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From the Department of Physical Medicine and Rehabilitation (S.E.H., S.T.W.); Department of Medicine (C.A.H.), Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Address correspondence and reprint requests to Susan E. Hofkamp, Department of Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Phipps 193, Baltimore, MD 21287. E-mail: shofkam1{at}jhmi.edu
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ABSTRACT |
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Key Words: angina • pain • biopsychosocial • silent ischemia
Abbreviations: CAD = coronary artery disease; HADS = Hospital Anxiety and Depression Scale; MMPI = Minnesota Multiphasic Personality Inventory; BDI = Beck Depression Inventory; TABP = Type A behavior pattern.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCONCLUSIONSNOTESREFERENCES |
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The study of angina is complicated by the fact that approximately 75% of ischemic episodes are silent and about two-thirds of reported chest pain episodes are not accompanied by detectable ischemia (2,9). Some patients have chest pain due to other causes, in addition to angina. Angina is typically described by patients as discomfort, tightness, or pressure in the chest with pain radiating to other areas such as the left arm, abdomen, or jaw. Anginal pain is generally associated with some level of exertion and often decreases with rest. In contrast, chest pain of other origins is usually more localized, variable, and described as sharp or burning. Noncardiac chest pain will not typically improve with rest. Determination of the cause of chest pain involves obtaining a careful medical history and diagnostic tests for ischemia such as electrocardiography (ECG), stress testing, or coronary angiography. There are several types of angina. Stable angina refers to chest pain that is predictable, reproducible with exertion, and relieved by rest or nitroglycerin. Unstable angina refers to a changing pattern of angina that is often present at rest and requires immediate medical attention. Variant angina usually occurs at rest or without stress, shows ST segment elevations on the ECG, and is due to coronary artery spasm (10). Cardiac Syndrome X involves chest pain with a normal angiogram, ischemia present on a stress test, transient ST segment depression, and is associated with abnormal pain perception (11).
Without concomitant measurements of pain and ischemic activity (e.g., Holter monitoring with a daily pain diary), there is no way to know if a reported pain episode is due to cardiovascular factors or some other cause. Many studies have not used such procedures or are vague in their methods, making it difficult to interpret the results. There is a lack of longitudinal studies, or where longitudinal studies have been done, the data related to cardiac chest pain are drawn from cross-sectional components of the study. These cross-sectional designs limit the ability of researchers to discuss the direction of causality of commonly studied factors. This article summarizes the current literature on pain related to angina, and proposes a model for combining the contributions of those studies to help understand the individual differences in pain reporting that are seen with angina patients.
Biological Factors
The pain present with myocardial ischemia may be visceral and/or referred pain to dermatomal distributions. Referred pain may inhibit the perception of visceral pain in the chest. The diverse presentation complicates the identification of underlying biological mechanisms. The presence or absence of anginal pain may be due to the manner in which peripheral sensory terminals are activated and the central processing of the pain signal (12). Both afferent sympathetic and vagal nerve fibers have been implicated in the transmission of the cardiac pain signal (3). The pain pathway for angina includes the convergence of visceral and somatic input onto one area of spinothalamic tract neurons. Neuropathy of the heart nerves may account for variations in pain sensation, particularly in diabetic individuals (12). Brain imaging studies have indicated that the hypothalamus, periaquaductal gray, thalamus, lateral prefrontal cortex, and left inferior anterocaudal cingulated cortex may be the areas responsible for the perception of anginal pain (13). Within these pathways, a number of mechanisms are thought to be responsible for the pain experienced during myocardial ischemia.
Mechanical Factors
Painful sensations with ischemic episodes may be due, in part, to mechanical factors such as spasm and/or distention of cardiac vessels. The most common cause of ischemia is coronary artery stenosis due to arteriosclerosis. The lesions present with arteriosclerosis interfere with increases in blood flow necessary to meet increased cardiac demand, which may lead to pain. Spasms in the coronary arteries and vessels are commonly seen in patients with variant angina and Cardiac Syndrome X, but may also be important mechanisms in stable and unstable angina (14). Mechanical distension of the coronary artery wall may activate sensory receptors at the periarterial level and cause pain (3). These mechanisms are controversial and more recent research has focused on other areas of interest, such as pain-producing substances (e.g., adenosine and endogenous opioids) (12).
Chemical Factors
Several biochemical substances are thought to be important in the pain experience. There is an increase of lactic acid, release of potassium ions, and production of kinins and other pain-producing substances in myocardial ischemia (15). Several studies have focused on the role of adenosine as a possible mediating factor in cardiac chest pain due to its rapid production and release during ischemia (15). Adenosine stimulates the A2 receptors in cardiac afferent nerve endings, which provokes the noxious signal associated with angina. However, adenosine also acts on A1 receptors to potentially mediate analgesic effects that are related to silent ischemia. Patients with mostly silent ischemic episodes may have less chest pain and tolerate larger doses of intravenous adenosine infusions than those with mostly painful ischemia (16). Other research has shown a similar decreased sensitivity to adenosine in patients with silent ischemia (17), which was independent of opioid receptor activity.
Variability in endogenous opioid activity and pain sensitivity has also been implicated as possible mechanisms in angina differences. Some studies have linked angina with lower thermal pain thresholds and higher resting levels of ß endorphins, suggesting a dysfunctional hypothalamic-pituitary-adrenal axis (18). However, others have found no difference between those with painful ischemia and those without painful ischemia in terms of pain sensitivity (19,20). Patients with silent ischemia may have higher levels of pain thresholds and tolerance, which may be mediated by endorphins (21). The discrepancies in the findings in this area may be due to the complications of measurement, and indicate that further research is needed to determine the role of biochemical factors in angina.
Comorbid Conditions
Various medical conditions are often concomitant with coronary artery disease (CAD) and may influence the perception of chest pain. These include diabetes, hypertension, kidney disease, and peripheral vascular disease. The prevalence of silent myocardial ischemia has been reported to be higher in diabetic versus nondiabetic patients (22–25). In addition, the prevalence of silent myocardial ischemia may increase with the severity of diabetic disease (24). However, one study found that diabetics reported more angina in daily life than did nondiabetics, with the diabetic group also reporting a higher intensity of pain, although the latter finding was not statistically significant (26). It is important to note that individuals with symptomatic neuropathy were excluded from the study, which could have greatly affected the results. Although autonomic neuropathy may be an important factor in the determination of silent versus painful ischemia, it cannot be the only mechanism at work because angina is reported in patients with diabetic neuropathy as well. Diabetic patients are at an increased risk of developing peripheral vascular disease, which has also been linked to silent myocardial ischemia particularly in early stages (27).
Hypertension has been linked to a decreased perception of pain. A large study of tooth pain perception showed that hypertensive individuals had more hypoalgesia than normotensive individuals (28). Hypertensive individuals also report less pain than normotensives postexposure to noxious thermal, electrocutaneous, and mechanical stimuli (29). Similar results have been found in studies more specific to cardiac pain. Participants with angina during exercise-induced ischemia have lower resting blood pressure, lower blood pressure at maximal exercise, and shorter duration of exercise than those with silent ischemia (30,31). High blood pressure has also been associated with a lack of chest pain with episodes of myocardial ischemia during ambulatory monitoring (29). There is evidence that hypoalgesia precedes the onset of high blood pressure from studies of normotensive individuals at risk for hypertension who report decreased pain perception (29). The baroreflex system and endogenous opioid activity have been implicated as important factors in the modulation of nociception in these studies (29,30,32,33). Researchers have also found an increased frequency of silent ischemia in patients with chronic renal disease, which is often caused by hypertension, and those undergoing hemodialysis (34,35).
Racial Differences
There is some evidence of racial differences in response to ischemic pain. An experimental pain study using a submaximal effort tourniquet procedure to assess pain tolerance found that African Americans reported higher levels of pain, decreased pain tolerance, and increased pain-related disability compared with Caucasians (36). In a study comparing the experience of angina in African American versus Caucasian individuals undergoing an exercise stress test, African Americans were more likely to experience angina and had a shorter time to symptom onset than Caucasians after controlling for disease severity and other potential confounders (37). Relationships between race and cardiac chest pain require further investigation to determine whether racial differences or other related factors may account for previous findings.
Sex Differences
Researchers have found extensive evidence of sex differences in the general pain experience. Females tend to report lower pain thresholds and reduced tolerance to noxious stimuli than males (7,38). Consistent with the overall pain literature, a number of studies have examined and found differences in the anginal experience between men and women. More females than males are diagnosed with angina, with a prevalence of 3.9 million in females and 2.3 million in males (39). Differences in the frequency, intensity, and duration of angina, depending on sex, have been noted in several studies. Females have reported higher overall pain intensity scores (40) and more severe angina pain (41). Females also seem to report more frequent angina during daily life and during times of mental stress than do men, but the same is not true during exercise (42). Even after percutaneous transluminal coronary angiogram, an intervention to reduce cardiac stenosis, females report more frequent episodes of angina than men (43).
Psychological factors may account for some of the differences between males and females when it comes to reports of painful ischemia. Sheps and colleagues (42) found that such factors represented the majority of variance in angina reporting between the sexes. Females diagnosed with chronic angina tended to score higher on measures of depression, anxiety, and somatic complaints (42,44,45). They also showed a greater level of intensity in their affective descriptors of the anginal experience (40). Although these factors may also have biological dimensions, they were measured and interpreted as psychological variables in these studies.
Psychological Factors
Depression
A number of studies have focused on the link between depression and angina. Thirty-two percent of subjects with chronic stable angina showed clinical depression on the Hospital Anxiety and Depression Scale (HADS), whereas another 25% of the subjects endorsed multiple depressive symptoms (46). Carney and colleagues (47) found that subjects with symptomatic ischemia reported significantly higher levels of depression than those with silent ischemia, whereas another study showed that depressed angina patients had a higher rate of pain reporting in general (44). More specific aspects of the pain experience also seem to vary with the degree of depression in the individual. The severity of angina was associated with depressive symptoms in participants undergoing coronary angioplasty (48) and in those with exercise-induced ischemia (49,50). One prospective study of community-dwelling women followed over 12 years found that severity of depression predicted development of chest pain (51). However, that study was unable to confirm whether reported chest pain was due to myocardial ischemia or other causes. Several studies have also found that subjects with higher scores on depression measures had a shorter time to onset (52) and longer duration of chest pain than those with lower scores (49,50).
Anxiety
Symptoms of anxiety may be even more prevalent than depression in those with angina (46), but fewer studies have focused on this problem. Much of the literature on anxiety and chest pain is on noncardiac pain, which is not the focus of this discussion. Studies relevant to cardiovascular disease include Moore and colleagues (46), who found that >55% of subjects with refractory angina also scored in the "definite cases" range on the anxiety subscale of the HADS, with another 25% endorsing some symptoms of anxiety. Both the severity (53) and the frequency (54) of cardiac chest pain have been associated with degree of anxiety in patients. The differences between those with symptomatic versus silent events have not been well studied with regard to anxiety, but one study found no difference between the two groups based on scores on the State-Trait Anxiety Inventory (47). Situational anxiety is more likely to be a factor in clinical cases of cardiac chest pain, where the patient's symptoms are less predictable than in experimentally provoked cases, which may be why there are few studies that have found significant results.
Anger
Although the connection between anger and cardiovascular disease in general has been well studied, there is little known about its specific association with angina. A significant correlation was found between anger and the frequency of angina in a group of subjects hospitalized for cardiac catheterization (55). Anger was not related to the severity of reported pain, but was correlated with the degree of interference in activities due to angina. It may be that episodes of anger can trigger angina, but do not affect the severity of pain experienced. Attempts to avoid angina may lead to decreases in activity, thus increasing feelings that angina interferes with patients' lifestyles. Findings in the chronic pain literature also suggest a link between anger expression and pain, with opioid dysregulation named as a possible mechanism (56). Although this idea has not been directly studied in cardiac chest pain, the mechanism may operate in that population.
Negative Emotion/Distress
The presence of emotional distress, other than clinical levels of depression and anxiety, has been documented as a common comorbidity found in all types of chest pain (e.g., angina, noncardiac chest pain, musculoskeletal) (57). Distress has also been found more specifically in patients diagnosed with CAD and angina (41). Higher levels of distress were associated with reports of more severe angina pain (41). Intervention studies have also provided evidence for a link between emotions and angina. For example, improvements in distress after an intervention to modify lifestyle were related to improvements in chest pain at a 3-month and 12-month follow-up from the program (58). Other intervention studies have shown success at reducing negative emotions and distress (59,60), which has been associated with better outcomes in cardiac patients.
Personality
The Type A behavior pattern (TABP) has been widely studied and found to be associated with the development and progression of cardiovascular disease (61–63). However, research on TABP and angina has produced mixed results. TABP is correlated with the degree of perceived interference caused by angina, but not with a tendency to avoid activities because of symptoms or the frequency of angina symptoms (55). In patients who had exercise-induced ischemia, a TABP did not increase the likelihood to report pain with ischemia over those with a Type B/X behavior pattern (49). So, although angina has not been directly correlated with TABP, it may be perceived as an annoyance to those who exhibit the driven, goal-focused characteristics of TABP.
More specific components of individual's personality have been studied as well, such as hostility and neuroticism. Greater hostility is related to more severe pain reports in males with atherosclerosis (48). Billing and colleagues (45) studied patients diagnosed with stable angina pectoris and matched healthy controls to examine a variety of psychosocial risk factors. They found that the patient group had higher ratings of hostility than controls. In a study that examined the contribution of neuroticism to the report of painful ischemia, Smith and colleagues (55) showed that it was correlated with both the degree of perceived interference caused by angina and avoidance of activities due to angina.
Other Psychological Factors
Other psychological factors that may be related to painful angina episodes have been studied, but no consistent pattern of findings have emerged. Stress, which has been widely studied with regard to its negative effects on health, has also been implicated in the problem of angina. Angina patients may experience more frequent stressors than individuals without painful ischemic episodes (45,64), and they experience worse pain when they are feeling stressed (65). Research has also shown that angina can negatively impact an individual's quality of life (66) and the level of impairment may depend on the severity of anginal symptoms (67). A systematic review of mental stress-induced myocardial ischemia (68) found that this is generally a silent event and may be an indicator of a susceptibility to psychological factors such as anxiety, depression, and anger. Although mental stress-induced ischemia has been more frequently studied in men, there is some indication that women are more likely to experience chest pain with this type of stressor than men (42).
Patients with painful episodes of myocardial ischemia, by definition, report experiencing more chest pain than do patients who have predominantly silent ischemia. It may be that those who report pain do so because they pay more attention to those signals and tend to have a greater overall somatic focus. Research indicates that angina patients report more somatic complaints and are more aware of bodily sensations than healthy controls and silent ischemia patients (45,47,52). In addition, patients with painful versus silent ischemia were more sensitive to cardiac and noncardiac bodily sensations (69), which points to a possible overall somatic focus in those who report chest pain during ischemic episodes.
Some studies suggest that appraisals of angina and the beliefs associated with the diagnosis are related to how the problem is experienced. Furze and colleagues (70) studied beliefs about angina and how they changed after an intervention aimed at educating patients about the condition and providing coping strategies. They found subjects who decreased maladaptive beliefs about the causation, physiology, and coping related to angina had decreased anxiety and improved physical functioning after the intervention at a 1-year follow-up visit. Those with more negative beliefs about their health, as determined by clinical interview, were more likely to experience angina before and after receiving a stent (71).
Social Factors
Although research in this area is limited, some studies suggest that there are also a number of social forces at work in the expression of angina in patients with CAD. Angina is more likely to occur in individuals with lower education, lower social class, lower level of job skill, a poor record of job stability, and those with inadequate social support (4,72,73). Social factors may also interact with sex to predict presence of angina and limitations that result from the condition. Female angina patients were more likely to have a lower social status than men (40). Also, women tend to experience angina symptoms differently than men and may not receive a proper diagnosis and treatment because of this difference (74). Those at higher risk for ischemic episodes may also be less likely to receive care for their cardiac problems and may not be able to afford medications to control angina. Individuals with a higher socioeconomic status may have a broader range of coping mechanisms available to them. It is likely that the relationships between cardiac chest pain and social variables are mediated by other factors, such as access to care, stress, depression, or anxiety.
An Integrated Model
The experience of pain related to cardiac ischemia is a complex issue and is likely influenced by a number of factors. Individuals with myocardial ischemia may or may not experience pain during such episodes, or they may experience pain during some ischemic episodes and not others. Some people may complain of chest pain that is not cardiac related, but also have pain resulting from myocardial ischemia. Correlational studies have provided evidence for a relationship between painful versus silent myocardial ischemia and a number of different factors, but despite recent efforts (51,58), the few prospective, longitudinal studies that can speak to causality have lacked adequate measurement.
There are significant measurement issues that must be attended to in the study of myocardial ischemia pain variability that undermine current findings. Many of the studies discussed in this review made use of ambulatory ECG testing to detect episodes of ischemia, but some researchers have argued that such methods may not be reliable. An increased number of false-positive ST segment depressions have been noted when using Holter monitoring compared with 12-lead ECG (75) or using increasingly stringent criteria for identifying ST segment depressions (76,77). Errors in identifying ST segment depressions may, therefore, have led to a mistakenly higher prevalence of silent ischemic episodes in some studies. The timing of cardiac monitoring could also have affected results. A number of studies have noted that there are circadian variations in ischemic activity (78–80), which could cause variation in the presence of myocardial ischemia depending on the time of day the study was conducted. These issues should be considered in future studies of transient myocardial ischemia.
A multifaceted, biopsychosocial approach may be the best way to examine, discuss, and understand the factors associated with painful versus silent myocardial ischemia. In the past, cardiac chest pain has been described as an acute phenomenon that is better explained using a medical model of disease. Other pain-related conditions, such as chronic low back pain, have often used the biopsychosocial model to broaden the focus of the problem and make use of a wider variety of interventions. By maintaining a medical model approach to angina, the focus becomes narrow; only biological influences are considered; and there is an emphasis on treating the problem with medications or procedures, rather than on management of contributing factors. Taking a broader, biopsychosocial view of myocardial ischemia is particularly important for patients who are not candidates for interventions to decrease the severity of their disease and must learn to manage symptoms on a long-term basis.
Although the biopsychosocial approach is not as commonly used with regard to cardiac chest pain, the research presented in this paper offers evidence of its relevance. Biological factors such as coronary arteriosclerosis and oxygen demand/supply ratios are responsible for the development of myocardial ischemia, but other variables are likely to influence painful versus silent episodes. Activation of mechanical and biochemical pathways play a role in angina, and an individual's overall level of pain sensitivity also is likely to be important. Hypoalgesia related to high blood pressure and neuropathy related to diabetes also affect the perception of chest pain in those with myocardial ischemia. Studies of psychosocial factors have provided support for a strong relationship with the presence of angina. Although the strongest documented link is with depression, a number of other psychological constructs such as anxiety, anger, personality factors, general negative emotion, and emotional distress also have been related to variability in pain reporting during ischemic episodes. Factors such as socioeconomic status, education level, and social support have also been linked to an increased risk of angina. Prospective research is needed to examine if these factors may also play a role in the variability of pain reporting seen in angina patients.
Based on the reviewed literature, we propose a model that incorporates biological, psychological, and social factors that are likely determinants of the presence of painful versus silent ischemia, as well as those that likely contribute to maintenance of the problem (Figure 1). The basic requirement for presence of symptomatic or asymptomatic ischemia is an imbalance between blood supply and oxygen demand, often due to the presence of CAD. The biological, psychological, and social factors mentioned in this article are artificially separated for ease of discussion, but in reality they overlap and interact with each other. Those variables may be related to cardiovascular disease in a bidirectional manner. For example, a diagnosis of CAD may prompt feelings of anxiety in an individual, activating release of stress-related hormones, which increases platelet activity, and leads to worsening of CAD. There is likely a reciprocal relationship with these factors and ischemic episodes. For example, the same individual who develops anxiety related to the diagnosis of CAD may also have anxiety related to experiences of chest pain, increasing a feedback loop that perpetuates those sensations and associated negative appraisals.
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According to research in the biological, psychological, and social realms of angina, sex likely modifies these relationships and interactions at multiple levels. For example, women tend to have lower blood pressure than men and report more pain in response to noxious stimuli (7,81). In addition, epidemiological research indicates that women are more likely to suffer from depression and anxiety than men (82). Females with angina also tend have a lower socioeconomic level than males (40). All of these variables, and others, may increase the risk for painful ischemic episodes that are reported more frequently in females. The biopsychosocial model explains this risk by showing that blood pressure is related to pain perception through hypertensive hypoalgesia, and less pain perception is related to decreased emotional distress, which is related to better social interactions. However, there are also sex differences seen in the development, maintenance, and mortality associated with cardiovascular disease, with men having a generally higher risk (83). Sex cannot be described as a risk factor itself, because men and women are at increased risk for different variables that contribute to the biopsychosocial model of angina, so sex may act as a modifier or surrogate variable. However, there does seem to be an overall risk for painful ischemic episodes in women compared with men based on the current research. In addition, differences in the intensity and duration of angina, depending on sex, have been reported.
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CONCLUSIONS |
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This work was supported by Grant MH075884 from the National Institutes of Health under Ruth L. Kirschstein National Research Service Award (S.E.H.).
DOI:10.1097/PSY.0b013e318151a4bd
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