Silent myocardial ischemia: Epidemiology, diagnosis, treatment, and prognosis

INTRODUCTION — Angina pectoris, the term used for symptoms thought to be attributable to myocardial ischemia, typically manifests as chest discomfort, although other associated symptoms with ischemia may be present (eg, exertional shortness of breath, nausea, diaphoresis, fatigue). While angina has long been considered the cardinal symptom of myocardial ischemia and coronary heart disease, "silent" (asymptomatic) myocardial ischemia is the most common manifestation of coronary heart disease (CHD), accounting for more than 75 percent of ischemic episodes during daily life as assessed by electrocardiographic (ECG) monitoring [1]. (See "Approach to the patient with suspected angina pectoris".)

The epidemiology, pathophysiology, diagnosis, treatment, and prognosis of silent myocardial ischemia will be reviewed here.

DEFINITION — Silent myocardial ischemia is defined as the presence of objective evidence of myocardial ischemia in the absence of chest discomfort or another anginal equivalent symptom (eg, dyspnea, nausea, diaphoresis, etc). Objective evidence of silent myocardial ischemia may be obtained in several ways:

●ST segment changes consistent with ischemia seen during exercise treadmill testing or ambulatory monitoring. (See "Exercise ECG testing: Performing the test and interpreting the ECG results", section on 'ST segment depression'.)

●Reversible myocardial perfusion defects noted during radionuclide myocardial perfusion imaging. (See "Stress testing for the diagnosis of obstructive coronary heart disease", section on 'Radionuclide myocardial perfusion imaging'.)

●Reversible regional wall motion abnormalities noted during exercise or dobutamine echocardiography. (See "Stress testing for the diagnosis of obstructive coronary heart disease", section on 'Stress echocardiography'.)

EPIDEMIOLOGY — Several reports in the 1980's and 1990's documented that between 25 and 45 percent of patients with coronary heart disease have myocardial ischemia during daily life, and most (greater than 75 percent) of these ischemic episodes are not associated with chest pain [2-5]. Furthermore, most "silent" ischemic episodes, as assessed by ambulatory electrocardiographic (ECG) monitoring, occur during minimal or no physical exertion [3-5]. Silent myocardial ischemia frequently occurs in patients in whom routine antianginal therapy appears to be effective in controlling anginal symptoms, probably suggesting suboptimal control of myocardial ischemia by these agents [5]. Patients with diabetes, older adults, and those with prior myocardial infarction or surgical revascularization have been suggested to be particularly susceptible to silent myocardial ischemia [1]. (See "Chronic coronary syndrome: Overview of care".)

The epidemiology of silent myocardial ischemia may be viewed from the standpoint of two groups of patients: patients with or without a known history of coronary heart disease (CHD).

Patients with known CHD — A number of studies have evaluated the prevalence of silent myocardial ischemia in patients with CHD who have a history of prior myocardial infarction (MI) and in those with angina pectoris [2-7]. Between 15 and 30 percent of survivors of acute MI, and between 30 and 40 percent of patients with unstable angina, have silent myocardial ischemia [1-4]. The largest group of patients at risk of silent myocardial ischemia is those with stable angina, among whom the prevalence of silent myocardial ischemia is estimated to be between 20 and 50 percent [1,5,8,9].

●In the prospective Heart and Soul Study, which enrolled 937 patients with stable CHD, the prevalence of "angina alone" was 14 percent, and the prevalence of "inducible ischemia without angina" (silent myocardial ischemia) was 20 percent. This study also demonstrated that inducible ischemia, in the absence of self-reported angina, predicts poor clinical outcomes.

●Patients with silent myocardial ischemia detected during ambulatory monitoring have more advanced CHD with frequent evidence of multivessel disease. As an example, in a study of 439 patients with silent myocardial ischemia detected during ambulatory monitoring who underwent coronary angiography, multivessel CHD was seen in 75 percent, one-half of whom had three-vessel involvement [10].

Revascularization in patients with CHD and silent myocardial ischemia may be associated with improved outcomes [6,7]. (See 'Revascularization' below.)

While atherosclerotic CHD is the most common underlying disorder responsible for myocardial ischemia, not all anatomic CHD results in myocardial ischemia. Thus, patients with CHD should not automatically be assumed to also have "silent myocardial ischemia." The diagnosis of silent myocardial ischemia in individuals with CHD requires confirmation of the occurrence of myocardial ischemia which is not associated with symptoms. Objective information regarding the occurrence of ischemia can be obtained from ECG stress testing, myocardial perfusion studies, Holter monitoring, or other established diagnostic techniques known to objectively identify myocardial ischemia. Thus, screening for CHD in patients who do not experience myocardial ischemia (whether symptomatic or asymptomatic silent myocardial ischemia) is discussed separately. (See "Screening for coronary heart disease" and "Screening for coronary heart disease in patients with diabetes mellitus".)

Patients without known CHD (asymptomatic individuals) — Data from screening studies and studies evaluating autopsy findings in people not known to have had CHD have been used to estimate the prevalence of asymptomatic CHD in the general population. The estimates of the prevalence of silent myocardial ischemia in subjects not known to have CHD (asymptomatic individuals) vary somewhat according to the methodology used to detect ischemia, but range from as low as 1 percent to as high as 20 to 40 percent [11-14]:

●In a study of 4842 asymptomatic Italian men ages 40 to 59 who underwent a three-stage diagnostic procedure (the first stage included rest electrocardiogram, exercise electrocardiogram, and 24-hour Holter electrocardiogram; the second stage included echocardiogram and radionuclide myocardial perfusion imaging; the third stage consisted of coronary angiography), patients advanced to subsequent stages if they were suspected of having silent myocardial ischemia or infarction in the preceding stage [12]. Silent myocardial ischemia or infarction was diagnosed in only 25 patients (adjusted prevalence 0.89 percent).

●In a study of 631 patients with diabetes and at least two additional CHD risk factors but no evidence of CHD, silent myocardial ischemia was seen on myocardial perfusion imaging in 22 percent of the patients [13].

●A larger study of 3664 asymptomatic patients without known CHD found a 27 percent prevalence of silent myocardial ischemia was detected by perfusion SPECT in 27 percent of patients [11].

●The role of coronary artery calcium scanning for identifying asymptomatic patients with myocardial ischemia was evaluated in a study of 411 patients who had an exercise stress test with radionuclide myocardial perfusion imaging within a close time period of the electron beam computed tomography (EBCT) [15]. Although most subjects (78 percent) with coronary calcium on EBCT did not have inducible ischemia with exercise testing, the likelihood of ischemia increased with calcium score, regardless of age or sex. No subject with a score <10 had ischemia, while 2.6 percent of those with a score of 11 to 100, 11.3 percent with a score of 101 to 399, and 46 percent of those with a score ≥400 had ischemia.

The prevalence of silent myocardial ischemia is substantially higher (as high as 20 to 40 percent in some estimates) in patients with diabetes, particularly if the patients have other risk factors for CHD. This is discussed in detail separately. (See "Screening for coronary heart disease in patients with diabetes mellitus", section on 'Prevalence of asymptomatic CHD'.)

PATHOPHYSIOLOGY — Myocardial ischemia occurs when there is an imbalance between myocardial oxygen supply and demand. 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. Coronary artery spasm is a known cause of primary reduction in blood supply that can lead to myocardial ischemia. (See "Approach to the patient with suspected angina pectoris".)

The precise mechanisms why, in a given individual, some ischemic episodes are associated with chest pain and others are symptom free are not well understood. Mechanisms that have been proposed to explain the development of silent myocardial ischemia include [1]:

●Inability to reach pain threshold during an episode of ischemia

●Lesser severity and shorter duration of ischemic episodes [16,17]

●Presence of higher threshold for pain

●Generalized defective perception of painful stimuli [18-21]

●Presence of a defective anginal warning system [3]

●Higher beta-endorphin levels [22,23]

●Higher production of anti-inflammatory cytokines, which may block pain transmission pathways and increase the threshold for nerve activation [24]

The vast majority of patients who experience silent myocardial ischemia during daily life also have evidence of inducible ischemia during exercise testing [1,5]. The triggers for silent myocardial ischemia do not seem to differ from those in typical angina pectoris. More than two-thirds of ambulatory ischemic episodes are preceded by increases in heart rate [25-29]. However, as also seen in angina-associated ischemia, not all episodes of silent myocardial ischemia are preceded by an increased heart rate. Additionally, mental stress and intrinsic physiologic changes due to the circadian rhythm are associated with significant hemodynamic changes (eg, increase in heart rate and blood pressure) that raise myocardial oxygen demand [30].

●Many episodes of silent myocardial ischemia occur during minimal or no physical activity, suggesting that increased myocardial oxygen demand (at least that associated with tachycardia) may not play a significant role in those particular instances [3-5]. This finding may also imply a role for a primary reduction in blood flow due to microvascular or epicardial coronary spasm or vasoconstriction as triggers for ischemia, as seen in symptomatic angina pectoris.

●Ambulatory monitoring studies have shown relatively small increases in the heart rate immediately preceding episodes of silent myocardial ischemia; this is in contrast to the prominent increases during exercise testing [31,32].

Exactly which mechanism or mechanisms play a role in a given patient with silent myocardial ischemia is dependent upon a variety of factors, including age, ethnic background, neuromodulatory factors, presence or absence of diabetes or other cause of autonomic neuropathy, prior myocardial infarction, or the use of certain medications.

Circadian pattern of silent ischemic episodes — Similar to the circadian pattern of myocardial infarction and sudden cardiac death, silent myocardial ischemia has a bimodal distribution, with a peak between 6 a.m. and noon [29,33]. The predominance of silent myocardial ischemia in the morning hours may be related to one or more of the physiologic changes observed during this period, including [1,32,33]:

●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 development of myocardial ischemia (figure 1) [26].

DIAGNOSTIC APPROACH — Silent myocardial ischemia can be detected during either stress testing or ambulatory monitoring. In current clinical practice, silent myocardial ischemia is detected much more commonly during stress testing.

Who should be screened? — In general, most patients without symptoms do not require evaluation, but there are some clinical scenarios in which patients should be evaluated for silent myocardial ischemia. The approach to screening for silent myocardial ischemia and coronary heart disease in general is discussed separately. (See "Screening for coronary heart disease" and "Screening for coronary heart disease in patients with diabetes mellitus".)

Stress testing — Stress testing, either electrocardiogram (ECG) exercise treadmill testing (ETT) alone or in conjunction with echocardiography or myocardial perfusion imaging (MPI), is the most commonly used testing modality for documenting silent myocardial ischemia [34].

Conventional ST segment analysis during ETT is moderately sensitive in detecting obstructive coronary heart disease (CHD). In patients with a normal baseline electrocardiogram, horizontal or downsloping ST segment depression of at least 1 mm during ETT is typically consistent with myocardial ischemia. However, ST segment depression has a low specificity because of a high rate (10 to 35 percent) of abnormal responses in the absence of documented epicardial CHD, particularly in asymptomatic persons and especially in women [35]. (See "Exercise ECG testing: Performing the test and interpreting the ECG results", section on 'ST segment depression' and "Electrocardiogram in the diagnosis of myocardial ischemia and infarction".)

Because of the low specificity of ST segment depression for myocardial ischemia and the diagnosis of obstructive CHD, the diagnosis of myocardial ischemia in asymptomatic individuals must often be confirmed by a stress testing modality which includes myocardial imaging (ie, stress radionuclide myocardial perfusion imaging or stress echocardiography) before the subject is labeled as having silent myocardial ischemia [36]. Compared with ETT alone, both stress radionuclide MPI and stress echocardiography have improved sensitivity and specificity for the diagnosis of ischemia, both silent and symptomatic. (See "Overview of stress radionuclide myocardial perfusion imaging" and "Overview of stress echocardiography".)

Ambulatory monitoring — Ambulatory monitoring is the second most frequently used diagnostic test for detecting silent myocardial ischemia. It has the advantage of providing long-term ECG recording of ischemic and arrhythmic events while patients are engaged in routine daily activities out of the hospital [37]. The use of 12-lead digital monitors may improve the diagnostic accuracy of the test. (See "Ambulatory ECG monitoring".)

Episodes of transient ischemia during Holter monitoring are diagnosed by a sequence of ECG changes that include a flat or downsloping ST depression of at least 1 mm, with a gradual onset and offset that lasts for at least one minute [1,38,39]. Although ST segment depression during Holter monitoring has not always been accepted as unequivocal evidence of myocardial ischemia, studies have shown an excellent correlation between ST depression recorded during Holter monitoring and other simultaneous objective evidence of ischemia by perfusion scintigraphy, radionuclide cardioangiography, and hemodynamic monitoring [16,40].

One potential limitation to the use of outpatient Holter monitoring, especially for the evaluation of therapeutic interventions, is the marked day-to-day variability in the frequency and duration of ST depression and ischemic episodes. As an example, 45 percent of patients had variability in frequency of ST depression, while 42 percent showed variability in the duration of ischemia [41].

Although ambulatory monitoring may be useful in further stratification of patients with a positive exercise test, stress testing remains the preferred initial diagnostic modality for identification of patients with silent myocardial ischemia.

DIAGNOSIS — The diagnosis of silent myocardial ischemia requires objective confirmation of myocardial ischemia in the absence of chest discomfort, and is done using either stress testing or continuous ambulatory monitoring. Stress testing is the preferred modality for diagnosis in the majority of patients, as significant additional information is available to the clinician from the test (eg, exercise capacity, physiology responses to exercise, amount of ischemic myocardium, distribution of myocardial ischemia, etc).

Silent myocardial ischemia is diagnosed during stress testing by one of the following means:

●Exercise treadmill testing – Horizontal or downsloping ST segment depression of at least 1 mm without associated symptoms.

●Radionuclide myocardial perfusion imaging – Reduced myocardial perfusion on stress imaging, with improved or normalized perfusion on rest imaging.

●Stress echocardiography – The induction of a regional wall motion abnormality during stress.

Silent myocardial ischemia is diagnosed during ambulatory monitoring by a sequence of electrocardiographic (ECG) changes that include a flat or downsloping ST depression of at least 1 mm, with a gradual onset and offset that lasts for at least one minute.

PROGNOSIS — The prognosis of patients with silent myocardial ischemia may be viewed from the standpoint of two groups of patients: those without a history of coronary heart disease (CHD) or angina pectoris, and those with a history of CHD [42]. Additionally, there appears to be a "dose dependence," with patients who have more frequent or more sustained episodes of silent ischemia at greater risk for adverse events [43,44].

The precise reason for the adverse prognosis associated with silent ischemia is not known. Hypotheses center around abnormalities such as necrosis or progressive fibrosis leading to left ventricular dysfunction and/or ventricular arrhythmias [45-47].

Patients with known CHD — The increased risk of coronary events and cardiac mortality in association with silent myocardial ischemia has been extensively documented in patients with CHD, including patients with prior myocardial infarction (MI), unstable angina, and stable angina [1,9,38]. Even though patients with silent myocardial ischemia are at less risk than symptomatic patients, silent myocardial ischemia is associated with a two- to fourfold increase in cardiac event rates compared with those without evidence of ischemia [3,4,48].

●Stable CHD – Silent myocardial ischemia in patients with stable CHD is associated with worse outcomes.

•In a study of 937 with stable CHD (prior myocardial infarction, documented coronary stenosis of at least 50 percent, prior ischemia on stress testing, or prior coronary revascularization) who underwent exercise stress echocardiography at baseline and were followed for an average of 3.9 years, 188 patients (20 percent) had silent myocardial ischemia, which was associated with a significant increase in cardiac death or myocardial infarction compared with patients without angina or ischemia (hazard ratio [HR] 2.2, 95% CI 1.4-3.5) [49].

•In a study of 107 patients with chronic stable angina who underwent ambulatory ECG monitoring and were followed for an average of 23 months, 46 patients (43 percent) had documented silent myocardial ischemia; patients with silent myocardial ischemia had a significantly greater likelihood of cardiac death [5,38].

•In a study of 678 patients with chronic stable angina who underwent 24-hour ambulatory ECG monitoring and exercise testing at baseline and were followed for an average of 40 months, 301 patients (44 percent) had silent myocardial ischemia documented on both tests [43]. Patients with silent myocardial ischemia were significantly more likely to develop adverse cardiac events, with the likelihood increasing further with increased frequency or duration of silent ischemia (as noted on ambulatory ECG monitoring).

●Post-acute coronary syndrome – For patients in the acute stages of an acute coronary syndrome, episodes of silent myocardial ischemia, particularly on ECG monitoring, are associated with worse outcomes. For patients past the acute stages of myocardial infarction, particularly those who are months to years removed from the event, the prognostic power of silent myocardial ischemia appears mixed; patients with silent myocardial ischemia have better outcomes compared with patients with symptomatic ischemia, but no significant difference in outcomes compared with patients without ischemia [50]. Exercise testing appears to be a predictor of future adverse cardiac events, while ambulatory ECG monitoring to assess for silent myocardial ischemia is limited in its usefulness to patients who cannot exercise to an adequate workload [51].

•In the era prior to routine early invasive revascularization, silent ischemia on pre-discharge exercise testing immediately following a myocardial infarction, even in the absence of associated chest pain, was predictive of an increased risk of recurrent coronary events and cardiac death [1,48].

•Silent ischemia after an episode of unstable angina has been associated with an adverse clinical outcome [2,52,53]. (See "Risk factors for adverse outcomes after non-ST elevation acute coronary syndromes".)

•Late after myocardial infarction, the data on the impact of silent myocardial ischemia are mixed.

-Silent myocardial ischemia appears to be an important prognostic marker in patients who undergo exercise testing late after myocardial infarction, particularly when compared with symptomatic patients. In a prospective study of 936 patients enrolled one to six months following an acute coronary syndrome, 503 patients demonstrated ischemia on stress testing, including 378 patient (75 percent) with silent myocardial ischemia [54]. While patients with symptomatic myocardial ischemia were significantly more likely to experience a future cardiac event (when compared with patients with silent myocardial ischemia or no ischemia), there was no significant difference in the likelihood of future events between patients with silent ischemia and the group without ischemia.

-When only asymptomatic patients are evaluated, patients with silent myocardial ischemia appear to have a similar prognosis to those without silent myocardial ischemia. In the same prospective study, patients with silent myocardial ischemia on either ambulatory ECG monitoring or exercise stress testing had similar outcomes as patients without silent myocardial ischemia [50].

Patients without known CHD (asymptomatic patients) — Among patients without a history of obstructive CHD, silent myocardial ischemia appears to be associated with an increased risk of adverse clinical outcomes, whether detected by exercise testing or ambulatory ECG monitoring [39,49,55-60].

●Silent ischemia is particularly important when associated with conventional risk factors [56-59]. As an example, among 12,866 asymptomatic middle-aged men with two or more coronary risk factors who were enrolled in the Multiple Risk Factor Intervention Trial (MRFIT), silent myocardial ischemia identified on exercise stress testing was associated with a threefold increase in cardiac mortality and nearly double overall mortality compared with patients without exercise-induced ECG changes [56].

●In a population-based study of 2682 men without CHD who were followed for 10 years, exercise-induced silent myocardial ischemia was associated with significant increases in mortality and acute coronary events among smokers, hypercholesterolemic patients, and hypertensive patients (figure 2), but was not associated with significantly worse outcomes in men without these risk factors [58].

●Among 678 patients between ages 55 and 75 years without known CHD who underwent 48-hour ambulatory ECG monitoring, 77 patients (11 percent) had evidence of silent myocardial ischemia, which was associated with a threefold increase in death or myocardial infarction compared with patients without silent myocardial ischemia (HR 3.1, 95% CI 1.2-8.0) [39].

Association with coronary artery calcium — CAC is present in most patients with myocardial ischemia, both symptomatic and asymptomatic. The relationship between silent ischemia, detected by stress testing, and CAC has been evaluated in a number of studies [15,61-63]. The following observations illustrate the range of findings, which show only a modest correlation between the abnormalities that is not sufficient to be predictive:

●In one report, 1195 patients without known CHD underwent both stress radionuclide myocardial perfusion imaging (rMPI) and CAC scanning in close temporal proximity [61]. Among the 76 patients with stress-induced ischemia, the CAC score was >0 in 95 percent, ≥100 in 88 percent, and ≥400 in 68 percent. CAC was also present, although less prevalent, in patients without stress-induced ischemia (seen in 78, 56, and 31 percent of patients with a CAC score >0, ≥100, and ≥400, respectively).

●Similar findings were noted in a study of 411 patients who had an exercise stress test with rMPI within a close time period of EBCT [15]. Only 22 percent of patients had inducible ischemia with exercise testing, but the likelihood of ischemia increased with CAC score; no one with a score <10 had ischemia, while ischemia was present in 2.6 percent of those with a score of 11 to 100, 11.3 percent with a score of 101 to 399, and 46 percent of those with a score ≥400.

TREATMENT — Patients with silent myocardial ischemia in the setting of known coronary heart disease (CHD) should all be treated with appropriate secondary prevention measures. (See 'Secondary prevention of cardiovascular disease' below and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

There is no ideal therapy specifically targeted at silent myocardial ischemia, although several options are available [42]. Experts agree that silent myocardial ischemia requires treatment to minimize potentially harmful effects of ischemic episodes on the myocardium. The mechanisms leading to silent ischemia are similar to those causing angina pectoris. In a large percentage of patients, particularly in those with obstructive coronary artery disease, increased myocardial oxygen demand appears to be the primary reason for the development of ischemia. However, some patients with microvascular angina may also experience myocardial ischemia due to increased oxygen demand in the presence of coronary microvascular dysfunction and despite having angiographically normal coronary arteries. In these cases, beta blockers and/or heart rate-reducing calcium channel blockers (eg, nondihydropyridine calcium channel blockers such as diltiazem or verapamil) are the logical therapeutic agents since these drugs decrease myocardial oxygen demand.

ST segment depression on ambulatory electrocardiogram (ECG) monitoring can be used to evaluate the effect of anti-ischemic therapies. However, the marked variability in the number and duration of ischemic episodes as detected with this ambulatory ECG monitoring may confound the accurate assessment of prescribed therapy, and this should be taken into account when assessing these patients [41].

The ACIP (Asymptomatic Cardiac Ischemia Pilot Study), which assessed diverse treatment strategies to reduce the occurrence of silent myocardial ischemia, included patients with asymptomatic ischemia on ambulatory ECG monitoring, ischemic ST segment changes on exercise ECG testing, and documented stable CHD with obstructive coronary artery stenosis >50 percent diameter reduction [64]. Approximately 30 percent of patients enrolled in the study were asymptomatic, although most patients had angina symptoms. Patients were randomized to receive medical therapy or myocardial surgical revascularization, and those in the medical therapy group were further subdivided into an angina-guided strategy group (to reduce symptoms) and an ischemia-guided strategy group (to eliminate silent ischemia on ambulatory ECG monitoring). At 12 weeks of follow-up, more patients (55 percent) in the revascularization group had no ischemic episodes on ambulatory ECG monitoring, compared with 39 percent of patients in the angina-guided group and 41 percent in the ischemia-guided group [65]. A trend toward improved clinical outcome was found in patients achieving a greater reduction of ischemic episodes (regardless of the treatment group assigned) during follow-up [64]. Improved clinical outcome was also during long-term (two-year) follow-up [66].

Secondary prevention of cardiovascular disease — Patients with silent myocardial ischemia and known CHD require appropriate secondary prevention measures in an effort to reduce the future burden of cardiovascular disease. In nearly all patients, these measures include:

●Antiplatelet therapy with aspirin

●Lipid lowering therapy with a statin

●Control of hypertension and diabetes, when present

●Lifestyle modifications including smoking cessation, adoption of a heart healthy diet, regular exercise, and weight reduction if overweight or obese

The optimal approach to secondary prevention of cardiovascular disease is discussed separately. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

Medical therapy directed at silent myocardial ischemia — In addition to secondary preventive measures, a variety of therapies have been evaluated in the treatment of silent myocardial ischemia. All of these therapies also have a role in the treatment of patients with symptomatic CHD. Patients with convincing evidence of silent myocardial ischemia should be treated with a beta blocker as the initial therapy.

Beta blockers — Although many antianginal drugs have been shown to reduce silent myocardial ischemia, beta blockers appear to be most effective and, in at least one study, were shown be improve outcomes [65,67-69]. Thus, beta blockers should be considered first-line therapy for silent myocardial ischemia [65,67-69].

●In one crossover trial involving 24 patients with stable angina and silent myocardial ischemia, both atenolol and nifedipine reduced the frequency and duration of transient silent ischemic events (figure 3), but atenolol produced a greater reduction in the average duration of silent ischemia in the high-risk period between 6 AM and noon [68]. (See 'Circadian pattern of silent ischemic episodes' above.)

●Similar results have been reported in the Total Ischemic Burden Bisoprolol Study (TIBBS), in which the beta blocker bisoprolol was found to be more effective than sustained release nifedipine in suppressing silent ischemia and in improving the clinical outcome (figure 4) [70].

●In the multicenter Atenolol Silent Ischemia Trial (ASIST), which in the early 1990s randomized 306 patients with mild or no angina and evidence of silent myocardial ischemia on exercise testing and ambulatory monitoring to atenolol (100 mg daily) or placebo, the patients randomly assigned to atenolol had significant reductions in the frequency and duration of silent myocardial ischemia as well as a prolonged event-free survival and an increased time to first event (120 versus 79 days) [69].

Calcium channel blockers — Although beta blockers produce the greatest reduction in the number and duration of ischemic episodes, calcium channel blockers are also effective. Monotherapy with calcium channel blockers should primarily be used in patients with a specific pathogenic mechanism that has been identified which is expected to respond better to calcium channel blockers (eg, vasospastic angina), or if a patient is intolerant of beta blockers. Amlodipine, long-acting nifedipine, and short- and long-acting diltiazem reduce ischemic episodes by 13 to 69 percent and decrease ischemia duration by 6 to 68 percent [28,67,68,70-74]. (See "Calcium channel blockers in the management of chronic coronary syndrome".)

Combination therapy — Combination drug therapy is necessary when monotherapy with beta blockers (or, rarely, calcium channel blockers) does not effectively suppress silent ischemia (as assessed by stress testing or ambulatory ECG monitoring) [1,65]. Ideally, the best combination consists of drugs that cancel or dampen the undesirable actions of each other, and prevent any increase in myocardial oxygen demand. Options for combination therapy include:

●Beta blocker and calcium channel blocker

●Beta blocker and long-acting nitrate

●Calcium channel blocker and long-acting nitrate

Stress reduction — Mental stress can provoke silent ischemia, especially in patients with underlying coronary disease. (See 'Pathophysiology' above.)

Some data suggest a possible benefit from behavioral stress reduction in such patients [75-77]. In patients at risk for cardiovascular events who are under increased psychosocial stress, a stress management program can be considered as part of an overall preventive strategy. In general the goal of a stress management program is to reduce the impact in the individual of stressful environmental events and to better regulate the stress response.

Pharmacologic interventions to reduce mental stress-induced myocardial ischemia have not been well studied. In the REMIT study, 123 patients with clinically stable coronary heart disease and laboratory diagnosed mental stress-induced ischemia were randomly assigned to receive escitalopram (dose of 5 mg per day, with titration to 20 mg per day in three weeks) or placebo [78]. At the end of six weeks, fewer patients taking escitalopram had stress-induced myocardial ischemia during the three mental stressor tasks compared with those on placebo (34 versus 18 percent; odds ratio 2.6, 95% CI 1.1-6.4).

Statin therapy — Statin therapy is a routine component of secondary prevention of cardiovascular disease for the majority of patients. (See 'Secondary prevention of cardiovascular disease' above.)

In addition to its role for secondary preventions, statin therapy has also been shown to reduce silent myocardial ischemia. In a study of 40 patients with known CHD, hyperlipidemia, and at least one minute of ST segment depression during 48 hours of ambulatory monitoring, in which patients were randomized to lovastatin or placebo and followed for six months, lovastatin significantly reduced the number of episodes of ST segment depression and abolished ST segment depression in a higher percentage of patients (65 versus 10 percent in the placebo group) [79]. In another study in 893 older patients with established CHD, ischemia on stress testing, and at least one episode of ischemia on ambulatory monitoring, in which patients were randomized to pravastatin or atorvastatin (given in addition to all prescribed anti-ischemic drugs), both statins were associated with significant reductions in the total duration of ischemia while on statin therapy compared with the baseline [80].

Revascularization — Decisions regarding the need for coronary artery revascularization are rarely, if ever, based exclusively on the finding of silent myocardial ischemia. There are limited data evaluating the efficacy of coronary revascularization in the treatment of silent ischemia [65,66,81,82]. However, the available data suggest that revascularization may improve patient outcomes. (See "Chronic coronary syndrome: Indications for revascularization".)

Silent myocardial ischemia following MI — In patients with acute myocardial infarction (MI) treated with thrombolytic therapy who have residual silent myocardial ischemia, coronary revascularization appears to improve outcomes. The best data come from two randomized trials: DANAMI and SWISSI II, both of which showed better outcomes with percutaneous coronary intervention (PCI) compared with medical therapy [6,7]. However, neither trial used current optimal medical therapy or optimal interventional therapy; as such, optimal medical therapy may abolish many of the benefits of revascularization seen in earlier trials [83]. (See "Percutaneous coronary intervention after fibrinolysis for acute ST-elevation myocardial infarction".)

All patients with acute MI are now treated with optimal medical therapy. Stress testing in asymptomatic patients after acute MI is only performed in those who have not been fully revascularized. Among such patients who are found to have asymptomatic ischemia, there are no clear criteria to determine which patients will undergo revascularization. We suggest the following approach:

●Coronary angiography followed by revascularization if appropriate is performed in patients with noninvasive evidence of suggesting a moderate to large amount of myocardium at risk. Examples include ischemia during stage I or II of the Bruce protocol, a hypotensive blood pressure response or symptoms of pulmonary congestion, more than 2 mm of ST segment depression, or imaging studies suggesting involvement of either a large portion of the anterior wall or showing multiple areas of ischemia.

●Patients with only mild ischemia can be continued on medical therapy alone, but patient preference may be important.

Silent myocardial ischemia not following MI — In the absence of acute MI, the potential benefit of revascularization for patients with silent myocardial ischemia was illustrated in an early 1990s study, the Asymptomatic Cardiac Ischemia Pilot (ACIP) study, which randomly assigned 558 patients to one of three treatment strategies: medical therapy guided by angina relief, medical therapy guided by absence of ischemia on ambulatory ECG monitoring, or revascularization [66,82]. Medical therapy included atenolol plus sustained release nifedipine or diltiazem if needed plus sustained release isosorbide dinitrate if needed. Surgical revascularization more effectively suppressed silent myocardial ischemia than did balloon angioplasty, and mortality at one and two years was lower for patients undergoing revascularization compared with those in either medical therapy group. Although the results suggested that surgical revascularization was more effective than percutaneous transluminal coronary angioplasty (PTCA) or medical therapy in suppressing myocardial ischemia and improving clinical outcome, drug therapies were not optimized and may have minimized the efficacy of medical therapy in improving the clinical outcome.

The lack of optimal medical therapy is not a trivial issue. Among patients with stable angina at increased risk, initial trials suggested better outcomes with PCI. Of greater relevance is the COURAGE trial published in 2007, which compared optimal medical therapy alone (both antianginal drugs and aggressive secondary prevention) with optimal medical therapy plus PCI with bare metal stents [83]. There was no difference between the groups in the primary end point of death from any cause and non-fatal MI at 4.6 years.

Silent myocardial ischemia following previous revascularization — Based on limited evidence, we do not routinely screen asymptomatic patients for silent myocardial ischemia after revascularization.

Patients who present with silent ischemia and then undergo revascularization are at risk of recurrent ischemia and coronary events. However, the optimal diagnostic and therapeutic approach to such individuals is not known. In a study of 769 asymptomatic individuals previously treated with either coronary artery bypass surgery or percutaneous coronary intervention who had myocardial ischemia identified by myocardial perfusion scintigraphy (MPS), 15 percent underwent revascularization at a median of 13 days after MPS, and the rest continued with medical therapy [84]. During a median follow-up of 5.7 years, there was no significant difference in mortality between the two groups (19.1 and 18.3 percent, respectively).

SUMMARY AND RECOMMENDATIONS

●Although angina pectoris is considered the cardinal symptom of myocardial ischemia and coronary heart disease (CHD), studies have established that silent myocardial ischemia (defined as objective evidence of ischemia without associated chest pain) is commonly found in patients with CHD. (See 'Introduction' above and 'Definition' above.)

●Silent myocardial ischemia is seen in both asymptomatic and symptomatic patients with CHD and appears to represent the majority of episodes of ischemia. (See 'Epidemiology' above.)

●Although the precise mechanism responsible for silent myocardial ischemia has not been established, a number of possible reasons for a lack of anginal symptoms during some episodes of ischemia have been proposed and include lesser severity and shorter duration of episodes, higher threshold for pain and/or inability to reach pain threshold, impaired perception of painful stimuli, defective anginal warning system, and higher beta-endorphin levels. (See 'Pathophysiology' above.)

●Silent myocardial ischemia can be detected during either stress testing or ambulatory monitoring. Silent myocardial ischemia is diagnosed during stress testing by one of the following means (see 'Diagnostic approach' above and 'Diagnosis' above):

•Exercise treadmill testing – Horizontal or downsloping ST segment depression of at least 1 mm without associated symptoms.

•Radionuclide myocardial perfusion imaging – Reduced myocardial perfusion on stress imaging, with improved or normalized perfusion on rest imaging.

•Stress echocardiography – The induction of a regional wall motion abnormality during stress.

•Ambulatory electrocardiogram monitoring – Flat or downsloping ST depression of at least 1 mm, with gradual onset and offset, that lasts for at least one minute.

●An increased risk of coronary events and cardiac mortality in association with silent myocardial ischemia has been extensively documented in patients with CHD, including patients with prior myocardial infarction (MI), unstable angina, and stable angina, as well as among patients without a history of obstructive CHD. (See 'Prognosis' above.)

●Patients with silent myocardial ischemia in the setting of known CHD should all be treated with appropriate secondary prevention measures. (See 'Secondary prevention of cardiovascular disease' above and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

●There is no ideal therapy specifically targeted at silent myocardial ischemia, although several options are available, including beta blockers, calcium channel blockers, nitrates, and combinations of these medications. In addition, coronary revascularization may be an option for specific patients.

•Patients with convincing evidence of silent myocardial ischemia should be treated with a beta blocker as the initial therapy. (See 'Beta blockers' above.)

•Monotherapy with calcium channel blockers should primarily be used in patients with a specific pathogenic mechanism that has been identified which is expected to respond better to calcium channel blockers (eg, vasospastic angina), or if a patient is intolerant of beta blockers. (See 'Calcium channel blockers' above.)

•Combination drug therapy is necessary when monotherapy with beta blockers (or, rarely, calcium channel blockers) does not effectively suppress silent ischemia. (See 'Combination therapy' above.)

•Decisions regarding the need for coronary artery revascularization are rarely, if ever, based exclusively on the finding of silent myocardial ischemia. However, the available data suggest that revascularization may improve patient outcomes, particularly following acute MI in patients treated with thrombolysis or who are incompletely revascularized. (See 'Revascularization' above.)