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What's "Unstable" in Unstable Angina?

Received May 2, 2003; revision received Sept. 20, 2003; accepted Oct. 17, 2003. From the Consultation/Liaison Psychiatry Department and Heart and Vascular Institute of the Henry Ford Health Sciences Center. Address reprint requests to Dr. Ketterer, Henry Ford Hospital/CFP6, 2799 West Grand Blvd., Detroit, MI 48202; MarkWKetterer{at}cs.com (e-mail).

ABSTRACT

TOP ABSTRACT INTRODUCTION Problems With the Assumption... Emotional Distress and ACD:... Emotional Distress and ACD:... Emotional Distress and ACD:... Summary REFERENCES

 
The role of emotional distress (e.g., anger, depression, and anxiety) in anginal chest discomfort (ACD) may have been underestimated. The authors review the empirical studies in this area, which are inconsistent with the standard theory on the ischemia-angina relationship; summarize the substantial evidence indicating a strong and consistent cross-sectional/prospective epidemiological association of emotional distress and ischemia/ACD; review the distress-targeted, interventional evidence confirming a causal relationship (i.e., reduced chest discomfort and health system utilization), thus confirming clinical utility of such interventions; and explore the possible mechanisms that might account for the relationship between emotional distress and chest discomfort. Substantial clinical benefit may be achieved by aggressively detecting and treating emotional distress in ACD patients.

INTRODUCTION

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"The ... sense of strangling and anxiety with which it is attended, may make it not improperly be called Angina Pectoris. . ... it will come on ... by any disturbance of mind. ... The opinion of its being a convulsion of the part affected will reasonably present itself to anyone, who considers. ... the influence which passionate affections of the mind have over it; ... "¹

In the late 1700s, pioneering surgeon John Hunter developed anginal chest discomfort (ACD)—chest pain/pressure/squeezing/fullness in a patient with known coronary artery disease—on exertion. An ambitious, bumptious, busy, cranky, demanding, perfectionistic, and opinionated man, he found it a challenge to titrate his workload to control the ACD. Several years later his angina began to be provoked by frustrating and annoying events. Being a Scotsman from the provinces, he was somewhat thin-skinned about the attitude of Londoners toward "Celts." He found it much harder to control his "turbulent, Celtic nature" than his physical activity, and he exclaimed during this period that "My life is in the hands of any rascal who chooses to annoy or tease me!" The final rascal was a fellow surgeon at St. George's Hospital who, on October 10, 1773, objected to the admission of two Scotch students to the training program on the grounds that people of Celtic origin were incapable of becoming true gentlemen. Hunter flushed red, stood up and stomped out of the room, and keeled over dead within seconds.²

Hunter's case illustrates the high risk for mortality occasioned by angry outbursts,³ the likelihood that anger is a frequent cause of the 90% of ischemic episodes during daily life that occur at rest,³ and a widely neglected target of therapy for controlling ACD as well as morbidity and mortality.^4–11 The relationship of ACD, ischemia, and emotional distress is a complex one that bears much further scrutiny. It is particularly timely to consider these relationships, given the recent initial release of the SADHART (Sertraline Antidepressant Heart Attack Randomized Trial) data,¹² which found a composite measure including "unstable angina" to be favorably affected by sertraline.

Historically, the "unstable" descriptor in "unstable angina" referred to chest discomfort occurring in the absence of an understandable stimulus. That is, "stable" angina refers to chest discomfort reliably provoked by exertion and relieved by rest or nitroglycerin. Unstable angina is now generally defined by the occurrence of ACD at rest in patients with previously documented coronary artery disease, new-onset exertional ACD within 2 months of revascularization, or acceleration of the frequency/severity of symptoms.¹³ Unstable ACD is a major clinical challenge, accounting for more than a million hospital admissions per year and predicting a 1-year mortality rate of 6%–8%.^14–16 ACD in patients with a known history of coronary artery disease is worrisome for both the patient and the physician. Because ischemia progressing to infarction is the cause of sudden death for about 500,000 Americans each year, and ACD is assumed to signal ischemia, it is a matter for grave concern, aggressive investigation, and aggressive therapy.¹⁷ Indeed, ACD is, in fact, a short-term marker for morbidity/mortality.^15,16 Thus, this sense of clinical urgency is not misplaced.

However, the assumptions that chest discomfort in patients with coronary artery disease generally signals the occurrence of ischemia and that "unstable" chest discomfort is due solely to localized oxygen supply/demand are open to debate. This review investigates the data suggesting a relationship between ACD and emotional distress, as well as the implications of this relationship for treatment. We review the data contradicting or demonstrating limitations of the conventional beliefs regarding ACD and ischemia, the epidemiological data demonstrating a strong relationship between emotional distress and ACD, and the effects of treatment of emotional distress on ACD, and we explore the mechanisms that may underlie these observations.

Problems With the Assumption That Ischemia Leads to Angina

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ACD is assumed to reflect localized ischemic events caused by an imbalance in the oxygen supply/demand ratio affecting heart muscle. This imbalance is believed to be caused by some combination of plaque rupture, thrombus formation, vasoconstriction, and/or oxygen demand distal to a plaque. In routine outpatient clinical practice, and in studies occurring outside of carefully controlled laboratory settings, it is technologically impossible to know for certain whether ischemia is occurring concomitant to the chest discomfort. The belief that ACD is attributable to ischemia is predicated primarily upon circumstantial evidence and mechanistic theory, which can be summarized as follows:

• chest discomfort is more common in people with known coronary artery disease than in those without,
  
• chest discomfort can sometimes be provoked by physical exertion in patients with coronary artery disease in laboratory settings where ischemia can be concomitantly measured,
  
• patients with more ischemia tend to have more angina, and
  
• chest discomfort is a prospective predictor of myocardial infarction and death.^14–16
  

These studies are correlational or prospective-correlational in nature and thus cannot entirely eliminate the possibility of a third factor causing both ischemia and angina. The strongest evidence for the relationship between ischemia and ACD occurs in standard-care controlled studies, where revascularization has been found to produce better control of chest discomfort than medication alone.¹⁸ Because no sham-controlled study has been performed, we cannot assume the elimination of a placebo effect in these studies.¹⁹

The occurrence of ACD is not correlated with several mechanisms that should be associated with increased chest discomfort according to the standard theory. These mechanisms include severity of coronary artery disease,^20,21 localized inflammation,²² and irregular plaque morphology.^23–25 In addition, patients with known coronary artery disease commonly experience chest discomfort that is unaccompanied by ST-segment changes or enzyme increases.²⁶ Despite these findings, rarely does emotional distress arise in the differential diagnosis of angina, even if all other explanations have been exhausted.^13–17 For the reasons discussed here, we consider this an erroneous, expensive, and harmful oversight.

The most obvious question that arises with ACD in patients with known coronary artery disease is whether the patient has concomitant ischemia. In studies of patients who were wearing a Holter monitoring device and were instructed to push a marker button when they experienced chest discomfort, about 75% of episodes of ischemia were "silent" (i.e., without subjective chest discomfort) and 66% of episodes of ACD were unaccompanied by ECG evidence of ischemia.²⁶ The latter finding could be due to measurement limitations, since the surface ECG may not detect all episodes of ischemia. But such findings raise the question of whether atypical (noncardiac) chest pain may not also be common in patients with coronary artery disease.^27,28

Emotional Distress and ACD: Epidemiological Associations

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Anxiety and depression are common in pain syndromes, and they clearly increase pain symptom intensity/frequency, decrease symptom tolerance, and increase disability and treatment seeking.²⁹ Similiarly, psychiatric comorbidities may cause or worsen ACD in patients with coronary artery disease, as shown in the studies summarized in Table 1 and Table 1 (continued). For example, findings from the multisite, NIH-sponsored Psychophysiological Investigations of Myocardial Ischemia Study showed that in patients with known coronary artery disease (positive catheterization and/or myocardial infarction), all of whom were required to have ischemia on a baseline qualifying treadmill examination, ACD by history (in the 3 months before study entry) and ACD on the treadmill were most strongly associated with scores on the Beck Depression Inventory and the Spielberger State Anxiety Scale.³⁴

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TABLE 1. Cross-Sectional and Prospective Studies Demonstrating Association of Emotional Distress and Anginal Chest Discomfort (ACD) in Patients With Coronary Artery Disease

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TABLE 1. Cross-Sectional and Prospective Studies Demonstrating Association of Emotional Distress and Anginal Chest Discomfort (ACD) in Patients With Coronary Artery Disease (continued)

However, such cross-sectional, correlational data cannot resolve the question of causal directionality, i.e., whether ACD causes anxiety/depression, or vice versa. One way of trying to avoid this bind is to do a prospective study. If anxiety/depression predate and predict ACD status, the causal argument is enhanced. In fact, in our own prospective study, all risk factors failed as predictors of ACD at 5-year follow-up, except the patient's anxiety as reported by a spouse or friend.²⁰ Depression, which is often comorbid with anxiety,⁴¹ has also been found to be a prospective predictor of ACD in at least two studies.^39,40 But even prospective-correlational studies cannot rule out third-factor influences. The gold standard test for inferring causality is the randomized, controlled clinical trial.⁴²

Emotional Distress and ACD: Intervention Effects

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Given that ACD-like symptoms in atypical chest pain respond to antianxiety/antidepressant therapies,^43,44 one is compelled to ask whether treatment of emotional distress also reduces ACD in patients with coronary artery disease. Several case reports have described this relationship,^45,46 and several intervention studies indicate that the answer is "yes".^5,7–10 For example, Gallacher et al.⁷ randomly assigned 452 male patients with ACD to stress management plus standard care or to standard care only. Their results for reduced exertional ACD approached significance, and they found a significant reduction in nonexertional ACD at 6-month follow-up. This effect may occur because treatment of emotional distress reduces ischemic episodes,^5,47 but it may also occur because treatment of emotional distress improves beta-endorphin production,³⁵ enhances treatment adherence (e.g., recommendations for smoking cessation, pill-taking, exercise, and/or treatment of diabetes), and reduces disease progression.⁶ Table 2 summarizes these studies. Missing from all but one of these studies is the aggressive use of psychotropic medications. Antidepressant medications, including the selective serotonin reuptake inhibitors (SSRIs), are commonly used to treat chronic pain syndromes, as well as to treat depression/anxiety. Noxious side effects (dry mouth, blurred vision, morning grogginess, orthostatic hypotension) and anticholinergic effects on the cardiac cycle (prolongation of the QRS interval) have led to reluctance to use the older tricyclic antidepressants. However, one naturalistic study suggested that the enhanced morbidity/mortality associated with depression may actually decrease with tricyclic antidepressant therapy.⁵³

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TABLE 2. Studies Demonstrating Association Between Use of Interventions Targeting Emotional Distress and Reduction of Anginal Chest Discomfort in Patients With Coronary Artery Disease

The SSRIs, which have few such side effects, have largely replaced tricyclic antidepressants as first-line therapy. Strik et al.⁵⁴ and Roose et al.⁵⁵ found no evidence of toxicity of these agents for cardiac patients. In fact, SADHART has documented efficacy for mood symptoms and safety in patients with coronary artery disease and major depressive disorder,¹² as well as efficacy for a composite cardiac outcome measure that included unstable ACD. In addition, a naturalistic case-control comparison found a dramatic reduction in risk (55%) for recurrent myocardial infarction.¹¹ But no published controlled trials have examined the efficacy of SSRIs in this population by using ischemia/ACD as the outcome measure. The findings of such a study would be highly valuable in improving clinical outcomes. Those SSRIs known to have minimal drug-drug interactions (e.g., sertraline and citalopram) should be high-priority agents for testing anti-ACD results in this multiply medicated population.

One potential clinical implication of these findings is that patients experiencing angina because of concomitant emotional distress should be, and indeed are, high utilizers of medical care.⁵⁶ In one study, clinical costs for the first 6 months after acute myocardial infarction were four times higher in emotionally distressed patients.⁵⁷ The corollary of these findings is that treatment of emotional distress should reduce medical system utilization while simultaneously improving clinical outcomes. In fact, earlier studies have found lower costs associated with treatment of emotional distress in patients with coronary artery disease. Thus, treatment of emotional distress is a "win-win" situation. These outcomes may be due to reduced ACD, but distress may also mimic or cause other symptoms such as fatigue.⁵⁸ These results are summarized in Table 3.

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TABLE 3. Studies Examining Medical System Utilization by Patients Treated for Emotional Distress

Emotional Distress and ACD: Putative Mechanisms

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Several potential mechanisms might account for these results:

• Patients experiencing ACD may become anxious and depressed. While ACD is plausibly a causal or aggravating event for depression/anxiety, this process cannot account for the prospective data^20,39,40 and, more important, for the treatment results discussed later in this review. That is to say, a randomized, controlled treatment trial targeting and modifying depression/anxiety that concomitantly results in reduced ACD provides true experimental evidence of the causal status of depression/anxiety for chest discomfort. With this kind of evidence, the burden of proof shifts to those who wish to argue that distress is not causal.⁴² Thus, the hypothesis that ACD leads to anxiety/depression is clearly inadequate to account for many findings.
  
• ACD in patients with coronary artery disease may be due to emotional distress (e.g., panic attacks) and may not be ischemic at all. In fact, most patients admitted for ACD to emergency departments are found not to have acute coronary events and leave the emergency department with no objective evidence of a medical etiology.^27,28 The fact that most episodes of ACD are unaccompanied by ST-segment depression is also consistent with the hypothesis that anxiety/panic may be a possible independent cause of ACD.²⁶ However, additional studies indicating that anxiety disorders are prospective risk factors for coronary events^65,66 would appear to contradict this hypothesis. It may be that panic disorder is a provocateur of ischemia only when coronary artery disease is present, as discussed later in this review.
  
• ACD may be ischemic and more readily perceived because of distress-related reduction of central beta-endorphins. Emotional distress is known to be associated with reduced central beta-endorphin production,³⁵ and thus a decreased pain threshold. In fact, ACD-accompanied ischemia is also known to be associated with reduced central beta-endorphin production, relative to "silent" ischemia.⁶⁷ Thus depressed/anxious patients may be hypersensitive to ischemic episodes.
  
• ACD may be due to ischemia provoked by distress (e.g., anger or fear/panic). Acute anger-provoked (and probably panic-provoked) cardiac effects (vasomotoric obstruction, induced plaque rupture, and/or anger-provoked aggregation of platelets) or peripheral vasoconstriction that increases cardiac workload^68–72 are plausible mechanisms for distress-related ischemia/ACD. To the extent that atherosclerotic plaque instability is an infectious/inflammatory process,^73,74 diminished immunocompetence induced by depression may be contributory.^75–80 This hypothesis has perhaps the best evidentiary support. Several studies using nuclear blood-pool imaging techniques have yielded objective evidence of ischemia (e.g., ST-segment depression, wall motion abnormalities) in response to mental stress in laboratory or in ambulatory settings.^3,81–94 These studies are summarized in Table 4. The most potent stimulus for provoking ischemia appears to be face-to-face verbal confrontation that elicits anger/hostility in the patient.^34,69,89 Acute fear, also a state characterized by fight-or-flight physiology, may also have the same effect. SCUD missile bombings in Israel,⁹⁵ the Athens⁹⁶ and Loma Prieta earthquakes,⁹⁷ and the World Trade Center attack⁹⁸ all provoked significant spikes in sudden cardiac deaths.
  
• Emotional distress adversely affects adherence to treatment recommendations and thus may increase ischemia/angina. Smoking cessation,⁹⁹ exercise,¹⁰⁰ pill-taking,¹⁰¹ and glucose control in diabetic patients¹⁰² have all been found to be adversely affected by emotional distress. Nonadherence to therapies that are known to be efficacious might be expected to affect ACD.
  
• Cocaine is known to induce both acute cardiac events^103–105 and depression with suicidal ideation.¹⁰⁶ Thus, a depressed patient who is in the hospital after experiencing a myocardial infarction may only coincidentally be depressed while withdrawing from cocaine. However, this hypothesis cannot account for the association of ACD and anxiety/depression during ischemia-positive treadmill testing. That is, why do depressed/anxious patients have a higher prevalence of ACD when both they and their nondepressed/anxious counterparts experience ischemia on treadmill testing? Thus, cocaine as a third-factor correlate cannot explain all findings.
  
• Finally, obstructive sleep apnea, a known predictor of cardiac events,^107–111 also mimics depression.¹¹² Thus, obstructive sleep apnea may provide a coincidental co-occurrence of depression and acute coronary syndromes. As with the cocaine hypothesis, however, the association of ACD with anxiety/depression during ischemia-positive treadmill testing cannot be plausibly explained by obstructive sleep apnea.
  

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TABLE 4. Laboratory and Ambulatory Studies of Mental Stress-Induced Ischemia in Patients With Coronary Artery Disease

From a clinical perspective, the critical issue is not which of the mechanisms may be occurring but whether the outcomes are real and reliable. If treatment of distress reduces ACD (along with other outcomes), the mechanisms are moot, except for further possible investigation.⁴²

Summary

TOP ABSTRACT INTRODUCTION Problems With the Assumption... Emotional Distress and ACD:... Emotional Distress and ACD:... Emotional Distress and ACD:... Summary REFERENCES

 
Contrary to conventional beliefs, most episodes of ischemia are clinically silent, and most episodes of chest discomfort in patients with coronary artery disease are unaccompanied by ECG evidence of ischemia in studies using Holter devices. ACD severity and frequency are not closely correlated with extent of coronary atherosclerosis, localized inflammation, or irregular plaque morphology. In contrast, emotional distress, particularly anxiety and depression, is strongly correlated with ACD in patients with known coronary artery disease, regardless of whether the patient displays objective evidence of ischemia. In addition, relatively low-intensity acute emotional arousal, particularly anger provoked by face-to-face verbal confrontations, can, in laboratory studies, elicit ischemia that is only rarely accompanied by ACD. And treatment of emotional distress has been found to reduce both chest discomfort and ischemia (in addition to other documented clinical benefits). Furthermore, treatment of distress in patients with coronary artery disease "spontaneously" reduces utilization (length of stay, readmissions). We believe this review implies a large and important role for the treatment of emotional distress as a strategy to control chest discomfort in patients with coronary artery disease, and we believe that treatment of emotional distress should be part of competent and comprehensive care of ACD in these patients.

REFERENCES

TOP ABSTRACT INTRODUCTION Problems With the Assumption... Emotional Distress and ACD:... Emotional Distress and ACD:... Emotional Distress and ACD:... Summary REFERENCES

 

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