| Prakash C Deedwania, MD |
Aug 25, 1999 |
Angina pectoris has been considered the cardinal symptom of myocardial ischemia for more than two centuries. However, studies beginning in the 1980s have clearly demonstrated that silent (asymptomatic) ischemia is the most common manifestation of coronary heart disease (CHD) [1]. As an example, several reports have documented that between 25 and 45 percent of patients with acute and chronic ischemic syndromes have evidence of myocardial ischemia during daily life, and most (greater than 75 percent) of these ischemic episodes are not associated with angina or anginal equivalent symptoms [2,3,4,5]. These studies have also demonstrated that most silent ischemic episodes occur during minimal or no physical exertion [3,4,5].
Silent ischemia frequently occurs in patients in whom routine antianginal therapy is effective in controlling anginal symptoms [5]. (See "Management of stable angina pectoris"). Patients with diabetes, the elderly, and those with prior myocardial infarction or surgical revascularization are particularly susceptible to silent ischemia [1].
This card will review the definition, epidemiology, and pathogenesis of silent ischemia. Issues related to diagnosis, screening, and treatment are discussed separately. (See "Silent myocardial ischemia: Diagnosis and screening" and see "Silent myocardial ischemia: Prognosis and therapy")
DEFINITION ！ Silent ischemia is defined as the presence of objective evidence of myocardial ischemia in the absence of chest discomfort or other anginal equivalents. Objective evidence of myocardial ischemia may be obtained in several ways:
• Exercise testing or ambulatory monitoring shows transient ST segment changes
• Nuclear imaging studies demonstrate myocardial perfusion defects
• Reversible regional wall motion abnormalities are provoked during stress or dobutamine echocardiography. (See "Stress echocardiography in the diagnosis of coronary heart disease").
Although silent ischemia was defined a number of years ago using electrocardiographic monitoring in coronary care units and exercise laboratories, it did not receive clinical attention until advances in technology permitted continuous ambulatory electrocardiographic (Holter) monitoring. This device provides an opportunity to evaluate the incidence and risk of silent ischemia during daily life.
EPIDEMIOLOGY ！ The epidemiology of silent ischemia may be viewed from the standpoint of two groups of patients: those who are asymptomatic (ie, patients with no history of CHD); and those who are symptomatic (ie, patients with a history of myocardial infarction or angina pectoris).
Asymptomatic patients ！ Data from screening studies, and studies evaluating autopsy findings in people not known to have had coronary disease, can be used to estimate the prevalence of asymptomatic but significant coronary disease in the general population.
• Significant coronary disease was found in 6.4 percent of men and 2.6 percent of women in one study evaluating autopsy data in 23,996 people age 30 to 69 not known to have CHD [6].
• The results of several large scale screening studies of asymptomatic middle-aged men who underwent exercise testing and coronary angiography revealed significant coronary disease in about 2.5 percent of subjects [7,8,9].
• An Italian study evaluated 4842 asymptomatic men aged 40 to 59 with a three stage diagnostic procedure; patients advanced to subsequent stages if they were suspected of having silent ischemia or infarction in each stage [10]. The first stage included rest electrocardiogram, hyperventilation test, exercise electrocardiogram, and 24 hour Holter electrocardiogram; the second stage included echocardiogram, thallium-201 scintigraphy in conjunction with exercise testing or dipyridamole test, exercise radionuclide ventriculography, and ergonovine test; the third stage consisted of coronary angiography. The final diagnosis of silent myocardial ischemia or infarction was reached in 25 patients (adjusted prevalence 0.89 percent).
• In a report from the Framingham Heart Study, 708 out of 5127 people (14 percent) suffered a new, silent myocardial infarction during a 30 year follow-up [11]. Among patients who were noted to have suffered a new MI during routine biannual electrocardiography, the MI was silent in 28 percent of the men and 35 percent of the women.
On the basis of these data, it has been estimated that between 2 and 4 percent of apparently healthy asymptomatic middle aged men have significant coronary disease. Furthermore, asymptomatic men with two or more major coronary risk factors (eg, smoking, obesity, family history of heart disease, over 45 years of age, diabetes, hypertension, and hypercholesterolemia), have an incidence of significant disease that may approach 10 percent. In one study of 925 patients with type 2 diabetes, for example, the incidence of silent ischemia on an exercise ECG stress test was 12 percent; one-half of these patients had perfusion defects on thallium scanning [12].
The data in women are inconclusive because of a higher incidence of false positive electrocardiograms. (See "Diagnosis and management of coronary heart disease in women").
Symptomatic patients ！ A number of studies have evaluated the prevalence of silent ischemia in patients with prior MI and in those with angina pectoris [2,3,4,5].
• A review of the available data suggests that between 15 and 30 percent of survivors of acute MI have silent ischemia [3,4].
• Studies in patients with unstable angina have revealed that silent ischemia occurs in 30 to 40 percent despite aggressive medical treatment (show figure 1) [1,2].
• The largest number of patients at risk of silent ischemia are those with stable angina. Studies in patients with stable angina who undergo exercise testing and ambulatory monitoring have shown that silent ischemic episodes are far more common than symptomatic episodes (show figure 2). The prevalence of silent ischemia in these patients is estimated to be between 25 and 50 percent; furthermore, 70 to 80 percent of ischemic episodes are silent [1,5,13,14].
Two other observations are of interest. First, conventional or intensive antianginal drug therapy aimed at symptom control does not eliminate silent ischemic episodes [5,14]. Second, patients with silent ischemia detected during Holter monitoring have more advanced CHD with frequent evidence of multivessel disease. As an example, the Asymptomatic Cardiac Ischemia Pilot (ACIP) study evaluated 439 patients with silent ischemia who underwent coronary angiography [15]. Multivessel coronary artery disease was seen in 75 percent, one-half of whom had three- vessel involvement. A significant proximal stenosis (>70 percent) was present in 39 percent. Plaque rupture and thrombus were infrequent, but 50 percent of patients had a "complex plaque" (ill-defined or irregular border and ulcer with eccentric lesion having overhanging edges).
PATHOPHYSIOLOGY AND PATHOGENESIS ！ The precise reasons for the development of angina during some episodes of myocardial ischemia and the absence of symptoms during other episodes is not known. Mechanisms that have been proposed to explain the development of silent ischemia include [1]:
• Inability to reach pain threshold during an episode of ischemia
• Lesser severity and shorter duration of ischemic episodes
• Presence of higher threshold for pain
• Generalized defective perception of painful stimuli
• Presence of a defective anginal warning system
• Higher beta-endorphin levels [16,17]
Although there is considerable controversy regarding each of the above postulates, there is also evidence to support several of these concepts. Compatible with the first two hypotheses is the observation in one of the first studies of silent ischemia that the duration of episodes and the magnitude of ST-segment depression were less during silent compared to painful ischemic episodes [18]. Similar findings have been observed in another report of 300 patients with well- established ischemia and reversible defects on quantitative exercise sestamibi tomography; the ischemic burden was lower in the patients with silent ischemia [19].
Evidence of generalized defective perception of painful stimuli has been provided by the demonstration of higher electrical and thermal pain thresholds in patients with silent ischemia compared to controls [20,21,22,23]. In addition, autonomic neuropathy involving cardiac afferent nerves in diabetes mellitus might account for the higher incidence of silent ischemia in diabetics [3].
Exactly which mechanism(s) plays a role in a given patient with silent ischemia is dependent upon a variety of factors. These include (but are not limited to) age, ethnic background, presence or absence of diabetes or other cause of autonomic neuropathy, prior MI, prior CABG, use of certain drugs, etc.
Development of myocardial ischemia ！ Myocardial ischemia occurs when there is an imbalance between myocardial oxygen supply and demand (see "Pathophysiology and diagnosis of ischemic chest pain"). Myocardial oxygen demand is dependent upon several factors, including heart rate, myocardial contractibility, afterload (for practical reasons systolic blood pressure is often taken as a surrogate), and ventricular wall tension (preload). However, for clinical purposes, heart rate, systolic blood pressure, and the calculated double product (HR x systolic BP) are considered the most important determinants of myocardial oxygen demand.
Atherosclerotic coronary artery disease is the most common underlying disorder responsible for myocardial ischemia. However, changes in vasomotor tone (coronary artery vasospasm) may also play a role. (See "Variant angina"). The normal coronary arterial bed has sufficient reserve capacity to match the increased oxygen demand during periods of physical activity or mental stress. In contrast, the atherosclerotic arterial bed (even in early stages before the lesion becomes occlusive) is unable to maintain normal coronary reserve due to endothelial dysfunction [24,25], as reflected in part by an inability to produce nitric oxide, the endothelial-derived relaxing factor [26].
When the atherosclerotic process has advanced to produce a critical stenotic lesion (usually 50 to 70 percent luminal narrowing), there is a threshold point beyond which an increase in myocardial oxygen demand may result in myocardial ischemia (commonly referred to as the ischemic threshold). The ischemic threshold varies from patient to patient, and can even change in a given patient based upon a variety of factors, including the time of day, level of mental stress, physical activities, and neurohormonal status.
Silent ischemia ！ Although most anginal episodes appear to result from increased myocardial oxygen demand, there has been considerable debate regarding the pathophysiologic mechanisms responsible for the genesis of silent myocardial ischemia. It has been suggested that primary reduction in coronary blood flow, rather than increased oxygen demand, plays a dominant role in this setting. However, this issue remains unresolved. A predominant role for decreased coronary blood flow is supported by the following observations:
• Most silent ischemic episodes occur during minimal or no physical activity, suggesting that increased myocardial oxygen demand was unlikely to play a significant role [3,4,5].
• Ambulatory monitoring studies have shown relatively small increases in the heart rate immediately preceding silent ischemic episodes; this is in contrast to the prominent increases during exercise testing [27,28]. One report, for example, used ambulatory monitoring to record episodes of transient myocardial ischemia in 30 patients with stable angina and a positive exercise test. On average, heart rate at the onset of both symptomatic and asymptomatic ST depression was significantly lower during Holter monitoring than during exercise testing (98 ＼ 20.5 versus 124 ＼ 17 beats/minute) [27]. Heart rate rose by more than 10 beats in the minute preceding ST depression in only 23 percent of ambulatory episodes. However, none of these studies actually documented a reduction in coronary blood flow during the ambulatory ischemic episodes. Furthermore, other reports suggest that increased myocardial oxygen demand from any cause plays a major role in the pathogenesis of silent ischemia [29,30].
However, the vast majority of patients who experience silent myocardial ischemia during daily life have evidence of inducible ischemia during exercise testing that is primarily due to an increase in myocardial oxygen demand [1,5].
• Several factors associated with silent ischemia, such as mental stress and intrinsic physiologic changes due to the circadian rhythm, are associated with significant hemodynamic changes that raise myocardial oxygen demand [29]. These include an increase in heart rate and blood pressure, mediated by an increase in plasma epinephrine and norepinephrine levels [31]. Associated with mental-stress induced myocardial ischemia are wall motion abnormalities which can be prevented by atenolol therapy, a result of a lower rate-pressure product. The observation that nifedipine is also effective against mental-stress induced ischemia suggests that coronary vasoconstriction and a decrease in myocardial blood flow also occur.
• One study examined the changes in heart rate and blood pressure preceding and during silent ischemic episodes in 25 patients with stable angina and myocardial ischemia during exercise testing [32]. Each patient underwent simultaneous ambulatory ECG and blood pressure monitoring which was preprogrammed to obtain blood pressure readings at 10-minute intervals during the periods that patients had been previously shown to have silent ischemia. Most silent ischemic episodes were preceded by significant increases in heart rate and systolic blood pressure (61 percent of silent events were preceded by an increase in heart rate of 5 beats/min or more, 73 percent showed an average increase of 10 mmHg in systolic blood pressure within six minutes preceding ST depression) (show figure 3). Similar observations have been made in other reports which demonstrated that more than two-thirds of ambulatory ischemic episodes are preceded by increases in heart rate [33,34,35,36].
Thus, similar to the pathophysiologic processes involved in the genesis of angina pectoris, most episodes of silent ischemia are preceded by an increase in oxygen demand; only 20 to 30 percent are due to reduced coronary flow secondary to vasospasm or other factors [32]. The importance of increased myocardial oxygen demand has obvious therapeutic implications. Although a number of antiischemic drugs have been evaluated for the treatment of silent ischemia, drugs that reduce heart rate (eg, beta blockers) are most effective. (See "Silent myocardial ischemia: Prognosis and therapy").
Circadian pattern ！ Similar to the circadian pattern of myocardial infarction and sudden cardiac death, silent myocardial ischemia has a bimodal distribution, with a peak between 6 AM and noon [37]. One report, for example, found that silent ischemic episodes occurring secondary to increased heart rate had a peak incidence between 6:00-9:00 AM [36].
The predominance of silent ischemia in the morning hours may be related to one or more of the physiologic changes observed during this period, including [1,28,37]:
• Increased heart rate and blood pressure
• Elevated catecholamine levels
• Heightened coronary vasomotor tone
• Enhanced platelet aggregation
• Decreased intrinsic fibrinolytic activity
The increase in ischemic episodes during the morning hours closely parallels the increase in heart rate and systolic blood pressure and the calculated double product, suggesting a major role for enhanced oxygen demand in the circadian pattern of myocardial ischemia (show figure 4) [33]. The simultaneous increase in ischemic events, heart rate, and blood pressure during the morning hours suggests that enhanced sympathetic activity may contribute to the morning surge of silent ischemia. It is also conceivable that a combination of factors, including increased vasomotor tone and heightened sympathetic activity, could act in concert and trigger the episodes of silent ischemia.
Role of mental stress ！ Mental stress is known to precipitate myocardial ischemia in some patients with coronary artery disease and has been implicated as a trigger for myocardial infarction and sudden cardiac death. (See "The role of psychosocial factors in acute myocardial infarction" and see "The role of psychosocial factors in sudden cardiac death"). The role of mental stress in patients with ischemia during daily life activities and exercise was evaluated in the Psychologic Investigations of Myocardial Ischemia (PIMI) study, which enrolled 196 patients with coronary artery disease and a positive exercise test [38]. Ischemia during mental stress, documented by
1
mm ST segment depression on ECG or reversible left ventricular dysfunction on
radionuclide ventriculography, developed in 58 percent of patients. There were
no differences in clinical or exercise test parameters or in blood pressure or
catecholamine levels at rest or with exercise or mental stress between those
with or without mental stress-induced ischemia, but those with ischemia during
mental stress were more likely to have daily life ischemia; ST segment during
exercise or mental stress was predictive of ST segment depression during
routine activities of daily life.
