- Email: [email protected]
Stress and the Heart
Review Articles Stress and the Heart: Biobehavioral Aspects ofSudden Cardiac Death M.D. M.D.
CATHRlNE FRANK. STEPHEN SMITH,
Stress has been implicated as a developmental factor in atherosclerotic heart disease, essential hypertension, and sudden cardiac death. This article reviews the mechanisms and biobehavioral effects of stress on the heart,focusing on its relation to sudden cardiac death. Epidemiologic evidence, cultural studies. animal experiments, and human research are reviewed to better understand the biobehavioral aspects ofstress on the heart. Emphasis is placed on understanding the interaction ofthe central nervous system's frontal cortex and hypothalamus with cardiovascular control areas. With today's understanding ofthe frontal cortex and the interaction of hormones and neurotransmitters with the cardiovascular system, clinical interventions utilizing psychotherapy and psychopharmacology are needed, particularly since both approaches are underutilized in combating arrhythmias.
T
he impact of stress on the body. and. in particular, on the heart. has captured both lay and scientific interest. For centuries, phrases such as "to die of a broken heart" or "to die of fright" have permeated our language. Engel's classic article, "Sudden and Rapid Death During Psychological Stress: Folklore or Folk Wisdom?" proposed the notion that psychological stress can induce lethal cardiac events. I Since then. clinical and epidemiological studies have investigated the biobehavioral effects of stress on atherosclerotic heart disease. essential hypertension. and sudden cardiac death. This article reviews the mechanism and effects of stress on the heart. especialIy as they relate to sudden cardiac death. DEFINITION OF SUDDEN CARDIAC DEATH Sudden cardiac death can best be defined as death due to cardiac causes. preceded by an abrupt loss of consciousness that occurs shortly (Le., within VOLUME 31 • NUMBER 3· SUMMER 1990
seconds to an hour) after the onset of acute symptoms; it may occur in an individual either with or without heart disease. Sudden cardiac death accounts for one-half to one-third of all deaths from coronary artery disease (CAD) and is estimated to result in 400.000 deaths per year in the United States.2 Not infrequently. sudden death will be the initial and only manifestation of heart disease. At autopsy. evidence of CAD typically is found. but its distribution and extent are not distinctive. To further confound the picture. there may be a paucity of acute pathomorphological changes. In a small percentage of patients, there are no obvious pathological cardiac lesions. The classic
Received January 16. 1989; revised July 31. 1989; accepted August 23. 1989. From the Psychiatric Consultation-Liaison Service and the Department of Cardiology. Henry Ford Hospital. Detroit. Address reprint requests to Dr. Frank. Consultation-Liaison Psychiatry. CFP-3. Henry Ford Hospital. 2199 West Grand Boulevard. Detroit. MI 48202. Copyright © 1990 The Academy of Psychosomatic Medicine. 255
Stress and the Heart
CAD risk factors of hypertension, smoking, and hypercholesterolemia do not identify those individuals predisposed to sudden cardiac death. 3 The occurrence of sudden cardiac death is not necessarily correlated with either activity or physical exertion. Although ventricular arrhythmias and, most commonly, ventricular fibrillation (VF) are the assumed pathophysiologic mechanisms, the definitive trigger is unknown. The interplay of behavioral and neural factors precipitating events is under investigation. EPIDEMIOLOGIC STUDIES Epidemiologic evidence has made significant contributions to an understanding of the role of psychological and social factors in CAD.4-8 Some ofthese same studies have highlighted a relationship, albeit not a causal one, between psychological stress and sudden cardiac death. Engel's paper, 1 a nonscientific gleaning from newspaper accounts of sudden death victims, described specific life settings in which sudden cardiac death may occur: loss or threat of loss of an object, threat of injury or danger, loss ofself-esteem, joy, or triumph. Rahe et al. 9 studied the effects of life stresses in postmyocardial infarction (MI) and sudden cardiac death patients. Evidence of life stress was gathered from the spouses of sudden cardiac death victims and from the post-MI patients and their spouses. The results showed marked elevations in the magnitude of life stresses during the six months prior to the infarction or sudden cardiac death, compared with the same interval one year earlier. This increase in life stress was particularly significant for sudden cardiac death victims. Follick et al. 10 did a prospective study of 125 post-MI patients equipped with transtelephonic electrocardiograph (ECG) monitors, examining the relationship between psychological distress and ventricular ectopy. There was a direct relationship between measured levels of distress and occurrence of ectopic beats, even when adjusted for age, cardiac risk factors, and the use of betablocking agents. Education and socioeconomic level also have been considered to be correlates of stress 256
that may contribute to sudden cardiac death. Investigators had found an inverse relationship between mortality from CAD and education.' Ruberman et al. 8 expanded on this with a prospective study of 2320 male survivors of MI who participated in the Beta-Blocker Heart Attack Trial, examining its effect on fatality from CAD and sudden cardiac death. They discovered that, over a three-year period, the cumulative probability of death was highest among those survivors with less than 10 years of schooling. In addition, high levels of stress and social isolation were most prevalent among the least educated men. Compared to those with low levels of both stress and social isolation, those who were socially isolated and stressed were at four times the risk of death; the increased risk was associated with total cardiac deaths and sudden cardiac deaths. In general, though there seems to be a relationship between psychosocial factors and sudden cardiac death, these factors are weak predictors of sudden cardiac death since the majority of people experience these events without resulting fatality. CULTURAL STUDIES Cultural studies have reported on the role ofstress primarily as it relates to CAD. Marmot and Syme ll studied Japanese men, who traditionally have a low incidence of CAD, in various cultural settings and discovered that the rate of CAD increased as they assimilated into Western culture. As the increased rate could not be explained on the basis of cardiac risk factors, it was suggested that the "stress of assimilation" might be a factor. Similarly, cultural influences may playa role in several sudden death syndromes: the Bangungut in young Filipino men,12 Pokkuri in the Japanese, and Non Latai in Laotians. Individuals who are afflicted die suddenly during sleep, in the absence of obvious organic heart disease or other major toxicologic or pathological lesions. 13 More recently. sudden cardiac death has been hypothesized in the Laotian Hmongs. following their immigration to the United States. 14 The deceased were generally in their thirties, in good health, and suffered from presumed and. in PSYCHOSOMATICS
Frank and Smith
some cases, documented nocturnal VF. One survivor had documented inducible ventricular tachycardia (VT).15 It has been hypothesized that the fatal arrhythmias in the Hmongs were due to the stress of "culture shock," following their emigration to the United States, but, as yet, the definite etiology and mechanism of these syndromes are unknown. ANIMAL STUDIES Animal studies have paralleled epidemiologic evidence in the understanding of the effects of stress on the heart. Lown et al. 16 set up a classic aversive conditioning paradigm in which dogs were placed either in an undisturbed environment, or in a Pavlovian sling, in which the dog received a transthoracic shock at the end of each experimental period for three successive days. The effects of the two environments were compared on the fourth and fifth days. The dogs in the stressed environment were restless, salivating, tremulous, with increased blood pressure and pulse as compared to the relaxed dogs in the undisturbed environment. The stressed dogs had a lower cardiac threshold for VF. If the dogs were transferred from the nonaversive to the aversive environment, their threshold decreased by 41 %.17 To clarify the effects of stress in diseased hearts, the same paradigm was repeated but was studied during a coronary occlusion-release sequence. IS The left anterior descending artery was occluded for 10 minutes and was followed by abrupt release and reperfusion. The experimental design was chosen to determine if acute ischemia or reperfusion, as might occur after coronary artery spasm or dislodgement of platelet aggregates, might provoke VF. The dogs were exposed either to the aversive sling environment or to the nonaversive environment. In the aversive environment with experimentally induced ischemia, the incidence of VF was three times greater than that in the nonaversive environment. The VF occurred within three to five minutes of coronary occlusion or within 20 to 30 seconds after release and reperfusion. Thus, the nonaversive environment protected against reperfusion fibrillation. Several studies have shown that pigs may VOLUME 3\ • NUMBER 3· SUMMER 1990
have enhanced reactivity to environmental stress. Cardiac dysrhythmias and cardiomyopathy may be induced when pigs are exposed to severe psychological stress. 19 Skinner et at. 20 produced similar results in pigs who either were allowed to adapt to a new environment for two to three days or not allowed to adapt. When myocardial ischemia was produced in the nonadapted animals, fibrillation occurred within a few minutes. In those pigs allowed to adapt to the new environment, fibrillation either was delayed Qr prevented. Thus, although myocardial ischemia was an important factor in the genesis of VF in these animals, it was modifiable by alleviation of stress. Verrier and Lown 21 attempted to elicit natural emotions by simulating anger in dogs by denying them access to food. After an overnight fast and period of acclimation to a new environment, a leashed dog was presented with food which then was given to, and devoured by, a second dog within his vision. The deprived dog displayed an angry-like response with increased heart rate, increased mean arterial blood pressure, increased catecholamines, and decreased repetitive extrasystole threshold (i.e., an indicator of risk to fibrillate). HUMAN STUDIES How do the animal studies translate into human experiences? Reich et at. 22 studied 117 patients who had recurrent life-threatening ventricular arrhythmias. These patients were followed by a task force consisting of a psychiatrist, psychologist, and members of a cardiovascular team. Twenty-five patients (21 %) were judged to have had a psychological trigger in the 24 hours before their arrhythmia. In 15 of the 25 patients, the psychologically stressful stimulus occurred less than one hour before the onset of the arrhythmias. These patients were differentiated from the other 92 patients for having experienced more lethal ventricular arrhythmias, yet they had less demonstrable cardiac pathology. In 17 ofthe 25 patients, the main affect associated with the stress was anger. It is neither known nor addressed by the authors of the study why 79% of the dead did not 257
Stress and the Heart
have a psychological trigger for the arrhythmia. There may be various subsets of patients susceptible to ventricular arrhythmias, with psychological factors representing one such subset. Greene et al.23 found that at least half of the 26 studied victims of sudden cardiac death had psychological or social stressors associated with the time of sudden death. The data suggested that the majority of these patients, all men, were depressed for a week to several months prior to their death and that anxiety and anger may have evoked hormonal or sympathetic nervous system responses conducive to arrhythmias. Thus, these data point to an association between psychological variables and ventricular arrhythmias, though not a causal one. Of the psychological variables, anger has been implicated in sudden cardiac death and in better defining the concept of the Type A personality. Case reports of malignant ventricular arrhythmias and sudden cardiac death are abundantY4-26 Olsson and Rehnquist 24 reported the case of a 70-year-old man with a history of two MIs who returned home after a six-month medical check-up with no acute changes in his condition. On the night following the check-up, he realized that some important papers were missing from his wallet. He called the hospital in an excited fashion. While on the phone, he developed VF and died. Lown et al. 25 reported the case of a healthy middle-aged man who developed VF while roughhousing with his sexually mature teenage daughters. Malignant arrhythmias could be triggered by a psychiatric interview, rapid eye movement (REM) sleep, and emotional stress. The arrhythmia was diminished by meditation, betaadrenergic blocking agents, phenytoin, and digitalization. A recent topic of interest in the study of sudden cardiac death has involved the concept of silent ischemia. Silent ischemia has been welldocumented in a variety of individuals with various cardiac ischemic syndromes. Deanfield et al. 27 demonstrated by ambulatory monitoring that most episodes of angina (75%) are silent. Other investigators have confirmed this finding by examining electrocardiographic ST segment alter258
ations,28 scintography,29 and left ventricular wall motion abnormalities. 30 Rozanski et al. 31 recently demonstrated that mental tasks, especially public speaking, actually can induce wall motion abnormalities. In fact, of the patients with inducible (presumably ischemic) wall motion abnormalities, 83% were silent and generally occurred at lower heart rates than exercise-induced ischemia. The investigators suggested that personally relevant mental stress, such as public speaking, was the stress most likely to provoke ischemia. While silent ischemia and sudden cardiac death have been well-studied, their exact relationship is obscure. To understand the possible interrelationship of sudden cardiac death and silent ischemia, four factors need to be considered: stress, ventricular ectopy, silent ischemia, and sudden cardiac death. Sudden cardiac death, silent ischemia, and myocardial infarction all follow a similar circadian pattern; i.e., upon awakening, the individual is at greatest risk from six A.M. to noon. 32 It has been hypothesized that ventricular ectopy is the bridge between silent ischemia and sudden cardiac death, i.e., that individuals with silent ischemia may develop ventricular ectopy, resulting in sudden cardiac death. This has been shown anecdotally,33.34 but in large studies utilizing angioplasty,35 exercise stress testing,36 and ambulatory monitoring,37 there has been little or no demonstrable connection between ischemia and ventricular ectopy. Thus, although, as yet, there is no proven mechanism to link sudden cardiac death to silent ischemia, there is "guilt by association." A MODEL OF SUDDEN CARDIAC DEATH A natural human model of sudden cardiac death is the long Q- T syndrome. This rare congenital abnormality of cardiac repolarization is associated with sudden cardiac death, particularly in situations known to increase sympathetic nerve activity, e.g., emotion and physical exertion. When exposed to stress, such as that resulting from loud noises,38 vigorous physical exercise, the valsalva maneuver,39 and from emotions such as fright, patients may develop episodic VT leading to VF, syncope, or death. Patients with this PSYCHOSOMATICS
Frank and Smith
syndrome are usuaIly symptomatic in childhood, although some may not present with symptoms until their 30s and 40s (e.g., as with the RomanoWard syndrome). Q-T lengthening also may be acquired through central nervous system (CNS) lesions, autonomic dysfunction, CAD, mitral valve prolapse, use of drugs such as the Vaughan-Williams group lA antiarrhythmics (e.g., procainamide, quinidine, disopyramide), phenothiazines, tricyclic antidepressants, or through starvation, liquid protein diets, and other electrolyte disorders. In these individuals, the degree ofQ-T prolongation may vary, and arrhythmogenesis is less marked, though present. In exploring the mechanism that underlies the long Q-T syndrome, Schwartz26 noted that stress leads to increased adrenergic output, and he examined the role of nerves that innervate the cardiac system in provoking arrhythmias. In animals he found that by stimulating the left stellate ganglion or by removing the right stellate ganglion, the Q-T interval was lengthened. He hypothesized that abnormally low right cardiac sympathetic activity and possible hyperactivity of the left-sided nerves create a sympathetic imbalance that is arrhythmogenic. In the treatment of long Q-T syndromes, medical therapy (primarily beta-blocking agents) and surgical therapy (i.e., stellate ganglionectomy) have predominated. Sedatives may be helpful in that they blunt the emotional response and thus diminish sympathetic output. 40 NEUROCARDIOLOGIC CONNECTIONS How is stress interpreted by the brain and translated into cardiac vulnerability? Stress is a supratentorial reaction or experience of a particular individual to a particular stimulus. The reaction lies not in the stressor itself, but in the individual's interpretation. The CNS, particularly the frontal cortex, acts as the major interpreter of stress. Eliot41 distinguished between the ways in which the CNS construes chronic and acute stress. Chronic stress is handled mainly through the CNS via the pituitary-adrenal-cortical axis, often with resulting increases in cortisol VOLUME 31 • NUMBER 3 • SUMMER \990
activity. Long-term effects of cortisol consist of sodium retention, increased blood volume, decreased ventricular ectopic threshold, and increased sensitivity of arterioles to catecholamines. On the other hand, acute stress (the fight or flight response) is mediated primarily by the limbic system, hypothalamus, and adrenal medulla and results in increased catecholamines and, on occasion, increased cortisol. A model of the limbic-hypothalamic-adrenal axis gone awry is pheochromocytoma. The leading causes of death in pheochromocytoma are "catecholamine myocarditis," ventricular arrhythmia, MI, hypertension, or sudden cardiac death. Metabolically, increased catecholamines result in increased cholesterol and free fatty acids, increased blood pressure, decreased VF threshold, and increased platelet aggregation. This is of interest in postulating how the limbic-hypothalamic-adrenal axis interprets stress and how stress may alter cardiac vulnerability. The effects of stress on cardiac vulnerability no doubt involve the brainstem where the cardiovascular control areas (the nucleus tractus solitarii, cardiovascular motor nuclei, and nucleus ambiguous) come in contact with pathways from the frontal cortex and hypothalamus. Skinner and Reed42 showed that a bilateral cryogenic blockade of the frontocortical pathways prevents reoccurrence of VF in pigs with an ischemic heart, even though the animal is under stress. Verrier et al. 43 studied 34 dogs and found that posterior hypothalamic stimulation led to a 40% reduction in VF threshold. The decreased threshold persisted even when increased heart rate and pressor response were prevented or when cervical vagotomy and bilateral adrenalectomy were performed. The study concluded that the reduction in VF threshold associated with posterior hypothalamic stimulation was due to the direct action of sympathetic nerves on the myocardium, and not from secondary hemodynamic effects. The role of the CNS on cardiac function also has been demonstrated in patients with cerebral insults such as subarachnoid hemorrhage, intracerebral hemorrhage, subdural hemorrhage, or ischemic strokes. In fact, up to 90% of those patients sustaining a cerebral accident may show 259
Stress and the Heart
ECG abnonnalities with changes in rhythm or repolarization:'4--46 Yamour et al. 47 observed ECG findings associated with cerebral damage in 65 patients without known cardiac disease or drug or electrolyte abnonnalities. While atrial arrhythmias predominated, frequent premature ventricular contractions (PVCs) occurred in 10% of the patients, mainly those with temporoparietal hemorrhage. Neurogenic T waves and Q-T prolongation occurred in 50%-80% of the patients with frontal lobe hemorrhages. Interestingly, all of these patients had left-hemispheric lesions. Other investigators have noted significant ventricular rhythm disturbances, including PVCs, VT, VF, inversion of T waves (the so-called cerebral T waves), and prominent U waves in patients with CNS events. 4 1.48-50 The separation of neural and honnonal effects of CNS disease on the heart has been problematic. Initially, the rapid reversibility of ECG findings was thought to indicate a neurological etiology. Subsequent work has suggested that a catecholamine release, especially a norepinephrine release at cardiac beta-receptor sites, may be responsible for direct cardiac effects 51 and may be modified by beta-blockade. 50.52 Samuels44 suggested that the combined effects of steroids and catecholamines may lead to myocardial injury. While these represent extreme examples of CNS damage, they suggest a mechanism by which sudden cardiac death through arrhythmogenesis may occur with or without cardiac disease. The role of the cerebral cortex in reaction to stress is also evident in patients with right-hemispheric and, in particular, with frontal-lobe damage. Heilman et al. 53 recorded galvanic skin responses following electrical stimulation of the ipsilateral foreann of patients with right hemispheric brain damage exhibiting neglect. Compared to healthy controls and to aphasic patients with left-hemispheric damage, the patients with right-hemispheric damage had lower galvanic skin responses. They had a markedly decreased autonomic response, suggesting that their cerebral reaction to stress was ablated. The role of the CNS in arrhythmogenesis was reviewed by Topaz et al. 54 in patients who supposedly were provoked to sudden cardiac 260
death by auditory stimuli. He cited case reports of individuals with nonnal coronary arteries who experienced fatal VF, caused by such diverse sounds as ringing doorbells, phones, screeching brakes, and loud music (cases reviewed were both documented and assumed VF). It was suggested that auditory stimuli may activate efferent pathways in the hypothalamus and quadrigeminal bodies where auditory pathways operate. Impulses may cross the reticular fonnation and, via the stellate ganglia, sympathetically innervate the heart. Thus, alanning noises may induce sympathetic activity and by neural and honnonal mechanisms predispose the individual to VF. The sympathetic nervous system is a major factor in the development of VF. Skinner et al. 55 set up an experiment in which phosphorylase A activation, which indicates the level of sympathetic tone, could be measured. Pigs were exposed to a stressful environment. It was discovered that phosphorylase A activation decreased linearly with behavioral adaptation in pigs who were in a resting state. The evidence supports a direct link between a psychological stressor, a specific myocardial response, and the role of high adrenergic tone in this regard. The high sympathetic tone, as indicated by the phosphorylase activation, and the high parasympathetic tone, as evidenced by the resting heart rate, suggest a dual regulating system for arrhythmias. Vagal influences playa role in modifying the effect of stress on cardiac vulnerability. DeSilva et al. 56 administered morphine to dogs, which enhances vagal tone, among other effects. In a stressful environment, the morphine increased the threshold for VF to the value observed in nonstressful situations. Administration of intravenous atropine negated this response. Administration of morphine in a nonstressful setting did not alter the vulnerable period threshold. Thus, during stress the vagus nerve serves a protective function, antagonizing the profibrillatory influence of increased adrenergic input to the heart. The sympathetic and vagal nerves are modulated through the brainstem, which is innervated by frontocortical areas and by neurons with neurotransmitters, such as y-aminobutyric acid PSYCHOSOMATICS
I.
Frank and Smith
(GABA), serotonin, acetylcholine, and norepinephrine. Interesting studies have been perfonned by Rabinowitz and Lown s7 on the role of serotonin and its modulation of autonomic neural activity in the brain. In an experiment they injected dogs with tryptophan, phenelzine, and carbidopa. L-tryptophan, the biochemical precursor of serotonin, was combined with phenelzine, which inhibits monoamine oxidase, and with carbidopa, an L-aromatic amino acid decarboxylase inhibitor, which served to decrease serotonin formation peripherally so as to increase CNS accumulation. The repetitive extrasystole threshold increased by 50%, thus indicating that an increase of central serotonin activity may decrease sympathetic input from the brain to the heart and have an antifibrillatory effect. CLINICAL IMPLICATIONS In this article we have reviewed a variety of known and postulated connections between stress and sudden cardiac death. One of the critical questions that remains is how to reduce stress by social, psychological, and pharmacological interventions in order to diminish a patient's vulnerability to a malignant arrhythmia. This is imperative because, although patients with VT or VF associated with acute MI have little risk of recurrence, survivors of out-of-the-hospital VT or VF without MI, who have refractory arrhythmias, are at a high risk for a similar event. 58 Patients with VT or VF have a 70%-90% chance of recurrence if a suitable antiarrhythmic therapy cannot be found. 59.6O From a psychiatric perspective, the need for trials ofpsychotherapy and psychopharmacology is compelling. Hostility and anger have been implicated for their effects on CAD in humans61 63 and, as reviewed in this article, as a potential trigger of malignant arrhythmias. 20 In studies of Type A behavior, first described by Friedman and Rosenman,64 it has been suggested that it is not the pattern of competitiveness, excessive drive, and time urgency that are most relevant to the increased risk of cardiovascular disease, but, rather, unexpressed hostility.61~3 Individual and group psychotherapies have been found to modVOLUME 31 • NUMBER 3 • SUMMER 1990
ify Type A behavior and to decrease the prevalence of recurrent nonfatal MI.6~7 Interventions consisted of behavioral learning, progressive muscle relaxation, and a fonn of cognitive affective learning aimed at having patients evaluate themselves, their internalized goals and beliefs, and their assumptions about themselves and others. 65 The therapy also focused on enabling subjects to channel anger into assertive, rather than aggressive, responses. Psychotherapy also could help with an array of stresses mentioned in this article, such as loss ofan object, social isolation, and low self-esteem. Although there are no known trials to support the efficacy of psychotherapy for patients at risk of developing arrhythmias, clinical trials would help explore this issue. Psychopharmacology is probably an underutilized tool in combating arrhythmias. Stern,68 for example, highlights the failure to diagnose and treat underlying psychiatric complications of MI in the coronary care unit and explains how this can aggravate the underlying cardiac condition. The literature points to the potential usefulness of agents that mediate catecholamines, serotonin, and GABA. Both systemic elevation of catecholamines and release by local cardiac nerves have been implicated in the genesis of arrhythmias. Stratten and Halter69 took a small sample of healthy men and gave them a stress exercise test during treatment with alprazolam. During drug treatment, the plasma epinephrine and norepinephrine levels were reduced significantly after eight and II minutes of exercise (although there was no statistical significance at maximal exercise). The alprazolam, according to the study, led to decreased sympathetic tone, a result that should aid stressed patients or acute MI patients who tend to have increased circulating levels of catecholamines. Similarly, Melson et al. 70 found decreased urinary adrenaline and free fatty acid concentrations after administering diazepam to patients with acute MI. Although 24hour cardiac monitoring was not maintained, the group treated with diazepam had a decreased incidence ofventricular arrhythmias. Diazepam71 and midazolam 72 have the added benefit of decreasing myocardial oxygen consumption. 261
Stress and the Heart
The work of Rabinowitz and Lown 57 on serotonin reported that serotonin modulates autonomic neural activity and sympathetic input from the brain to the heart. Of interest is the fact that research is exploring the role of serotonin in a number of psychiatric disorders and conditions. notably depression. anxiety. obsessive-compulsive disorder. and suicide. Pharmacological agents such as fluoxetine and buspirone enhance serotonin. although by different mechanisms. Buspirone has been utilized in anxiety disorders. Fluoxetine has been helpful with affective disorders. panic disorders. and obsessive-compulsive disorder. These agents and others like them may have a role in cardiac patients susceptible to stress. It is now established that benzodiazepines interact with their receptors to facilitate the inhibitory neuronal properties of GABA. 73 The benzodiazepine receptors have their highest concentration in the limbic system, which is involved in the control of emotion and visceral function. 74 Benzodiazepines have been shown to suppress neuronal activity in the limbic system. which includes the hypothalamus. amygdala. hippocampus. and septal region. This leads to the hypothesis that the limbic system is involved in the etiology of anxiety. 74 Of interest is the fact that the hypothalamus and frontal cortex pathways interface with cardiovascular control centers in the brainstem. The posterior hypothalamus. in particular. has been implicated experimentally in the reduction of the YF threshold. 43 This "neural wiring." in addition to the benzodiazepine effect on sympathetic tone. on enhancement of GABA's inhibitory effect on the limbic system. and the lack of cardiotoxicity. makes the benzodiazepines potentially useful agents. Controlled trials are needed to evaluate benzodiazepine efficacy in patients at risk for malignant arrhythmias. Beta-adrenergic blockers should be mentioned not only because they typically are used in the treatment of symptomatic patients with long Q-T syndrome and some tachyarrhythmias, but also because these agents are sparking interest in psychiatric disorders such as performance anxiety. generalized anxiety disorder (GAD), and in 262
the violent behavior of patients with organic brain syndrome. These agents are competitive antagonists of norepinephrine and epinephrine at beta-adrenergic receptors. Beta-I receptors appear to be the prevailing noradrenergic receptors on neurons in the brain. 74 Beta-adrenergic blockers are effective in treating autonomic symptoms associated with performance anxiety. GAD, and panic attacks. 74 They seem less effective in treating the psychological aspects of anxiety. The use of beta-blockers in stressed individuals and in patients meeting the DSM-III-R 75 criteria for anxiety disorders needs further exploration. An understanding of the interplay of psychoneurologic and cardiovascular factors has immediate and practical importance. The research reviewed in this article postulates that "stressors." such as bereavement. loss of social support. and free-floating hostility may have a role in the genesis of some arrhythmias and. in some patients. may be amenable to psychotherapy. It also points to the role of the frontal cortex and limbic system and to the importance of neurotransmitters such as norepinephrine. serotonin. and GABA. Likewise. it considers the feasibility of treatment with benzodiazepines. among others. Controlled trials with psychotherapy and psychopharmacology are needed to transform these theoretical constructs into life-saving therapies.
The authors wish to thank Theodore A. Stem, MD., o/Massachusetts General Hospital,for his support and guidance in the preparation 0/ this manuscript.
References I. Engel GL: Sudden and rapid death during psychological stress. Ann Intern Med 74:77 1-782. 1971 2. Cobb LA. Werner JA: Predictors and preventions of sudden cardiac death. in The Heart. Edited by Hurst JW. New York. McGraw Hill. 1986. pp 538-546 3. Kuller LH: Sudden death: definition and epidemiologic considerations. Prog Cardiol'Qsc Dis 23: 1-12. 1980 4. Rees WD. Lutkins SG: Monality of bereavement. Br MedJ 4:13-16.1967 5. Parkes CM. Benjamin B. Fitzgerald R: Broken hean: a statistical study of increased monality among widowers. BrMedJ 1:740-743. 1969 6. Helsing KJ. Szklo M. Comstock GW: Factors associated
PSYCHOSOMATICS
Frank and Smith
with monality after widowhood. Am J Public Health 71:802-809.1981 7. Shekelle RB: Educational status and risk of coronary anery disease. Science 163:97-98. 1969 8. Ruberman W. Weinblan E. Goldberg JO. et al: Psychosocial influences on monality after myocardial infarction. N Engl J Med 311:552-559.1984 9. Rahe RH. Romo M. Bennett L. et al: Recent life changes. myocardial infarction and abrupt coronary death. Arch Intern Med 133:221-228. 1974 10. Follick MI. Gorkin L. Capone RJ. et al: Psychological distress as a predictor of ventricular arrhythmias in a post-myocardial infarction population. Am Heart J 116:32-36. 1988 II. Marmot MG. Syme SL: Acculturation and coronary hean disease in Japanese-Americans. Am J Epidemiol 104:225-247. 1976 12. Aponte GE: The enigma of Bangungut. Ann Int Med 52:1259-1263. 1960 13. Myerburg RJ. Costellanos A: Cardiac arrest and sudden cardiac death. in Braunwald E: Heart Disease: A Textbook of Cardiovascular Medicine. New York. WB Saunders, 1987. pp 742-777 14. Baron RC, Thacker SB. Gorelkin L. et al: Sudden death among southeast Asian refugees: an unexplained natural phenomenon.JAMA 250:2947-2951,1983 15. Otto CM. Tauxe RV. Cobb LA. et al: Ventricular fibrillation causes sudden cardiac death among southeast Asian immigrants. Ann Intern Med 101 :45-47. 1984 16. Lown B. Verrier RL. Corbalan R: Psychologic stress and threshold for repetitive ventricular response. Science 182:8~36. 1973 17. DeSilva RA, VerrierRL. Lown B: The effects of psychological stress and vagal stimulation with morphine on vulnerability to ventricular fibrillation in the conscious dog. Am Heart J 95:197-203. 1978 18. Verrier RL, Lown B: Influence of psychologic stress on susceptibility to spontaneous ventricular fibrillation during acute myocardial ischemia and reperfusion. Clin Res 27:570A, 1979 19. Johansson G. Jonsson L. Lannek N. et al: Severe stress induced cardiomyopathy in pigs. Am Heart J 87:451457. 1974 20. Skinner JE, Lie JT, Entman ML: Modification of ventricular fibrillation latency following coronary anery occlusion in the conscious pig. Circulation 51 :656--666. 1975 21. Verrier RL. Lown B: Behavioral stress and cardiac arrhythmias. Annu Rev Physiol 46:155-176.1984 22. Reich P. DeSilva RA. Lown B. et al: Acute psychological disturbance preceding life-threatening ventricular arrhythmia. JAMA 246:233-235. 1981 23. Greene WA. Goldstein S, Moss AJ: Psychosocial aspects of sudden cardiac death. Arch Intern Med 129:725-731. 1972 24. Olsson G. Rehnquist N: Sudden death precipitated by psychological stress. Acta Med Scand 212:437-441, 1982
VOLUME31·NUMBER3·SUMMER 1990
25. Lown B. Temte JV, Reich P, et al: Fibrillation in the absence of coronary hean disease and its management. N Engl J Med 294:623~29. 1976 26. Schwanz PJ: Stress and sudden cardiac death: the role of the autonomic nervous system. Journal ofClinical Psychiatry Monograph 2:7-13.1984 27. Deanfield JE, Mesari A, Selwyn AP, et al: Myocardial ischemia during daily life in patients with stable angina: its relation to symptoms and hean rate changes. Lancet 2:753-758. 1983 28. Amsterdam EA. Manschniske R, Laskett CJ. et al: Symptomatic and silent ischemia during exercise testing in coronary anery disease. Am J Cardiol 58:43B-46B. 1986 29. Deanfield JE. Shea M. Ribiero P. et al: Transient ST segment depression as a marker of myocardial ischemia during daily life. Am J Cardiol 54:1195-1200.1984 30. Cohn PE, Brown ES, Wynne J: Global and regional ejection fraction abnormalities during exercise on patients with silent myocardial ischemia. J Am Coli Cardiol 1:931-933, 1983 31. Rozanski A. Bairey CN. Krantz OS, et al: Mental stress and the induction of silent myocardial ischemia in patients with coronary anery disease. N Engl J Med 318:1005-1012.1988 32. Rocco MB, Nabel EG. Selwyn AP: Circadian rhythms and coronary anery disease. Am J Cardiol 59:13C-17C. 1987 33. Grodman AH, Bell PA. DeBusk RF: Sudden death during ambulatory monitoring: clinical and electrocardiographic correlations: repon of a case. Circulation 55:210-211.1977 34. Savage 00. Castelli WP. Anderson SJ. et al: Sudden unexpected death during ambulatory electrocardiographic monitoring: the Framingham Study. Am J Med 74:148-152. 1983 35. Bairn OS, Faxon OP: Coronary Angiography. in Cardiac Catheterization and Angiography. Edited by Grossman W. Philadelphia. Lea and Febiger. 1986. pp 473-492 36. Jelinek MV, Lown B: Exercise testing for exposure of cardiac arrhythmias. Prog Cardiovasc Dis 16:497-522. 1974 37. Nademanee K,lntarachot V, Singh PN, et al: Characteristics and clinical significance of myocardial infarction in unstable angina. Am J Cardiol 58:268-33B, 1986 38. Wellens HJJ, Vermeulen A, Ourrer 0: Ventricular fibrillation occurring on arousal from sleep by auditory stimuli. Circulation 46:661-665, 1972 39. Mitsutake A, Takeshita A, Kuroiwa A. et al: Usefulness of the valsalva maneuver in management ofthe long Q-T syndrome. Circulation 63: I029-1 035. 1981 40. Surawicz B, Knoebel SB: Long Q-T: good, bad, or indifferent? J Am Coli Cardiol 4:398-413.1984 41. Eliot RS: Coronary anery disease: biobehavioral factors. Circulation 76:1-110.1987 42. Skinner JE, Reed JC: Blockade of frontoconical-brainstem pathway prevents ventricular fibrillation of isch· emic hean. AmJ Physiol 240:HI56-HI63. 1981
263
Stress and the Heart
43. Verrier RL. Calvert A. Lown B: Effect of posterior hypothalamic stimulation on ventricular fibrillation threshold. Am J PhysioI228:923-927. 1975 44. Samuels MA: Electrocardiographic manifestations of neurologic disease. Seminars in Neurology 4:453-461. 1984 45. Perloff J: Neurologic disorders and hean disease. in Heart Disease: A Textbook ofCardiovascular Medicine. Edited by Braunwald E. New York. WB Saunders. 1988. pp 1782-1799 46. Melin J. Fogelholm R: Electrocardiographic findings in subarachnoid hemorrhage. Acta Med Scand 213:5-8. 1983 47. Yamour BJ. Sridharan MR, Rice JF.et al: Electrocardiographic changes in cerebrovascular hemorrhage. Am Heart J 99:294-300.1980 48. Mikolich JR. Jacobs WC. Fletcher GF: Cardiac arrhythmias in patients with acute cerebrovascular accidents. JAMA 246:1314-1317.1981 49. Mcleod AA. Neil-Dywer G. Meyer CH, et al: Cardiac sequelae of acute head injury. Br Heart J 47:221-226. 1982 50. Weidler OJ: Myocardial damage and cardiac anhythmias after intracranial hemorrhage. Stroke 5:759-764. 1974 51. Hackenberry LE. Miner ME. Rea GL.et al: Biochemical evidence of myocardial injury after severe head trauma. Crit Care Med 1O:64I--M4. 1982 52. Weintraub BM. McHenry LC: Cardiac abnormalities in subarachnoid hemorrhage: a resume. Stroke 5:384-392. 1974 53. Heilman KM. Schwanz HD. Watson RT: Hypoarousal in patients and the neglect syndrome and emotional indifference. Neurology 28:229-232. 1978 54. Topaz O. Castellanos A. Grobman LR. et al: The role of arrhythmogenic auditory stimuli in sudden cardiac death. Am Heart J 116:222-226. 1988 55. Skinner JE, Beder SO. Entrnan ML: Psychological stress activates phosphorylase in the hean of the conscious pig without increased hean rate and blood pressure. Proc Natl Acad Sci USA 80:451~517. 1983 56. DeSilva RA. Verrier RL. Lown B: The effects of psychological stress and vagal stimulation with morphine on vulnerability to ventricular fibrillation in the conscious dog. Am Heart J 95: 197-203. 1978 57. Rabinowitz S. Lown B: Central neurochemical factors related to serotonin metabolism and cardiac ventricular vulnerability for repetitive electrical activity. Am J Cardiol 41 :51 ~522. 1978 58. Fricchione GL. Vlay SC: Psychiatric aspects of patients with malignant ventricular arrhythmias. Am J Psychiatry 143:1518-1526.1986 59. Ruskin J. Dimarco J. Garvan H: Out of the hospital cardiac arrest: electrophysiological observations and selection of long-term anti-arrhythmic therapy. N Engl J Med 303:607-612.1980
264
60. Swerdlow C. Winkle R. Mason J: Determinants of survival in patients with ventricular tachyarrhythmias. N EnglJ Med 308: 1436--1442. 1983 61. Dembroski TM. MacDonald JM. Williams RD. et al: Components of type A. hostility. and anger in relationship to angiographic findings. Psychosom Med 47:219233. 1985 62. Matthews KA. Glass DC. Rosenman RH. et al: Competitive drives. pattern A. and coronary hean disease: a further analysis of some data from the Western Collaboratory study. J Chronic Dis 30:489-498.1977 63. Matthews KA. Haynes SG: Type A behaviorpanern and coronary disease risk: update and critical evaluation. Am J EpidemioI123:923-960. 1986 64. Friedman M. Rosenman RH: Association of specific covert behavior panern with blood and cardiovascular findings.JAMA 169:1286--1295.1959 65. Friedman M. Thorensen CEo Gill JJ. et al: Feasibility of altering type A behavior pattem after myocardial infarction. Circulation 66:83-92. 1982 66. Friedman M. Thorensen CEo Gill JJ. et al: Alteration of type A behavior and reduction in cardiac recurrences in post myocardial infarction patients. Am Heart J 108:237-248. 1984 67. Friedman M. Thorensen CEo Gill JJ. et al: Alteration of type A behavior and its effect on cardiac recurrence in post myocardial infarction patients: summary results of the recurrent coronary prevention project. Am Heart J 112:653-665.1986 68. Stem TA: Psychiatric management of acute myocardial infarctions in coronary care unit. Am J CardioI6O:59J67J. 1987 69. Stratten JR. Halter JB: Effects of a benzodiazepine (alprazolam) on plasma epinephrine and norepinephrine levels during exercise stress. Am J Cardiol56: 136--139. 1985 70. Melson M. Andreassen D. Melson H. et al: Diazepam in acute myocardial infarction: clinical effects and effects on free fatty acids and cortisol. Br Heart J 38:804-810. 1976 71. Cote p. Gueret p. Bourassa MG: Systemic and coronary hemodynamic effects of diazepam in patients with normal and diseased coronary arteries. Circulation 50:1210-1216. 1974 72. Many J. Nitenberg A. Blanchet F. et al: Effects of midazolam on the coronary circulation in patients with coronary artery disease. Anesthesiology 64:206--210. 1986 73. Greenblatt OJ. Shader RI. Abernathy DR: Current status ofbenzodiazepines. I. N Engl J Med 309:354-358.1983 74. Hyman SE. Arana GW: Handbook of Psychiatric Drug Therapy. Boston. Little Brown Co. 1987. pp 115-133 75. American Psychiatric Association: Diagnostic and Statistical Manual of Menial Disorders. 3rd Edition. Revised. Washington. DC. American Psychiatric Association. 1987
PSYCHOSOMATICS
CATHRlNE FRANK. STEPHEN SMITH,
Stress has been implicated as a developmental factor in atherosclerotic heart disease, essential hypertension, and sudden cardiac death. This article reviews the mechanisms and biobehavioral effects of stress on the heart,focusing on its relation to sudden cardiac death. Epidemiologic evidence, cultural studies. animal experiments, and human research are reviewed to better understand the biobehavioral aspects ofstress on the heart. Emphasis is placed on understanding the interaction ofthe central nervous system's frontal cortex and hypothalamus with cardiovascular control areas. With today's understanding ofthe frontal cortex and the interaction of hormones and neurotransmitters with the cardiovascular system, clinical interventions utilizing psychotherapy and psychopharmacology are needed, particularly since both approaches are underutilized in combating arrhythmias.
T
he impact of stress on the body. and. in particular, on the heart. has captured both lay and scientific interest. For centuries, phrases such as "to die of a broken heart" or "to die of fright" have permeated our language. Engel's classic article, "Sudden and Rapid Death During Psychological Stress: Folklore or Folk Wisdom?" proposed the notion that psychological stress can induce lethal cardiac events. I Since then. clinical and epidemiological studies have investigated the biobehavioral effects of stress on atherosclerotic heart disease. essential hypertension. and sudden cardiac death. This article reviews the mechanism and effects of stress on the heart. especialIy as they relate to sudden cardiac death. DEFINITION OF SUDDEN CARDIAC DEATH Sudden cardiac death can best be defined as death due to cardiac causes. preceded by an abrupt loss of consciousness that occurs shortly (Le., within VOLUME 31 • NUMBER 3· SUMMER 1990
seconds to an hour) after the onset of acute symptoms; it may occur in an individual either with or without heart disease. Sudden cardiac death accounts for one-half to one-third of all deaths from coronary artery disease (CAD) and is estimated to result in 400.000 deaths per year in the United States.2 Not infrequently. sudden death will be the initial and only manifestation of heart disease. At autopsy. evidence of CAD typically is found. but its distribution and extent are not distinctive. To further confound the picture. there may be a paucity of acute pathomorphological changes. In a small percentage of patients, there are no obvious pathological cardiac lesions. The classic
Received January 16. 1989; revised July 31. 1989; accepted August 23. 1989. From the Psychiatric Consultation-Liaison Service and the Department of Cardiology. Henry Ford Hospital. Detroit. Address reprint requests to Dr. Frank. Consultation-Liaison Psychiatry. CFP-3. Henry Ford Hospital. 2199 West Grand Boulevard. Detroit. MI 48202. Copyright © 1990 The Academy of Psychosomatic Medicine. 255
Stress and the Heart
CAD risk factors of hypertension, smoking, and hypercholesterolemia do not identify those individuals predisposed to sudden cardiac death. 3 The occurrence of sudden cardiac death is not necessarily correlated with either activity or physical exertion. Although ventricular arrhythmias and, most commonly, ventricular fibrillation (VF) are the assumed pathophysiologic mechanisms, the definitive trigger is unknown. The interplay of behavioral and neural factors precipitating events is under investigation. EPIDEMIOLOGIC STUDIES Epidemiologic evidence has made significant contributions to an understanding of the role of psychological and social factors in CAD.4-8 Some ofthese same studies have highlighted a relationship, albeit not a causal one, between psychological stress and sudden cardiac death. Engel's paper, 1 a nonscientific gleaning from newspaper accounts of sudden death victims, described specific life settings in which sudden cardiac death may occur: loss or threat of loss of an object, threat of injury or danger, loss ofself-esteem, joy, or triumph. Rahe et al. 9 studied the effects of life stresses in postmyocardial infarction (MI) and sudden cardiac death patients. Evidence of life stress was gathered from the spouses of sudden cardiac death victims and from the post-MI patients and their spouses. The results showed marked elevations in the magnitude of life stresses during the six months prior to the infarction or sudden cardiac death, compared with the same interval one year earlier. This increase in life stress was particularly significant for sudden cardiac death victims. Follick et al. 10 did a prospective study of 125 post-MI patients equipped with transtelephonic electrocardiograph (ECG) monitors, examining the relationship between psychological distress and ventricular ectopy. There was a direct relationship between measured levels of distress and occurrence of ectopic beats, even when adjusted for age, cardiac risk factors, and the use of betablocking agents. Education and socioeconomic level also have been considered to be correlates of stress 256
that may contribute to sudden cardiac death. Investigators had found an inverse relationship between mortality from CAD and education.' Ruberman et al. 8 expanded on this with a prospective study of 2320 male survivors of MI who participated in the Beta-Blocker Heart Attack Trial, examining its effect on fatality from CAD and sudden cardiac death. They discovered that, over a three-year period, the cumulative probability of death was highest among those survivors with less than 10 years of schooling. In addition, high levels of stress and social isolation were most prevalent among the least educated men. Compared to those with low levels of both stress and social isolation, those who were socially isolated and stressed were at four times the risk of death; the increased risk was associated with total cardiac deaths and sudden cardiac deaths. In general, though there seems to be a relationship between psychosocial factors and sudden cardiac death, these factors are weak predictors of sudden cardiac death since the majority of people experience these events without resulting fatality. CULTURAL STUDIES Cultural studies have reported on the role ofstress primarily as it relates to CAD. Marmot and Syme ll studied Japanese men, who traditionally have a low incidence of CAD, in various cultural settings and discovered that the rate of CAD increased as they assimilated into Western culture. As the increased rate could not be explained on the basis of cardiac risk factors, it was suggested that the "stress of assimilation" might be a factor. Similarly, cultural influences may playa role in several sudden death syndromes: the Bangungut in young Filipino men,12 Pokkuri in the Japanese, and Non Latai in Laotians. Individuals who are afflicted die suddenly during sleep, in the absence of obvious organic heart disease or other major toxicologic or pathological lesions. 13 More recently. sudden cardiac death has been hypothesized in the Laotian Hmongs. following their immigration to the United States. 14 The deceased were generally in their thirties, in good health, and suffered from presumed and. in PSYCHOSOMATICS
Frank and Smith
some cases, documented nocturnal VF. One survivor had documented inducible ventricular tachycardia (VT).15 It has been hypothesized that the fatal arrhythmias in the Hmongs were due to the stress of "culture shock," following their emigration to the United States, but, as yet, the definite etiology and mechanism of these syndromes are unknown. ANIMAL STUDIES Animal studies have paralleled epidemiologic evidence in the understanding of the effects of stress on the heart. Lown et al. 16 set up a classic aversive conditioning paradigm in which dogs were placed either in an undisturbed environment, or in a Pavlovian sling, in which the dog received a transthoracic shock at the end of each experimental period for three successive days. The effects of the two environments were compared on the fourth and fifth days. The dogs in the stressed environment were restless, salivating, tremulous, with increased blood pressure and pulse as compared to the relaxed dogs in the undisturbed environment. The stressed dogs had a lower cardiac threshold for VF. If the dogs were transferred from the nonaversive to the aversive environment, their threshold decreased by 41 %.17 To clarify the effects of stress in diseased hearts, the same paradigm was repeated but was studied during a coronary occlusion-release sequence. IS The left anterior descending artery was occluded for 10 minutes and was followed by abrupt release and reperfusion. The experimental design was chosen to determine if acute ischemia or reperfusion, as might occur after coronary artery spasm or dislodgement of platelet aggregates, might provoke VF. The dogs were exposed either to the aversive sling environment or to the nonaversive environment. In the aversive environment with experimentally induced ischemia, the incidence of VF was three times greater than that in the nonaversive environment. The VF occurred within three to five minutes of coronary occlusion or within 20 to 30 seconds after release and reperfusion. Thus, the nonaversive environment protected against reperfusion fibrillation. Several studies have shown that pigs may VOLUME 3\ • NUMBER 3· SUMMER 1990
have enhanced reactivity to environmental stress. Cardiac dysrhythmias and cardiomyopathy may be induced when pigs are exposed to severe psychological stress. 19 Skinner et at. 20 produced similar results in pigs who either were allowed to adapt to a new environment for two to three days or not allowed to adapt. When myocardial ischemia was produced in the nonadapted animals, fibrillation occurred within a few minutes. In those pigs allowed to adapt to the new environment, fibrillation either was delayed Qr prevented. Thus, although myocardial ischemia was an important factor in the genesis of VF in these animals, it was modifiable by alleviation of stress. Verrier and Lown 21 attempted to elicit natural emotions by simulating anger in dogs by denying them access to food. After an overnight fast and period of acclimation to a new environment, a leashed dog was presented with food which then was given to, and devoured by, a second dog within his vision. The deprived dog displayed an angry-like response with increased heart rate, increased mean arterial blood pressure, increased catecholamines, and decreased repetitive extrasystole threshold (i.e., an indicator of risk to fibrillate). HUMAN STUDIES How do the animal studies translate into human experiences? Reich et at. 22 studied 117 patients who had recurrent life-threatening ventricular arrhythmias. These patients were followed by a task force consisting of a psychiatrist, psychologist, and members of a cardiovascular team. Twenty-five patients (21 %) were judged to have had a psychological trigger in the 24 hours before their arrhythmia. In 15 of the 25 patients, the psychologically stressful stimulus occurred less than one hour before the onset of the arrhythmias. These patients were differentiated from the other 92 patients for having experienced more lethal ventricular arrhythmias, yet they had less demonstrable cardiac pathology. In 17 ofthe 25 patients, the main affect associated with the stress was anger. It is neither known nor addressed by the authors of the study why 79% of the dead did not 257
Stress and the Heart
have a psychological trigger for the arrhythmia. There may be various subsets of patients susceptible to ventricular arrhythmias, with psychological factors representing one such subset. Greene et al.23 found that at least half of the 26 studied victims of sudden cardiac death had psychological or social stressors associated with the time of sudden death. The data suggested that the majority of these patients, all men, were depressed for a week to several months prior to their death and that anxiety and anger may have evoked hormonal or sympathetic nervous system responses conducive to arrhythmias. Thus, these data point to an association between psychological variables and ventricular arrhythmias, though not a causal one. Of the psychological variables, anger has been implicated in sudden cardiac death and in better defining the concept of the Type A personality. Case reports of malignant ventricular arrhythmias and sudden cardiac death are abundantY4-26 Olsson and Rehnquist 24 reported the case of a 70-year-old man with a history of two MIs who returned home after a six-month medical check-up with no acute changes in his condition. On the night following the check-up, he realized that some important papers were missing from his wallet. He called the hospital in an excited fashion. While on the phone, he developed VF and died. Lown et al. 25 reported the case of a healthy middle-aged man who developed VF while roughhousing with his sexually mature teenage daughters. Malignant arrhythmias could be triggered by a psychiatric interview, rapid eye movement (REM) sleep, and emotional stress. The arrhythmia was diminished by meditation, betaadrenergic blocking agents, phenytoin, and digitalization. A recent topic of interest in the study of sudden cardiac death has involved the concept of silent ischemia. Silent ischemia has been welldocumented in a variety of individuals with various cardiac ischemic syndromes. Deanfield et al. 27 demonstrated by ambulatory monitoring that most episodes of angina (75%) are silent. Other investigators have confirmed this finding by examining electrocardiographic ST segment alter258
ations,28 scintography,29 and left ventricular wall motion abnormalities. 30 Rozanski et al. 31 recently demonstrated that mental tasks, especially public speaking, actually can induce wall motion abnormalities. In fact, of the patients with inducible (presumably ischemic) wall motion abnormalities, 83% were silent and generally occurred at lower heart rates than exercise-induced ischemia. The investigators suggested that personally relevant mental stress, such as public speaking, was the stress most likely to provoke ischemia. While silent ischemia and sudden cardiac death have been well-studied, their exact relationship is obscure. To understand the possible interrelationship of sudden cardiac death and silent ischemia, four factors need to be considered: stress, ventricular ectopy, silent ischemia, and sudden cardiac death. Sudden cardiac death, silent ischemia, and myocardial infarction all follow a similar circadian pattern; i.e., upon awakening, the individual is at greatest risk from six A.M. to noon. 32 It has been hypothesized that ventricular ectopy is the bridge between silent ischemia and sudden cardiac death, i.e., that individuals with silent ischemia may develop ventricular ectopy, resulting in sudden cardiac death. This has been shown anecdotally,33.34 but in large studies utilizing angioplasty,35 exercise stress testing,36 and ambulatory monitoring,37 there has been little or no demonstrable connection between ischemia and ventricular ectopy. Thus, although, as yet, there is no proven mechanism to link sudden cardiac death to silent ischemia, there is "guilt by association." A MODEL OF SUDDEN CARDIAC DEATH A natural human model of sudden cardiac death is the long Q- T syndrome. This rare congenital abnormality of cardiac repolarization is associated with sudden cardiac death, particularly in situations known to increase sympathetic nerve activity, e.g., emotion and physical exertion. When exposed to stress, such as that resulting from loud noises,38 vigorous physical exercise, the valsalva maneuver,39 and from emotions such as fright, patients may develop episodic VT leading to VF, syncope, or death. Patients with this PSYCHOSOMATICS
Frank and Smith
syndrome are usuaIly symptomatic in childhood, although some may not present with symptoms until their 30s and 40s (e.g., as with the RomanoWard syndrome). Q-T lengthening also may be acquired through central nervous system (CNS) lesions, autonomic dysfunction, CAD, mitral valve prolapse, use of drugs such as the Vaughan-Williams group lA antiarrhythmics (e.g., procainamide, quinidine, disopyramide), phenothiazines, tricyclic antidepressants, or through starvation, liquid protein diets, and other electrolyte disorders. In these individuals, the degree ofQ-T prolongation may vary, and arrhythmogenesis is less marked, though present. In exploring the mechanism that underlies the long Q-T syndrome, Schwartz26 noted that stress leads to increased adrenergic output, and he examined the role of nerves that innervate the cardiac system in provoking arrhythmias. In animals he found that by stimulating the left stellate ganglion or by removing the right stellate ganglion, the Q-T interval was lengthened. He hypothesized that abnormally low right cardiac sympathetic activity and possible hyperactivity of the left-sided nerves create a sympathetic imbalance that is arrhythmogenic. In the treatment of long Q-T syndromes, medical therapy (primarily beta-blocking agents) and surgical therapy (i.e., stellate ganglionectomy) have predominated. Sedatives may be helpful in that they blunt the emotional response and thus diminish sympathetic output. 40 NEUROCARDIOLOGIC CONNECTIONS How is stress interpreted by the brain and translated into cardiac vulnerability? Stress is a supratentorial reaction or experience of a particular individual to a particular stimulus. The reaction lies not in the stressor itself, but in the individual's interpretation. The CNS, particularly the frontal cortex, acts as the major interpreter of stress. Eliot41 distinguished between the ways in which the CNS construes chronic and acute stress. Chronic stress is handled mainly through the CNS via the pituitary-adrenal-cortical axis, often with resulting increases in cortisol VOLUME 31 • NUMBER 3 • SUMMER \990
activity. Long-term effects of cortisol consist of sodium retention, increased blood volume, decreased ventricular ectopic threshold, and increased sensitivity of arterioles to catecholamines. On the other hand, acute stress (the fight or flight response) is mediated primarily by the limbic system, hypothalamus, and adrenal medulla and results in increased catecholamines and, on occasion, increased cortisol. A model of the limbic-hypothalamic-adrenal axis gone awry is pheochromocytoma. The leading causes of death in pheochromocytoma are "catecholamine myocarditis," ventricular arrhythmia, MI, hypertension, or sudden cardiac death. Metabolically, increased catecholamines result in increased cholesterol and free fatty acids, increased blood pressure, decreased VF threshold, and increased platelet aggregation. This is of interest in postulating how the limbic-hypothalamic-adrenal axis interprets stress and how stress may alter cardiac vulnerability. The effects of stress on cardiac vulnerability no doubt involve the brainstem where the cardiovascular control areas (the nucleus tractus solitarii, cardiovascular motor nuclei, and nucleus ambiguous) come in contact with pathways from the frontal cortex and hypothalamus. Skinner and Reed42 showed that a bilateral cryogenic blockade of the frontocortical pathways prevents reoccurrence of VF in pigs with an ischemic heart, even though the animal is under stress. Verrier et al. 43 studied 34 dogs and found that posterior hypothalamic stimulation led to a 40% reduction in VF threshold. The decreased threshold persisted even when increased heart rate and pressor response were prevented or when cervical vagotomy and bilateral adrenalectomy were performed. The study concluded that the reduction in VF threshold associated with posterior hypothalamic stimulation was due to the direct action of sympathetic nerves on the myocardium, and not from secondary hemodynamic effects. The role of the CNS on cardiac function also has been demonstrated in patients with cerebral insults such as subarachnoid hemorrhage, intracerebral hemorrhage, subdural hemorrhage, or ischemic strokes. In fact, up to 90% of those patients sustaining a cerebral accident may show 259
Stress and the Heart
ECG abnonnalities with changes in rhythm or repolarization:'4--46 Yamour et al. 47 observed ECG findings associated with cerebral damage in 65 patients without known cardiac disease or drug or electrolyte abnonnalities. While atrial arrhythmias predominated, frequent premature ventricular contractions (PVCs) occurred in 10% of the patients, mainly those with temporoparietal hemorrhage. Neurogenic T waves and Q-T prolongation occurred in 50%-80% of the patients with frontal lobe hemorrhages. Interestingly, all of these patients had left-hemispheric lesions. Other investigators have noted significant ventricular rhythm disturbances, including PVCs, VT, VF, inversion of T waves (the so-called cerebral T waves), and prominent U waves in patients with CNS events. 4 1.48-50 The separation of neural and honnonal effects of CNS disease on the heart has been problematic. Initially, the rapid reversibility of ECG findings was thought to indicate a neurological etiology. Subsequent work has suggested that a catecholamine release, especially a norepinephrine release at cardiac beta-receptor sites, may be responsible for direct cardiac effects 51 and may be modified by beta-blockade. 50.52 Samuels44 suggested that the combined effects of steroids and catecholamines may lead to myocardial injury. While these represent extreme examples of CNS damage, they suggest a mechanism by which sudden cardiac death through arrhythmogenesis may occur with or without cardiac disease. The role of the cerebral cortex in reaction to stress is also evident in patients with right-hemispheric and, in particular, with frontal-lobe damage. Heilman et al. 53 recorded galvanic skin responses following electrical stimulation of the ipsilateral foreann of patients with right hemispheric brain damage exhibiting neglect. Compared to healthy controls and to aphasic patients with left-hemispheric damage, the patients with right-hemispheric damage had lower galvanic skin responses. They had a markedly decreased autonomic response, suggesting that their cerebral reaction to stress was ablated. The role of the CNS in arrhythmogenesis was reviewed by Topaz et al. 54 in patients who supposedly were provoked to sudden cardiac 260
death by auditory stimuli. He cited case reports of individuals with nonnal coronary arteries who experienced fatal VF, caused by such diverse sounds as ringing doorbells, phones, screeching brakes, and loud music (cases reviewed were both documented and assumed VF). It was suggested that auditory stimuli may activate efferent pathways in the hypothalamus and quadrigeminal bodies where auditory pathways operate. Impulses may cross the reticular fonnation and, via the stellate ganglia, sympathetically innervate the heart. Thus, alanning noises may induce sympathetic activity and by neural and honnonal mechanisms predispose the individual to VF. The sympathetic nervous system is a major factor in the development of VF. Skinner et al. 55 set up an experiment in which phosphorylase A activation, which indicates the level of sympathetic tone, could be measured. Pigs were exposed to a stressful environment. It was discovered that phosphorylase A activation decreased linearly with behavioral adaptation in pigs who were in a resting state. The evidence supports a direct link between a psychological stressor, a specific myocardial response, and the role of high adrenergic tone in this regard. The high sympathetic tone, as indicated by the phosphorylase activation, and the high parasympathetic tone, as evidenced by the resting heart rate, suggest a dual regulating system for arrhythmias. Vagal influences playa role in modifying the effect of stress on cardiac vulnerability. DeSilva et al. 56 administered morphine to dogs, which enhances vagal tone, among other effects. In a stressful environment, the morphine increased the threshold for VF to the value observed in nonstressful situations. Administration of intravenous atropine negated this response. Administration of morphine in a nonstressful setting did not alter the vulnerable period threshold. Thus, during stress the vagus nerve serves a protective function, antagonizing the profibrillatory influence of increased adrenergic input to the heart. The sympathetic and vagal nerves are modulated through the brainstem, which is innervated by frontocortical areas and by neurons with neurotransmitters, such as y-aminobutyric acid PSYCHOSOMATICS
I.
Frank and Smith
(GABA), serotonin, acetylcholine, and norepinephrine. Interesting studies have been perfonned by Rabinowitz and Lown s7 on the role of serotonin and its modulation of autonomic neural activity in the brain. In an experiment they injected dogs with tryptophan, phenelzine, and carbidopa. L-tryptophan, the biochemical precursor of serotonin, was combined with phenelzine, which inhibits monoamine oxidase, and with carbidopa, an L-aromatic amino acid decarboxylase inhibitor, which served to decrease serotonin formation peripherally so as to increase CNS accumulation. The repetitive extrasystole threshold increased by 50%, thus indicating that an increase of central serotonin activity may decrease sympathetic input from the brain to the heart and have an antifibrillatory effect. CLINICAL IMPLICATIONS In this article we have reviewed a variety of known and postulated connections between stress and sudden cardiac death. One of the critical questions that remains is how to reduce stress by social, psychological, and pharmacological interventions in order to diminish a patient's vulnerability to a malignant arrhythmia. This is imperative because, although patients with VT or VF associated with acute MI have little risk of recurrence, survivors of out-of-the-hospital VT or VF without MI, who have refractory arrhythmias, are at a high risk for a similar event. 58 Patients with VT or VF have a 70%-90% chance of recurrence if a suitable antiarrhythmic therapy cannot be found. 59.6O From a psychiatric perspective, the need for trials ofpsychotherapy and psychopharmacology is compelling. Hostility and anger have been implicated for their effects on CAD in humans61 63 and, as reviewed in this article, as a potential trigger of malignant arrhythmias. 20 In studies of Type A behavior, first described by Friedman and Rosenman,64 it has been suggested that it is not the pattern of competitiveness, excessive drive, and time urgency that are most relevant to the increased risk of cardiovascular disease, but, rather, unexpressed hostility.61~3 Individual and group psychotherapies have been found to modVOLUME 31 • NUMBER 3 • SUMMER 1990
ify Type A behavior and to decrease the prevalence of recurrent nonfatal MI.6~7 Interventions consisted of behavioral learning, progressive muscle relaxation, and a fonn of cognitive affective learning aimed at having patients evaluate themselves, their internalized goals and beliefs, and their assumptions about themselves and others. 65 The therapy also focused on enabling subjects to channel anger into assertive, rather than aggressive, responses. Psychotherapy also could help with an array of stresses mentioned in this article, such as loss ofan object, social isolation, and low self-esteem. Although there are no known trials to support the efficacy of psychotherapy for patients at risk of developing arrhythmias, clinical trials would help explore this issue. Psychopharmacology is probably an underutilized tool in combating arrhythmias. Stern,68 for example, highlights the failure to diagnose and treat underlying psychiatric complications of MI in the coronary care unit and explains how this can aggravate the underlying cardiac condition. The literature points to the potential usefulness of agents that mediate catecholamines, serotonin, and GABA. Both systemic elevation of catecholamines and release by local cardiac nerves have been implicated in the genesis of arrhythmias. Stratten and Halter69 took a small sample of healthy men and gave them a stress exercise test during treatment with alprazolam. During drug treatment, the plasma epinephrine and norepinephrine levels were reduced significantly after eight and II minutes of exercise (although there was no statistical significance at maximal exercise). The alprazolam, according to the study, led to decreased sympathetic tone, a result that should aid stressed patients or acute MI patients who tend to have increased circulating levels of catecholamines. Similarly, Melson et al. 70 found decreased urinary adrenaline and free fatty acid concentrations after administering diazepam to patients with acute MI. Although 24hour cardiac monitoring was not maintained, the group treated with diazepam had a decreased incidence ofventricular arrhythmias. Diazepam71 and midazolam 72 have the added benefit of decreasing myocardial oxygen consumption. 261
Stress and the Heart
The work of Rabinowitz and Lown 57 on serotonin reported that serotonin modulates autonomic neural activity and sympathetic input from the brain to the heart. Of interest is the fact that research is exploring the role of serotonin in a number of psychiatric disorders and conditions. notably depression. anxiety. obsessive-compulsive disorder. and suicide. Pharmacological agents such as fluoxetine and buspirone enhance serotonin. although by different mechanisms. Buspirone has been utilized in anxiety disorders. Fluoxetine has been helpful with affective disorders. panic disorders. and obsessive-compulsive disorder. These agents and others like them may have a role in cardiac patients susceptible to stress. It is now established that benzodiazepines interact with their receptors to facilitate the inhibitory neuronal properties of GABA. 73 The benzodiazepine receptors have their highest concentration in the limbic system, which is involved in the control of emotion and visceral function. 74 Benzodiazepines have been shown to suppress neuronal activity in the limbic system. which includes the hypothalamus. amygdala. hippocampus. and septal region. This leads to the hypothesis that the limbic system is involved in the etiology of anxiety. 74 Of interest is the fact that the hypothalamus and frontal cortex pathways interface with cardiovascular control centers in the brainstem. The posterior hypothalamus. in particular. has been implicated experimentally in the reduction of the YF threshold. 43 This "neural wiring." in addition to the benzodiazepine effect on sympathetic tone. on enhancement of GABA's inhibitory effect on the limbic system. and the lack of cardiotoxicity. makes the benzodiazepines potentially useful agents. Controlled trials are needed to evaluate benzodiazepine efficacy in patients at risk for malignant arrhythmias. Beta-adrenergic blockers should be mentioned not only because they typically are used in the treatment of symptomatic patients with long Q-T syndrome and some tachyarrhythmias, but also because these agents are sparking interest in psychiatric disorders such as performance anxiety. generalized anxiety disorder (GAD), and in 262
the violent behavior of patients with organic brain syndrome. These agents are competitive antagonists of norepinephrine and epinephrine at beta-adrenergic receptors. Beta-I receptors appear to be the prevailing noradrenergic receptors on neurons in the brain. 74 Beta-adrenergic blockers are effective in treating autonomic symptoms associated with performance anxiety. GAD, and panic attacks. 74 They seem less effective in treating the psychological aspects of anxiety. The use of beta-blockers in stressed individuals and in patients meeting the DSM-III-R 75 criteria for anxiety disorders needs further exploration. An understanding of the interplay of psychoneurologic and cardiovascular factors has immediate and practical importance. The research reviewed in this article postulates that "stressors." such as bereavement. loss of social support. and free-floating hostility may have a role in the genesis of some arrhythmias and. in some patients. may be amenable to psychotherapy. It also points to the role of the frontal cortex and limbic system and to the importance of neurotransmitters such as norepinephrine. serotonin. and GABA. Likewise. it considers the feasibility of treatment with benzodiazepines. among others. Controlled trials with psychotherapy and psychopharmacology are needed to transform these theoretical constructs into life-saving therapies.
The authors wish to thank Theodore A. Stem, MD., o/Massachusetts General Hospital,for his support and guidance in the preparation 0/ this manuscript.
References I. Engel GL: Sudden and rapid death during psychological stress. Ann Intern Med 74:77 1-782. 1971 2. Cobb LA. Werner JA: Predictors and preventions of sudden cardiac death. in The Heart. Edited by Hurst JW. New York. McGraw Hill. 1986. pp 538-546 3. Kuller LH: Sudden death: definition and epidemiologic considerations. Prog Cardiol'Qsc Dis 23: 1-12. 1980 4. Rees WD. Lutkins SG: Monality of bereavement. Br MedJ 4:13-16.1967 5. Parkes CM. Benjamin B. Fitzgerald R: Broken hean: a statistical study of increased monality among widowers. BrMedJ 1:740-743. 1969 6. Helsing KJ. Szklo M. Comstock GW: Factors associated
PSYCHOSOMATICS
Frank and Smith
with monality after widowhood. Am J Public Health 71:802-809.1981 7. Shekelle RB: Educational status and risk of coronary anery disease. Science 163:97-98. 1969 8. Ruberman W. Weinblan E. Goldberg JO. et al: Psychosocial influences on monality after myocardial infarction. N Engl J Med 311:552-559.1984 9. Rahe RH. Romo M. Bennett L. et al: Recent life changes. myocardial infarction and abrupt coronary death. Arch Intern Med 133:221-228. 1974 10. Follick MI. Gorkin L. Capone RJ. et al: Psychological distress as a predictor of ventricular arrhythmias in a post-myocardial infarction population. Am Heart J 116:32-36. 1988 II. Marmot MG. Syme SL: Acculturation and coronary hean disease in Japanese-Americans. Am J Epidemiol 104:225-247. 1976 12. Aponte GE: The enigma of Bangungut. Ann Int Med 52:1259-1263. 1960 13. Myerburg RJ. Costellanos A: Cardiac arrest and sudden cardiac death. in Braunwald E: Heart Disease: A Textbook of Cardiovascular Medicine. New York. WB Saunders, 1987. pp 742-777 14. Baron RC, Thacker SB. Gorelkin L. et al: Sudden death among southeast Asian refugees: an unexplained natural phenomenon.JAMA 250:2947-2951,1983 15. Otto CM. Tauxe RV. Cobb LA. et al: Ventricular fibrillation causes sudden cardiac death among southeast Asian immigrants. Ann Intern Med 101 :45-47. 1984 16. Lown B. Verrier RL. Corbalan R: Psychologic stress and threshold for repetitive ventricular response. Science 182:8~36. 1973 17. DeSilva RA, VerrierRL. Lown B: The effects of psychological stress and vagal stimulation with morphine on vulnerability to ventricular fibrillation in the conscious dog. Am Heart J 95:197-203. 1978 18. Verrier RL, Lown B: Influence of psychologic stress on susceptibility to spontaneous ventricular fibrillation during acute myocardial ischemia and reperfusion. Clin Res 27:570A, 1979 19. Johansson G. Jonsson L. Lannek N. et al: Severe stress induced cardiomyopathy in pigs. Am Heart J 87:451457. 1974 20. Skinner JE, Lie JT, Entman ML: Modification of ventricular fibrillation latency following coronary anery occlusion in the conscious pig. Circulation 51 :656--666. 1975 21. Verrier RL. Lown B: Behavioral stress and cardiac arrhythmias. Annu Rev Physiol 46:155-176.1984 22. Reich P. DeSilva RA. Lown B. et al: Acute psychological disturbance preceding life-threatening ventricular arrhythmia. JAMA 246:233-235. 1981 23. Greene WA. Goldstein S, Moss AJ: Psychosocial aspects of sudden cardiac death. Arch Intern Med 129:725-731. 1972 24. Olsson G. Rehnquist N: Sudden death precipitated by psychological stress. Acta Med Scand 212:437-441, 1982
VOLUME31·NUMBER3·SUMMER 1990
25. Lown B. Temte JV, Reich P, et al: Fibrillation in the absence of coronary hean disease and its management. N Engl J Med 294:623~29. 1976 26. Schwanz PJ: Stress and sudden cardiac death: the role of the autonomic nervous system. Journal ofClinical Psychiatry Monograph 2:7-13.1984 27. Deanfield JE, Mesari A, Selwyn AP, et al: Myocardial ischemia during daily life in patients with stable angina: its relation to symptoms and hean rate changes. Lancet 2:753-758. 1983 28. Amsterdam EA. Manschniske R, Laskett CJ. et al: Symptomatic and silent ischemia during exercise testing in coronary anery disease. Am J Cardiol 58:43B-46B. 1986 29. Deanfield JE. Shea M. Ribiero P. et al: Transient ST segment depression as a marker of myocardial ischemia during daily life. Am J Cardiol 54:1195-1200.1984 30. Cohn PE, Brown ES, Wynne J: Global and regional ejection fraction abnormalities during exercise on patients with silent myocardial ischemia. J Am Coli Cardiol 1:931-933, 1983 31. Rozanski A. Bairey CN. Krantz OS, et al: Mental stress and the induction of silent myocardial ischemia in patients with coronary anery disease. N Engl J Med 318:1005-1012.1988 32. Rocco MB, Nabel EG. Selwyn AP: Circadian rhythms and coronary anery disease. Am J Cardiol 59:13C-17C. 1987 33. Grodman AH, Bell PA. DeBusk RF: Sudden death during ambulatory monitoring: clinical and electrocardiographic correlations: repon of a case. Circulation 55:210-211.1977 34. Savage 00. Castelli WP. Anderson SJ. et al: Sudden unexpected death during ambulatory electrocardiographic monitoring: the Framingham Study. Am J Med 74:148-152. 1983 35. Bairn OS, Faxon OP: Coronary Angiography. in Cardiac Catheterization and Angiography. Edited by Grossman W. Philadelphia. Lea and Febiger. 1986. pp 473-492 36. Jelinek MV, Lown B: Exercise testing for exposure of cardiac arrhythmias. Prog Cardiovasc Dis 16:497-522. 1974 37. Nademanee K,lntarachot V, Singh PN, et al: Characteristics and clinical significance of myocardial infarction in unstable angina. Am J Cardiol 58:268-33B, 1986 38. Wellens HJJ, Vermeulen A, Ourrer 0: Ventricular fibrillation occurring on arousal from sleep by auditory stimuli. Circulation 46:661-665, 1972 39. Mitsutake A, Takeshita A, Kuroiwa A. et al: Usefulness of the valsalva maneuver in management ofthe long Q-T syndrome. Circulation 63: I029-1 035. 1981 40. Surawicz B, Knoebel SB: Long Q-T: good, bad, or indifferent? J Am Coli Cardiol 4:398-413.1984 41. Eliot RS: Coronary anery disease: biobehavioral factors. Circulation 76:1-110.1987 42. Skinner JE, Reed JC: Blockade of frontoconical-brainstem pathway prevents ventricular fibrillation of isch· emic hean. AmJ Physiol 240:HI56-HI63. 1981
263
Stress and the Heart
43. Verrier RL. Calvert A. Lown B: Effect of posterior hypothalamic stimulation on ventricular fibrillation threshold. Am J PhysioI228:923-927. 1975 44. Samuels MA: Electrocardiographic manifestations of neurologic disease. Seminars in Neurology 4:453-461. 1984 45. Perloff J: Neurologic disorders and hean disease. in Heart Disease: A Textbook ofCardiovascular Medicine. Edited by Braunwald E. New York. WB Saunders. 1988. pp 1782-1799 46. Melin J. Fogelholm R: Electrocardiographic findings in subarachnoid hemorrhage. Acta Med Scand 213:5-8. 1983 47. Yamour BJ. Sridharan MR, Rice JF.et al: Electrocardiographic changes in cerebrovascular hemorrhage. Am Heart J 99:294-300.1980 48. Mikolich JR. Jacobs WC. Fletcher GF: Cardiac arrhythmias in patients with acute cerebrovascular accidents. JAMA 246:1314-1317.1981 49. Mcleod AA. Neil-Dywer G. Meyer CH, et al: Cardiac sequelae of acute head injury. Br Heart J 47:221-226. 1982 50. Weidler OJ: Myocardial damage and cardiac anhythmias after intracranial hemorrhage. Stroke 5:759-764. 1974 51. Hackenberry LE. Miner ME. Rea GL.et al: Biochemical evidence of myocardial injury after severe head trauma. Crit Care Med 1O:64I--M4. 1982 52. Weintraub BM. McHenry LC: Cardiac abnormalities in subarachnoid hemorrhage: a resume. Stroke 5:384-392. 1974 53. Heilman KM. Schwanz HD. Watson RT: Hypoarousal in patients and the neglect syndrome and emotional indifference. Neurology 28:229-232. 1978 54. Topaz O. Castellanos A. Grobman LR. et al: The role of arrhythmogenic auditory stimuli in sudden cardiac death. Am Heart J 116:222-226. 1988 55. Skinner JE, Beder SO. Entrnan ML: Psychological stress activates phosphorylase in the hean of the conscious pig without increased hean rate and blood pressure. Proc Natl Acad Sci USA 80:451~517. 1983 56. DeSilva RA. Verrier RL. Lown B: The effects of psychological stress and vagal stimulation with morphine on vulnerability to ventricular fibrillation in the conscious dog. Am Heart J 95: 197-203. 1978 57. Rabinowitz S. Lown B: Central neurochemical factors related to serotonin metabolism and cardiac ventricular vulnerability for repetitive electrical activity. Am J Cardiol 41 :51 ~522. 1978 58. Fricchione GL. Vlay SC: Psychiatric aspects of patients with malignant ventricular arrhythmias. Am J Psychiatry 143:1518-1526.1986 59. Ruskin J. Dimarco J. Garvan H: Out of the hospital cardiac arrest: electrophysiological observations and selection of long-term anti-arrhythmic therapy. N Engl J Med 303:607-612.1980
264
60. Swerdlow C. Winkle R. Mason J: Determinants of survival in patients with ventricular tachyarrhythmias. N EnglJ Med 308: 1436--1442. 1983 61. Dembroski TM. MacDonald JM. Williams RD. et al: Components of type A. hostility. and anger in relationship to angiographic findings. Psychosom Med 47:219233. 1985 62. Matthews KA. Glass DC. Rosenman RH. et al: Competitive drives. pattern A. and coronary hean disease: a further analysis of some data from the Western Collaboratory study. J Chronic Dis 30:489-498.1977 63. Matthews KA. Haynes SG: Type A behaviorpanern and coronary disease risk: update and critical evaluation. Am J EpidemioI123:923-960. 1986 64. Friedman M. Rosenman RH: Association of specific covert behavior panern with blood and cardiovascular findings.JAMA 169:1286--1295.1959 65. Friedman M. Thorensen CEo Gill JJ. et al: Feasibility of altering type A behavior pattem after myocardial infarction. Circulation 66:83-92. 1982 66. Friedman M. Thorensen CEo Gill JJ. et al: Alteration of type A behavior and reduction in cardiac recurrences in post myocardial infarction patients. Am Heart J 108:237-248. 1984 67. Friedman M. Thorensen CEo Gill JJ. et al: Alteration of type A behavior and its effect on cardiac recurrence in post myocardial infarction patients: summary results of the recurrent coronary prevention project. Am Heart J 112:653-665.1986 68. Stem TA: Psychiatric management of acute myocardial infarctions in coronary care unit. Am J CardioI6O:59J67J. 1987 69. Stratten JR. Halter JB: Effects of a benzodiazepine (alprazolam) on plasma epinephrine and norepinephrine levels during exercise stress. Am J Cardiol56: 136--139. 1985 70. Melson M. Andreassen D. Melson H. et al: Diazepam in acute myocardial infarction: clinical effects and effects on free fatty acids and cortisol. Br Heart J 38:804-810. 1976 71. Cote p. Gueret p. Bourassa MG: Systemic and coronary hemodynamic effects of diazepam in patients with normal and diseased coronary arteries. Circulation 50:1210-1216. 1974 72. Many J. Nitenberg A. Blanchet F. et al: Effects of midazolam on the coronary circulation in patients with coronary artery disease. Anesthesiology 64:206--210. 1986 73. Greenblatt OJ. Shader RI. Abernathy DR: Current status ofbenzodiazepines. I. N Engl J Med 309:354-358.1983 74. Hyman SE. Arana GW: Handbook of Psychiatric Drug Therapy. Boston. Little Brown Co. 1987. pp 115-133 75. American Psychiatric Association: Diagnostic and Statistical Manual of Menial Disorders. 3rd Edition. Revised. Washington. DC. American Psychiatric Association. 1987
PSYCHOSOMATICS