animal and human data suggests that even before Hollywood weighed in on heart attacks, dramatists understood how mood might affect disease. After all, it was none other than William Shakespeare who wrote in his early comedy Love's Labour's Lost that "a light heart lives long."