The Spring 1999 issue of Cerebrum looked at how the brain and heart interact in the weeks following a heart attack (“Looking to the Brain to Save the Heart”). Now two Yale University scientists ask what role the brain may play in setting us up for coronary artery disease, heart attacks, and sudden death.
For decades, acute and chronic stress have been leading suspects in this story, but how do our brains actually translate life’s myriad stresses into heightened risk for the heart? As scientists answer that question, they are also discovering who among us is most vulnerable to that risk—and what we can do about it.
You cannot miss your 8:00 a.m. meeting. You leave home an extra 30 minutes early for the hour’s drive to work. Two miles from your office, an accident brings trafﬁc to a virtual standstill. The clock on your dashboard reads 7:45. It will take you at least 45 minutes to creep the last two miles. As you rhythmically tap on the steering wheel, your forehead and palms become moist. You switch on the radio for a traffic report, but the announcer is describing last night’s crime news. Your heart races; your blood pressure soars.
The body’s response to psychological and social stress engages many organs: the brain, heart, kidneys, adrenal glands, and intestines, to name a few. The nature of the body’s response is hardwired, genetically programmed to promote your survival. But all stressful events are not equal. There are concrete catastrophes like the September 11 terrorist attacks, and there are the hassles of daily life, including interactions with your family, friends, and colleagues. The biological response that readies you to cope with both types of threat is the ﬁght-or-ﬂight reaction. Perceiving danger unleashes a cascade of biological reactions that start in your brain, causing the release of hormones such as norepinephrine and epinephrine (commonly called adrenaline) that make your pupils dilate, the better to see the events unfolding around you; your heart beat faster, the better to pump more blood to your brain; and your muscles react more quickly, the better to defend yourself or to ﬂee.
If prolonged or constantly repeated, this biological reaction may heighten your risk for coronary artery disease, the leading cause of death in America. That risk appears to be pervasive in our society. Stress is experienced by a new vice president of the United States and by a worker who punches a time card. Today’s investigation of the role of stress in developing heart disease is driven, in part, by the realization that the traditional risk factors—smoking, high cholesterol, and high blood pressure—do not fully account for the frequency of heart disease in Western culture.
Intuitively, we sense that our personal attitudes and coping styles are signiﬁcant, but do they get translated into damage to the heart?
Your biological responses to stress are determined by a combination of genetic, behavioral, and cultural variables. New research is helping us identify who may be most susceptible to stress-related heart disease and enable them to modify at least some of the factors that put them at higher risk.
A fundamental issue is determining the brain’s action in bringing about stress-induced coronary artery disease. Intuitively, we sense that our personal attitudes and coping styles are signiﬁcant, but do they get translated into damage to the heart? We know, for example, that the brain releases hormones that direct the body’s response to stress and have temporary or long-term effects on the heart, but for which people does this process become life-threatening, and what can be done to intervene in that process?
THE AROUSED BRAIN, THE REACTING HEART
To answer those questions, we must ask three more:
- Why are some people consistently more emotionally reactive than others?
- Are there consistent and repeatable traits that make these people more likely to suffer stress-related heart disease?
- Are there tests that can detect this potentially risky interaction of brain and heart?
Our individual pattern of emotional reactivity is related to our own memories, stored in various brain regions. These regions, acting within a complex network, shape our bodily sensations. The brain then reacts to these sensations by generating our biological coping response. If that coping response is called on again and again in a susceptible person, it can have long-term effects on the brain and cardiovascular system. Not everyone has the same coping style, however, so we are not all equally vulnerable to the effects of stress on the brain, the heart, or both. We know now that individual differences in cardiac vulnerability to mental stress arise from differences in the formation, consolidation, and retrieval of long-term memories, emotional reactivity (coping responses), and psychological proﬁle. As in many other ﬁelds, imaging techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have catalyzed this research. We can now watch how speciﬁc regions of the brain act in the presence of different kinds of stress.
If the brain is pivotal in our body’s response to stress and, as research now suggests, may initiate (or further) stress-mediated coronary artery disease, we can begin by describing the patterns in the brain that appear to correspond with the biological response to stressful events.
When they are appropriate, stress and fear may heighten our performance and aid us in attaining our goals. For competition in sports or achievement in school or business, an appropriate level of stress may be essential. But the same stress response, when inappropriate to the situation—such as in stalled trafﬁc or while waiting in line or puzzling over a computer glitch—may have biological consequences that are potentially harmful, particularly for our hearts. How does the ﬁght-or-ﬂight response, which can be essential for survival, become a stressful reaction to circumstances that apparently present no realistic threat at all? The answer may be found in the concept of conditioning, developed early in the 20th century by the Soviet scientist Ivan Pavlov.
How does the fight-or-flight response, which can be essential for survival, become a stressful reaction to circumstances that apparently present no realistic threat at all?
Through conditioning, a natural or appropriate trigger to a physiological reaction may be replaced by an inappropriate trigger. Pavlov’s famous experiments showed that dogs could be conditioned to have a distinct physiological response (salivating and secreting digestive juices in their stomachs) not when they saw food, as was usual, but when they heard a bell. In these experiments, Pavlov sounded a bell whenever the dog was fed; the dog’s brain associated the bell and the food so closely that just hearing the bell would stimulate the full biological response. The dog’s brain now associated an unnatural trigger (the bell) with the food (a natural trigger). For human beings, appropriate triggers of a stress response may become paired with inappropriate triggers, so that our stress and fear become unnecessary, or excessive, for the circumstances. For example, a child punished in a basement on several occasions could develop into an adult afraid of basements, because basements and punishment have become paired. This reﬂexive response of the brain involves both learning and memory.
To explain exactly how the brain makes the associations that underlie conditioning, neuroscientists invoke the concept of brain plasticity. Plasticity is what allows our brains to incorporate new information through a process that occurs at the level of our neurons. In 1949, the Canadian physiologist Donald Hebb showed that if several neurons receive a stimulus at the same time, they ﬁre together. When they do, they tend to form connections and thereafter to ﬁre in response to the same kind of stimulus. The working groups of neurons involved in this dynamic process are called neuronal assemblies; the process that connects them is called long-term potentiation or LTP. LTP and plasticity can explain the association of unnatural to natural triggers that we call conditioning.
Components of the brain that contribute to emotion are located in the limbic system (left), which includes the hypothalamus, hippocampus, amygdala, and cingulate gyrus. As part of the brain circuit that mediates the fear response, the limbic system can increase heart rate and blood pressure. Although the cerebral cortex can become hyperactive during mental stress (right, brain scan on the left); it also can deactivate (brain scan right), masking pain that otherwise might warn of potential cardiovascular distress.
Courtesy of Robert Soufer and Assen Chekerdjiev
Where does this take place? Much of our knowledge of LTP and plasticity comes from studying the hippocampus, the brain region most often associated with memory. In the hippocampus, LTP occurs at the level of cells and molecules, molding and changing the brain in response to circumstances in ways that may profoundly alter the nature of the stress/fear conditioned response.
This theory may explain how we come to experience stress in reaction to various cues in daily life, cues that have been established through memory and learning that occurs in a speciﬁc structure of the brain. There are other brain structures and regions, however, that coordinate critical components of our biological response to stress.
A BRAIN MAP OF STRESS
Building on the work of the famed American physiologist Walter B. Cannon, James Papez, a professor at Cornell University, advanced the idea of discrete areas deep in the brain that constitute a kind of Emotion Central. He called this hub, where the different components of the brain that contribute to emotion interact with one another, the limbic system (see earlier illustration). Its components are the hypothalamus, which controls various biological functions; the hippocampus complex, which supplies memories and context; the amygdala, which integrates information from other brain regions; and the cingulate gyrus, which helps form connections that create our awareness of emotions. Together these structures of the limbic system make possible our perception of danger, our experience of fear (amygdala), and the assigning of meaning and context to our perceptions.
The brain’s role in switching on this neurochemical contribution to fear, stress, and anxiety is the crux of brain-heart interaction.
In this model, ﬁrst we perceive a stimulus, which enters a portion of the brain called the thalamus. The role of the thalamus is to ﬁlter stimuli, producing signals that get sent to the brain’s higher centers (the cortex) or to the hypothalamus (a part of the limbic system that ampliﬁes our emotions through the overlay of memory). The hippocampus and amygdala cooperate in calling up long-term memories that shape how we behave in response to stress. Our biological reaction to the activation of these areas in the limbic system can be increased heart rate and blood pressure, bringing harm to the cardiovascular system.
The chemical link between the brain (limbic system) and the body’s response is adrenaline and the related hormone noradrenaline. The brain’s role in switching on this neurochemical contribution to fear, stress, and anxiety is the crux of brain-heart interaction. Adrenaline itself is secreted by a small gland on top of our kidneys called the adrenal gland, but the secretion is a response to stimuli from the brain—speciﬁcally the hypothalamus. This process can be self-reinforcing because adrenaline, in turn, affects the brain by stimulating a small island of gray matter at the base of the brain called the locus ceruleus, which then completes the loop by producing more noradrenaline or norepinephrine.
Noradrenaline secreted by the locus ceruleus has direct pathways to two areas of the limbic system: the amygdala and the hippocampus. Scientists are now asking how stress hormones activate memories and contextual information in the brain so as to initiate and aggravate the progression of heart disease. We must also look at how the brain may mask important warning symptoms of stress-related heart disease, such as chest pain.
AFFECTING THE HEART
The ﬂow of adrenaline hormones stimulates our nervous system. Research has linked this stimulation to the occurrence of sudden cardiac death and to increases in overall deaths from cardiac-related causes. How does this occur?
The nervous systems has two parts, one that speeds up many bodily functions (the sympathetic nervous system) and one that slows them down (the parasympathetic system). When control of the parasympathetic system is impaired—for example, as a result of increased stress and anxiety—a person can become vulnerable to abnormal heart rhythms that boost the risk of sudden death. People with increased stress and anxiety do not seem to have control over this portion of their nervous system.
Look at this process in more detail. The increase in adrenal hormones as a result of stress can have effects ranging from a more rapid heart rate and higher blood pressure to reduced ﬂow of blood through coronary artery vessels that feed the heart. Animal studies have shown that hyperactivation of our nervous system can actually contribute to accumulation of fatty deposits (atheromatous plaque) and make platelets stickier in the coronary blood vessels. Furthermore, under conditions of chronic psychological stress, the linings of the blood vessels may be damaged; blood ﬂow through the coronary arteries can be impaired because the blood vessels do not dilate in appropriate situations. New studies in humans suggest that stress-related heart disease does not require critical narrowing of the heart blood vessels. Emotional stress activates our nervous system with a release of hormones that contribute to sluggish blood ﬂow to the heart by increasing the size of our plaques, causing these vessels to constrict. This occurs just as the heart muscle requires more blood, because the same hormones increases heart rate and blood pressure.
There are situations, such as the death of a loved one, that can create signiﬁcant acute stress. Stress at this level has been reported to contribute to the development of heart disease, to increase the incidence of heart attacks, and to lead to death. The incidence of cardiac-related events is increased similarly in the immediate aftermath of a stressful event such as an earthquake, ﬂood, or terrorist activity. On the day the massive Los Angeles earthquake of 1994 struck, cardiac deaths from coronary artery disease soared from a daily average of 4.6 to 24. Similarly, the ﬁrst day of Iraqi missile strikes on Israeli cities during the Gulf War saw a sharp rise in cardiac deaths in Israel.
To understand these dramatic changes, we should look at the different ways the heart responds to mental stress. The response begins with the amount of blood ﬂowing to the heart muscle. If, in response to mental stress, this blood ﬂow is mildly inadequate, it is called myocardial ischemia. If the blood ﬂow to the heart is moderately to severely reduced as a result of mental stress over time, a heart attack, or myocardial infarction, may occur. During myocardial ischemia and infarction, abnormal heart rhythms can occur; when they are fatal, we speak of sudden cardiac death. Our laboratory and others have performed several experiments in which psychological stress is induced in order to measure its effects on the heart. Among patients with coronary artery disease, half will experience myocardial ischemia from the stress, often without chest pain and not discernible by routine EKG. This can be reﬂected in a decrease in pumping ability, as seen on an echocardiogram, or as a “cold spot”on a nuclear perfusion image, indicating that the area is getting an inadequate blood supply.
Mental-stress-induced myocardial ischemia results from a mild elevation of the person’s heart rate, along with a greater elevation in blood pressure. The ischemia may be substantial—comparable to that experienced during exercise. During stressful periods, oxygen demand increases, as it does during exercise. Stress may also reduce blood ﬂow by constricting coronary vessels, which may occur in patients with coronary artery disease. A person need not suffer from severe coronary artery disease for coronary constriction to occur, because this constriction, and the increase in blood pressure and heart rate, result directly from the neurohormonal stimulation initiated by the brain.
Our laboratory conducted an experiment that combines several of these concepts. The earlier illustration shows activation (left side) and deactivation (right side) of the brain during stress induced in the laboratory. The activated areas on the left are regions of the brain we have been discussing —such as the hippocampus—in a patient who exhibited myocardial ischemia in response to stress. The ﬁgure on the right illustrates different areas of the brain, the areas of less activity, which were deactivated during myocardial ischemia induced by stress. The latter areas of the brain, which are responsible for pain, have less blood ﬂow and less activation; this may account for the absence of pain—a potentially crucial warning signal—during myocardial ischemia caused by stress.
WHO IS MOST VULNERABLE?
Many scientists have asked whether particular personality patterns or individual personality traits might promote the development of coronary artery disease, in particular, stress-related myocardial ischemia and heart attacks. In the 1950s, Friedman and Rosen-man made famous what they called the Type A behavior pattern, characterized by hostility, competition, and an extremely intense commitment to work. Other studies conﬁrmed and reﬁned this concept. Researchers monitoring subjects for eight and a half years linked Type A behavior with a twofold increase in coronary artery disease and a ﬁvefold increase in recurrent heart attacks.
Another series of studies, however, reported no correlation between Type A behavior and risk for developing coronary artery disease. Why this inconsistency? One good hypothesis is that it results from failure to take into account important differences in the lives of Type A people. The amount of social support they have in life has been shown to be a factor, for example.
Looking still more closely, speciﬁc traits such as hostility may loom large in the vulnerability of the Type A personality (and even hostility may be colored by variables such as anger, cynicism, or mistrust). So the overall problems such a person has with personal relationships may be analyzed into speciﬁc patterns that will be pertinent predictors of mental stress-induced myocardial ischemia. Studies have reported that patients with coronary artery disease who have high levels of hostility more frequently experience coronary closure after balloon angioplasty; they also experience more rapid progression of atheromatous plaques in their carotid arteries (which provide blood ﬂow to the brain). These patients also manifest more myocardial ischemia during routine exercise stress testing than other patients with the same disease. What seems to make the Type A personality more vulnerable to these heart problems is a stronger emotional reaction and greater activation of the nervous system during psychological and social confrontations.
Among patients who have had a heart attack, those with very little social support are three times as likely to have another heart attack as those with strong social support.
Since social support is a key variable in predicting the Type A person’s vulnerability, the nature of a person’s social support system (or how much emotional support he feels he is getting) has been studied in relation to development of coronary artery disease. Having very little social support has been found on average to double or triple the incidence of coronary artery disease; these consequences can occur over as little as a two-and-a-half-year or as long as a ﬁfteen-year period. Among patients who have had a heart attack, those with very little social support are three times as likely to have another heart attack as those with strong social support.
Another crucial variable is depression. Quite apart from personality traits and social support, mood disorders like depression can predispose a person to heart problems. In particular, studies show that depression increases the risk of subsequent heart attacks after the ﬁrst one. One of every six heart attack patients is clinically depressed, but the risk of subsequent heart attacks apparently decreases when the depression is treated. Beyond the risk of recurrent heart attacks, depression is now known to have negative effects on our health in diverse cardiovascular situations: balloon angioplasty and stent replacement, coronary artery bypass surgery, and myocardial infarction. In all these clinical situations, depression worsens all outcomes.
WHAT WE CAN DO
Obviously we must ﬁnd more therapies that reduce the risk of stress-related heart disease. Recent work gives us important clues to the direction that might be taken. A new study published afﬁrms the value of psychosocial treatment for myocardial ischemia that is induced by mental stress. Scientists at Duke University examined the effects of exercise and training in stress management on how well some 100 patients with coronary artery disease, and evidence of vulnerability to mental-stress-induced myocardial ischemia, fared over ﬁve years. The patients in the study were given a tailored stress-management program that focused on how they interacted with their surroundings. In 16 sessions of 90 minutes each, groups of eight subjects were taught how to lessen emotional and behavioral components of stress. They also learned muscle relaxation techniques and biofeedback. The people who got this training had many fewer cardiac-related problems than people in a comparison group who received only training in exercise for aerobic conditioning.
In particular, stress management appeared to reduce the number of heart attacks and the need for diagnostic evaluation using a catheter or balloon angioplasty. Health care costs dropped by more than a third for the patients who were taught stress management. An important ﬁnding of the study was that psychosocial interventions were more likely to produce good results when they targeted individuals already identiﬁed by clinical interviews as being at increased risk for emotional stress-related heart problems.
But once again, as with the study of the Type A personality, we see conﬂicting results. Studies similar to the one just described have demonstrated no signiﬁcant reduction in negative outcomes from coronary artery disease. The difference may be that the psychosocial interventions used by the other studies did not speciﬁcally reduce emotional distress, perhaps because they were not directed toward patients who were likely, because of their mood, to need and beneﬁt from an such intervention.
More studies are needed on a larger patient population, including women. Reports in the last few years have shown the potential to improve long-term cardiac prognosis and psychological status for both men and women with depression. Those patients who actually respond to behavioral therapy with reduced anxiety levels and depression have an improved overall cardiovascular prognosis.
Newer therapies for patients with depression combine antidepressant medication with cognitive therapy. Initial results are promising, indicating the value of treatment with antidepressants for patients who have had heart attacks. Although it is too early to say for sure, it appears that drugs such as Prozac may be helpful in reducing the chances for additional heart attacks in these patients. This class of drugs is also known to reduce the stickiness of platelets, potentially lessening the possibility of thrombi that form in the coronary artery— the initial event in the heart attack process.
WHAT WE HAVE LEARNED
These, then, are the vital links in the brain-heart interaction during stress. Our emotional reactivity and psychosocial stress are processed in the brain, activating various regions that evaluate complex situations and integrate our memory and emotional variables to produce an increased response from our nervous system. This increase in discharge from the sympathetic nervous system has certain biological effects that result in an increase in heart rate, blood pressure, and constriction of our coronary artery vessels. These biological effects may increase the frequency of fatal heart rhythms and promote further atheromatous plaque, which decreases blood ﬂow to the heart muscle and results in myocardial ischemia or, if progressive, heart attack. Certain personality traits such as hostility, cynicism, and anger, as well as social variables such as social support and mood disorders, may make some people more vulnerable to myocardial ischemia induced by mental stress. Studies at present support the idea that, for these people, cognitive and behavioral therapies can reduce emotional reactivity. In addition, the medical treatment of mood disorders and attention to social support may have a beneﬁcial effect on stress-related heart disease.
Just a decade ago, there was no consensus among scientists that a person’s attitude or mood could have profound effect on the progression of heart disease. Now, the concept is taking hold among cardiologists. But the small studies we have mentioned, which examined the beneﬁt of cognitive therapy and tailored drug therapy, need to be reinforced with larger studies of both men and women.
A well-informed patient today can ﬁnd a hospital or doctor known to be sensitive to the psychosocial aspects of coronary artery disease, but in the future, visits to your cardiologist may routinely involve questionnaires that assess your psychosocial status, social support, and mood. In many communities, health psychologists are supporting the treatment of coronary artery disease in the same way that nutritionists support an endocrinologist who is treating diabetes. Growing evidence of how psychosocial intervention can reduce the risks faced by coronary artery disease patients should lead to an emphasis on behavioral modiﬁcation, drug therapy, or both for patients at high risk for stress-related heart disease. We are encountering patients keenly aware of these concepts and receptive to suggestions that their lifestyle and psychosocial problems affect their health. Such awareness can only increase as we grasp that to protect the heart, we must understand the brain.