Looking to the Brain to Save the Heart

Cardiologists have a growing arsenal of potent therapies to combat heart disease. They range from agents that prevent clotting (or entirely dissolve clots) to drugs that turn off the liver’s ability to synthesize cholesterol. Improved catheter techniques for coronary have revolutionized management of patients with coronary artery disease. With advances such as these, physicians have substantially reduced deaths from cardiac ailments, including acute myocardial infarction (heart attack), heart failure, and arrhythmias (variations in the normal rhythm of the heart). Unfortunately, it is becoming clear that—for all of this remarkable progress—the development and progression of heart disease remain poorly understood. We are paying a heavy price for our ignorance:

• Despite our best efforts, the incidence of new cases of heart disease remains essentially the same as in earlier decades.
• Heart disease remains the leading cause of death in the Western world.
• The prevalence of heart disease is rising in the whole developed world.

One study estimates that as many as half of all men and a quarter of all women will suffer from cardiovascular illness during their lives. As our population ages, even that proportion is likely to worsen unless we can improve our ability to identify those at risk and head off the disease. At the same time, we must find better ways to treat a growing population of patients who already have heart disease. Given the complexity of cardiovascular disease, even understanding the molecular mechanisms responsible for it may not be enough. Looking for a new avenue of attack, scientists are asking what can be learned from other fields. What they are discovering (or more properly, rediscovering) is the role of the brain.

While researchers have argued for years that a close link exists between brain and heart, most doctors have acted as if any apparent connections they observed in their patients were inconsequential. Patients who were depressed or anxious after a heart attack were, at best, given a pat on the shoulder and told it was only natural to feel “a bit down.”

Yet there are many well-described neural-cardiac syndromes. Among the best known is the profound change in the heart’s electrical system following severe neurologic injuries such as stroke or massive head trauma. These “cerebral” changes in heart functioning may actually result in fatal cardiac arrhythmias. Other less common associations have been recorded, including acute myocardial infarction caused by spasm of coronary arteries following brain hemorrhage. Another example is neurologically induced abnormality of cardiac rhythm. In one remarkable study, the heart rhythms of healthy medical residents were monitored during a routine in-hospital call. When the residents encountered unexpected stress, their ECG readings showed marked abnormalities (occasionally accompanied by life-threatening arrhythmias). Finally, emotional states of fear, anger, and “vital exhaustion” are linked with various acute, unstable coronary syndromes. In the days immediately following the 1994 Northridge California earthquake, the incidence of sudden death from heart attacks shot up sixfold.

Given this intriguing evidence of the brain–heart connection, and the need to find the “mystery ingredient” keeping the incidence of heart diseases so high, scientists are becoming very interested in the role of the neurologic system in the development, propagation, and exacerbation of heart disease. In recent years this interdisciplinary approach has been dubbed “neurocardiology.”

First, a little background.

Palpitating Worriors

For thousands of years, both the medical community and folk wisdom accepted that there was a close relationship between the mind and the heart. Even our modern understanding of the brain-heart connection goes back to the nineteenth century. In 1836 John C. Williams published a seminal text on “nervous and sympathetic palpitations of the heart,”¹ and following decades saw works describing neurologically based (“neurasthenic”) cardiac disorders. In the twentieth century, thinking about the brain-heart connection continued to evolve. At the turn of the century, the great physician Sir William Osler described his typical patient with angina pectoris as “a man whose engine is always set a full speed ahead.” Later, Osler noted that his coronary patients characteristically were “worriers.”²

Early pioneers in psychoanalysis seemed to confirm that certain emotional tendencies (e.g., anger, anxiety, or depression) and personality traits (e.g., the “Type A” personality) promoted coronary artery disease and could trigger heart attacks. These psychological states were assumed, as well, to have a negative impact on long-term prognosis following a heart attack.

In the 1960s, Stewart Wolf, M.D., reported what he called “joyless striving”³ among his cardiac patients, while Ray Rosenman, M.D., studied how individual personality traits might affect coronary artery disease. This period also saw pioneering work in cardiac electrophysiology by Bernard Lown, M.D., of the Harvard Medical School, who demonstrated an increased risk of sudden death caused by intense emotion. He hypothesized that a neurologically induced “electrical accident” of the heart could result in fatal cardiac arrhythmia.

In the 1980s, the link between brain and heart was studied by the neuroscientist Benjamin Natelson, M.D., who coined the term “neurocardiology.”⁴ Natelson set forth this interdisciplinary concept in response to modern medicine’s trend toward ultraspecialization, with its focus not on the patient as a whole but a given specialty’s organ of interest—the very error that Hippocrates had warned against in 200 B.C., advising, “Let no one persuade you to cure the headache until he has first given you his soul to be cured. For this is the great error of our day in the treatment of the human body, that physicians separate the soul from the body.”

Natelson argued that to understand the cardiovascular system scientists must take into account the intricate network of nerves linking sites in the brain to cardiac structures, including blood vessels, heart muscle, and even the specialized myocardial conduction system—the very “wiring” of the heart. In elegant studies, he and his contemporaries demonstrated the significance of these neurologic connections, including their potential pathologic roles.

Despite all this research, however, physicians and non-physicians alike became skeptical of the brain-heart link.

The “Type A” Personality

A close link between mood disorders and coronary artery disease had been suggested by large population-based studies in the 1970s and 1980s. In one study, the prevalence of depressed patients with demonstrable coronary artery disease was 18 percent, as compared with 5 percent in the general population. Similarly designed studies of patients with clinically diagnosed anxiety, as well as anger or hostility (identified via psychometric testing), all suggested a threefold to sixfold increase in risk for heart disease. The problem was the design of these studies. Most, if not all, were based on analysis of data not originally collected for psychiatric study. This raised justifiable concerns about bias.

The most famous example of shifting winds in neurocardiology’s interpretation of psychosocial factors is the concept of “Type A” personality disorder (TAPD). Characterized by hostility, aggressiveness, and urgency, TAPD may be the most extensively studied psychologic trait relating to heart disease. After it was implicated as a possible risk factor by Rosenman,⁵ in the late 1950s, TAPD was soon espoused by many others (and confirmed by several small and variably designed trials) as the marker for a true “coronary-prone personality.” Surprisingly, however, subsequent large-scale trials not only contradicted the link between TAPD and heart disease but suggested a possible salutary effect of TAPD on patients after their heart attack.

These paradoxical findings remain puzzling. It is possible that TAPD patients have better coping skills or that they more thoroughly modify their lifestyles (e.g., successfully quit smoking or comply better with medication), following a heart attack. Also, most of the contradictory studies looked only at the overall personality construct of TAPD. They did not consider the individual “toxic” components of TAPD such as hostility, cynicism, or anger. Those traits, although more common among Type A patients as a whole, are not universal among them.

Given these seemingly conflicting data on TAPD, many physicians by the mid-1980s discarded the idea that psychosocial risk factors could lead to or influence cardiovascular disease. Many who originally espoused the concept of the “coronaryprone personality” became skeptical of a causal link between mood and cardiovascular disease. They assumed instead that the mood disorders were, at best, unrelated to the patient’s heart disease, or at worst, a dysfunctional (but “justifiable”) reaction to it. The concept of neurocardiology was largely discarded, not to be rediscovered until the 1990s.

Based on better-designed studies, researchers in the 1990s are asserting once more that mood and the development of heart disease are closely related. Specifically, several large studies have reported that patients with anxiety, depression, or social isolation seem to be at greater risk of developing heart disease. In most studies this risk was the same for men and women. It did not depend on other medical conditions that increase cardiovascular risk (e.g., diabetes or smoking).

What about the possible effects of mood disorders on the course of established heart disease? That, too, has been a focus of recent research. We now know that dysfunctional patterns of coping (including anger, fear, regression, and denial), as well as stress, anxiety, and depression, appear more frequently in patients with overt heart disease. They appear to have serious adverse effects after a heart attack.

Anxiety, Stress, and Depression After Heart Attack

Stress, anxiety, and depression each can have physiological effects. Each seems to have a worrisome impact on patients with overt heart disease.

First, anxiety. In a study at Massachusetts General Hospital, Theodore Stern, M.D., showed that patients in the coronary care unit often had high anxiety. He also demonstrated that this anxiety was very inadequately managed. Cardiologists caring for these patients seemed to assume that fear and anxiety were normal phenomena following a heart attack. In fact, however, recent data suggest that there is nothing at all normal about the combination of anxiety and heart disease. On the contrary, this combination may have devastating consequences.

The first conclusive demonstration of this, by Nancy Frasure-Smith, M.D., and her colleagues at Montreal Heart Institute, used a questionnaire to detect symptoms of stress and anxiety among heart attack patients in the hospital. The results were striking. Patients who had elevated levels of stress (relative to other hospitalized patients) following their heart attacks were three times as likely to die over the next five years. These findings were subsequently corroborated. Another study showed an almost fivefold increased risk for recurrent heart attacks or death among the highly stressed heart attack patients. (Because anxiety frequently coexists with depression, some have argued that the increased mortality found in anxious patients may result from the depression, not the anxiety itself. But taken together with the data on how stress and anxiety affect the development of fatal heart disease, there can be no doubt of the association between mood disorders and cardiac problems.)

What about depression?  The prevalence of depression in patients with established heart disease is stunning. Fully 65 percent of patients following a heart attack will suffer mild to severe depression, with up to 25 percent developing severe, recurrent major depression. (Some symptoms are changes in sleep patterns, decreased ability to concentrate, appetite changes, suicidal thoughts, decreased energy or interest, feelings of guilt, and psychomotor agitation or retardation.) This coexistence of depression and heart disease is enormously significant because the effects of the two diseases in concert can be devastating.

We know that the impact of major depression alone is far-reaching. The Medical Outcomes Study⁶ suggested that depression causes as much disruption in daily function as chronic medical conditions, including heart disease itself. The combination of major depression and heart disease is a social and medical “double whammy,” with multiplicative adverse effects on daily functioning, social adjustment, and overall well-being. These patients are miserable, and their medical care suffers as a consequence.

Following a heart attack, depressed patients are more likely to smoke, less likely to take their medicine, and overwhelmingly less likely to follow proven therapies like cardiac rehabilitation. They are more frequently rehospitalized for recurrent chest pains and suffer more recurrent heart attacks than do non-depressed patients. Of greatest concern, however, is the growing evidence that depression enhances the risk of death following a heart attack.

Scientists at Montreal Heart Institute found that major depression among hospitalized patients after a heart attack made death four times as likely over the next six months.⁷ These compelling data would be remarkable in isolation. With 18-month follow-up, however, these same researchers showed that depressive symptoms were associated with an almost eightfold increase in mortality.⁸ In fact, depression was the best predictor for death following a myocardial infarction—more so than the size of the initial heart attack, tobacco use, or the presence of high blood pressure or diabetes. In a subgroup of patients who combined depression, heart attack, and a predisposition to life-threatening cardiac arrhythmia there was a thirtyfold risk for death—much higher than in non-depressed patients with a similar cardiac status.

More confirmation came from a large study using Duke University data. Recent evidence, although still preliminary, suggests that depression may have the same deadly effect on patients with unstable angina. This greatly raises the ante; patients with unstable angina far outnumber those who have suffered an acute heart attack.

How the Brain Affects the Heart

Theories abound, but as yet we do not fully understand how affective disorders such as depression actually harm the heart. Several abnormalities of the autonomic nervous system (ANS) have been noted in patients with mood disorders, however, and there are provocative findings about the effects of abnormal serotonin metabolism on the heart. We must pursue these clues to make progress in saving lives.

The autonomic nervous system modulates the performance of many organ systems, including the heart and blood vessels. The ANS has millions of nerve connections in the heart, exerting its influence by delicately balancing the “activating” sympathetic nervous system with the “deactivating” parasympathetic nervous system. Both systems or “arms” of the ANS exert their influence through chemical messengers known as neurotransmitters. The neurotransmitter mediators of the sympathetic (activating) nervous system—catecholamines—include epinephrine (adrenaline) and norepinephrine (noradrenaline). These are responsible for the “fight or flight” reflex, our primitive response to stress that prepares our bodies for action.

Elevated levels of circulating catecholamines, as well as abnormally brisk production of catecholamines under stress, have consistently been found in patients with mood disorders such as anxiety, depression, chronic stress, and hostility. If such a patient also has heart disease, both phenomena—the baseline elevation in catecholamines and abnormally high secretion when under duress—may result in significant negative consequences. How does this occur?

Catecholamines have many effects on cardiac functions, including increasing heart rate, driving up blood pressure, and strengthening heart muscle contractions, all of which increase consumption of oxygen by the heart. Increased oxygen consumption is normally accommodated by an increased blood flow through the coronary arteries, but if the coronary arteries are blocked, (as in coronary artery disease), the heart may not receive the oxygen it needs. This lack of oxygen may cause angina pectoris or even a heart attack. In studies of patients with high levels of stress, catecholamines actually induced spasm of coronary arteries and possibly promoted coronary thrombosis, damaging heart muscle.

Catecholamines affect the body in other ways. The catecholamine epinephrine (and to a lesser extent norepinephrine) increases the “stickiness” of blood platelets (the cells in the bloodstream responsible for forming clots) and at the same time decreases naturally occurring anticlotting compounds. This could lead to a clot that blocks a coronary artery, resulting in a heart attack.

Understanding the relationships among anxiety, depression, and arrhythmia is critical because nearly half of the roughly 500,000 patients who die of heart attacks each year in the United States never make it to a hospital, presumably succumbing to a fatal arrhythmia.

Patients with mood disorders also have abnormalities in the balance between their sympathetic and parasympathetic nervous systems that may lead to abnormalities in cardiac rhythm. One abnormal balance results in decreased ability to adjust the heart rate in response to the stresses of daily life. This is a powerful predictor of sudden cardiac death, which most likely occurs as a direct result of cardiac arrhythmia.* Understanding the relationships among anxiety, depression, and arrhythmia is critical because nearly half of the roughly 500,000 patients who die of heart attacks each year in the United States never make it to a hospital, presumably succumbing to a fatal arrhythmia. Better diagnosis and treatment of anxiety and depression could change this.

Besides studying ANS abnormalities in patients with mood disorders, researchers have been looking at how abnormal serotonin metabolism affects the heart. Serotonin is a neurotransmitter found in nerve endings, both centrally in the brain and in several organ systems, including the heart. We know that abnormal serotonin metabolism is a key to mood disorders, including panic, anxiety, and depression. When compared to normal subjects, patients with these conditions often have higher concentrations of serotonin circulating in their blood, as well as much higher concentrations in their blood platelets. Antidepressant drug therapies that influence sertonin metabolism are very effective for these for patients, although their exact mechanismremains unknown.

How do chronically elevated serotonin levels affect the cardiovascular system? Experimentally, continuous exposure to serotonin has been shown to stimulate formation of coronary artery blockages, which may result in an increased risk of heart attack. Serotonin has interesting acute effects as well. Local infusion of serotonin may provoke a spasm of blood vessels; if the vessel is a coronary artery, a heart attack may result. We need to know much more about this.

Compounding these many biologic risks, anxious or depressed cardiac patients have critical behavioral issues that can worsen their long-term prognosis. For example, they are less likely to adhere to their drug regimen and less likely to stop smoking or otherwise modify their behavior.

Mainstreaming Diagnosis and Treatment

We have learned much about the connections between mood disorders and heart disease, but the most consistent and remarkable finding, from every study of psychosocial factors and heart disease, is that the anxiety and major depression of these patients are under-recognized and under treated. We need more studies, of course, but it is urgent to move now to implement what we do know.

Why are the affective disorders of patients with cardiovascular disease not more often recognized and treated? One cause is the ultraspecialized, single-organ approach to patient care. Another is lack of physician understanding of the incidence and significance of mood disorders in cardiac patients. Yet another, surprisingly, is concern about the safety of treating patients with anxiety and depression. Changes in the structure of patient care may also be at fault.

Considering today’s emphasis on ever-shorter hospital stays, along with genuine improvements in the medical management of cardiac patients, it is not unusual for a patient to be sent home only one or two days after a heart attack. Since follow-up visits do not normally take place until days or weeks after discharge, an emerging depression can go unnoticed—and this initial period is just when the negative effects of depression are greatest and the need for therapeutic intervention highest. Then, too, in the managed-care era, follow-up visits with physicians are so abbreviated that there may be no time to find out if the patient is experiencing any significant mood problems.

Nor should we underestimate the reluctance of patients to complain to their physicians of anxiety or depression, fearing the stigma of a psychiatric diagnosis. Also, like their physicians, patients may assume that feeling anxious or depressed after a heart attack is “only natural.” These notions are outdated and indeed wrong. Anxiety and depression in heart patients have catastrophic effects on quality of life as well as long-term prognosis. They must not be ignored. Physicians and patients alike must understand that mood disorders should be sought out and, when found, treated.

The benefits of treating anxiety or depression in any patient are clear. Irrespective of benefits for the patient’s heart, improving the patient’s quality of life is a priority. Although there is remarkably little information on the management of depressed or anxious heart patients, and more studies are urgently needed, experts do agree that treatment of their mood disorders is generally safe. It should be undertaken whenever appropriate.

The time has come for a standard approach to identifying heart patients who require psychosocial intervention. This approach should begin with increased suspicion of the possible presence of mood disorders, especially anxiety, among hospitalized patients. As the vast majority of patients with acutely unstable heart disease will be discharged relatively early in their illness, an outpatient program to identify those who need psychosocial intervention is essential. With this goal in mind, the growing interest in combining psychosocial evaluation and intervention with standard cardiac rehabilitation is a welcome trend.

The core component of rehabilitation is a proven life saver: cardiovascular exercise therapy. Cardiopulmonary exercise itself not only improves exercise tolerance but lowers blood pressure, decreases cholesterol, improves patient self-image, improves compliance with medications, reduces social isolation, improves depression independently of any other intervention (including drug therapy), restores normal heart rate variability, and decreases mortality by more than 25 percent. These benefits seem to extend equally to all patients, including diabetics and elderly patients who are considered at highest risk following a heart attack. An already remarkably powerful therapy could be improved still further by interventions such as stress-reduction classes, smoking-cessation seminars, nutrition courses, and, when appropriate, access to formal psychotherapy.

Despite their impressive benefits, cardiovascular rehabilitation programs are sorely underused. A recent study suggested that only 8.6 percent of patients eligible for rehab programs ever get enrolled. We should find out why, then work to increase awareness among physicians and patients of the benefits of this benign, highly effective therapy. It is not helpful that many third-party payers are reluctant to pay for rehabilitation unless the patient’s physician can convince them of its medical necessity.

Once psychosocial intervention is decided upon, the mainstays of therapy for mood disorders are cognitive–behavioral psychotherapy and drugs. Both have been shown safe and effective in patients with stable cardiovascular disease. (The safety and efficacy of cognitive–behavioral therapy and pharmacotherapy for patients with acute unstable coronary syndromes are being studied in two large-scale, multi-center trials.)

Cognitive behavioral therapy is particularly effective in managing mild anxiety states and minor depression. It is an ideal choice for many cardiac patients. The major obstacle is public acceptance. As Fredric Schiffer, M.D., explains in his book Of Two Minds: The Revolutionary Science of Dual-Brain Psychology, “”..for a cardiac patient to be referred to a psychiatrist meant that his esteemed cardiologist regarded him as a mental case or a weakling, or both.”⁹ Patients and physicians have acted as though referral to a psychiatrist implies either that the patient’s heart disease is inconsequential or so severe that regular intervention is hopeless. This is not true, but it has kept many eligible heart patients from being treated for anxiety or depression.

If a patient has severe or refractory psychiatric symptoms, the next step is to consider drug therapy. For acute anxiety in cardiac patients, physicians usually prescribe drugs of the benzodiazepine type, for example Valium or Ativan. They were found safe and effective in managing the anxiety of patients in the coronary care unit of Massachusetts General Hospital. Similar findings were reported from several other small trials. Benzodiazepines decrease anxiety and have positive effects on heart rate and blood pressure; in the case of triazolam (Xanax), they may block the function of blood platelets, potentially a desirable side effect for these patients.

Drug therapy for depression has evolved considerably over the past decade. Early agents such as monoamine oxidase inhibitors (Nardil, Parnate) and tricyclic antidepressants (Elavil, Pamelor, Norpramin, Anafranil, Tofranil) were effective but had side effects that made use in cardiac patients difficult and possibly hazardous. Many physicians became reluctant to consider drug therapy for their depressed patients. With the recent introduction of the selective serotonin reuptake inhibitor class of medications (Paxil, Prozac, Zoloft), safe and effective drug therapy for depressed patients with cardiac disease is now possible.

From Ignorance to Successful Intervention

Our understanding and acceptance of neurocardiology is evolving too slowly. Most physicians are still unaware of the significant incidence of mood disorders among their patients with heart disease and would be surprised at the devastating effects of these disorders. But now, previously discarded beliefs about the connections between the heart and the brain are being rediscovered and proved true. As a consequence, there is growing interest among physicians in how to manage this complex mixture of organ systems. This interest must be translated into research and clinical practice that will alleviate the heavy toll of heart disease.

Education of caregivers and cardiac patients alike should improve not only the quality of health care delivery, but the quality and length of life. Encouraging cardiovascular specialists to broaden their medical management of their patients from a “one organ” approach will lead to increased recognition of anxiety or depression among hospitalized patients, allowing for early therapeutic intervention. For the patient who has been discharged from the hospital, comprehensive cardiovascular rehabilitation programs will offer a way to be identified for psychosocial intervention—including cognitive behavioral therapy or drug therapy—while undergoing valuable cardiopulmonary rehabilitation.

We must further elucidate the pathophysiology underlying the brain-heart connection. Exactly how affective disorders exert their bad effects on the heart remains purely speculative, but basic-science investigators are finally unraveling this complex problem. With better understanding of the basic biology, we can see how to intervene when the brain-heart connection becomes diseased. We have no hard data yet about the good effects on the heart of treating mood disorders, but at least major quality–of–life benefits can be reaped from treating anxiety and depression when they occur with heart disease.

Twenty years after it was reborn, the “new” field of neurocardiology is coming into its own. As a result, insights into brain-heart interaction will help to improve our treatment and ultimate prevention of heart disease, the number one cause of death in the Western world.

*There may be a complicated connection here, since abnormalities of heart rate variability and arrhythmia both are found in patients with anxiety and depression. (A study from Washington University has demonstrated an increased incidence of life-threatening arrhythmias in depressed cardiac patients.) Sudden cardiac death is most common among patients who exhibit a predisposition toward arrhythmia; and their poor prognosis is explainable by fatally irregular heart rhythms, further promoted by abnormal heart rate variability.

Authors’ acknowledgment:

We wish to thank Marisa A. Januzzi, Ph.D., for her insightful comments on the manuscript.