Download silent ischemia and diabetes mellitus

Vuk Vrhovac University Clinic
Dugi dol 4a, HR-10000 Zagreb, Croatia
Review
Received: April 28, 2010
Accepted: June 6, 2010
SILENT ISCHEMIA AND DIABETES MELLITUS
Jozo Boras, Neva Brkljačić, Antonela Ljubičić, Spomenka Ljubić
Key words: silent myocardial ischemia - diagnosis
and treatment, diabetes mellitus
SUMMARY
Silent myocardial ischemia (SMI) is defined as the
presence of objective evidence of myocardial ischemia
in the absence of chest discomfort or other anginal
equivalents. Most silent ischemic episodes occur
during minimal or no physical exertion. The exact
reasons for the development of angina during some
episodes of myocardial ischemia and the absence of
symptoms during other episodes are not known. Some
mechanisms include 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 and presence of a
defective anginal warning system. Coronary artery
disease (CAD) is the major cause of morbidity and
mortality in patients with diabetes. CAD is usually
more advanced at the time of diagnosis and has
unfavorable prognosis in diabetic patients. Later
diagnosis of CAD may be explained by the presence of
Corresponding author: Jozo Boras, MD, PhD, Vuk Vrhovac University
Clinic, Dugi dol 4a, HR-10000 Zagreb, Croatia
E-mail: [email protected]
Diabetologia Croatica 39-2, 2010
SMI, which is more frequent in patients with diabetes
(probably because of diabetic neuropathy). The
prevalence of SMI is 10%-20% in diabetic patients
versus 1%-4% in nondiabetic patients. Exercise
treadmill test (ETT) and ambulatory (Holter)
monitoring are the most readily available and
frequently used tests to identify SMI in clinical
practice. The exact reason for unfavorable prognosis
associated with SMI is not known. It is possible that
repeated episodes of SMI could lead to progressive
fibrosis and development of left ventricular
dysfunction, and to life-threatening arrhythmias,
especially in patients with an electrical substrate for
arrhythmias. SMI is associated with an increase in
coronary risk that may be reversible with appropriate
therapy.
Silent myocardial ischemia (SMI) is defined as the
presence of objective evidence of myocardial ischemia
in the absence of chest discomfort or other anginal
equivalents. Patients with silent ischemia have been
stratified by Cohn into three categories (1). Type I
silent ischemia is the least common form that occurs in
fully asymptomatic patients with obstructive coronary
artery disease (CAD). These patients do not
experience angina at any time. They probably have
defective anginal warning system. Type II silent
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J. Boras, N. Brkljačić, A. Ljubičić, S. Ljubić / SILENT ISCHEMIA AND DIABETES MELLITUS
ischemia occurs in patients with documented previous
myocardial infarction. Type III silent ischemia, much
more frequent, occurs in patients with the usual forms
of chronic stable angina, unstable angina and
Prinzmetal’s angina. These patients exhibit some
episodes of ischemia that are associated with chest
discomfort and some episodes that are not (silent,
asymptomatic ischemia). The ‘total ischemic burden’
in these patients refers to the total period of ischemia,
both symptomatic and asymptomatic.
Anginal pain is a poor indicator and underestimates
the frequency of significant cardiac ischemia (2). Most
silent ischemic episodes occur during minimal or no
physical exertion. Silent ischemia is associated with an
increase in coronary risk that may be reversible with
appropriate therapy. Sudden death is the initial
manifestation of coronary disease in 18% of coronary
events (3), and more than one-half of sudden deaths
occur without a prior history of coronary heart disease
(CHD) (4).
EPIDEMIOLOGY AND PATHOGENESIS
The epidemiology of silent ischemia can be viewed
from the standpoint of those who are asymptomatic
(no history of CHD) and those who are symptomatic
(patients with a history of myocardial infarction or
angina pectoris).
The risk of silent ischemia is increased substantially
in patients with diabetes, particularly if they have
other risk factors.
Symptomatic patients
A review of available data suggests that 15%-30% of
acute myocardial infarction (MI) survivors have silent
ischemia (5,6). The largest number of patients at risk
of silent ischemia are those with stable angina (the
prevalence of silent ischemia is 25%-50% and up to
70%-80% of ischemic episodes are silent (7,8).
Atherosclerotic coronary artery disease is the most
common underlying cause responsible for myocardial
ischemia.
Two observations are interesting. First, conventional
or intensive antianginal drug therapy aimed at
symptom control does not eliminate silent ischemic
episodes (9,16). Second, patients with silent ischemia
detected during Holter monitoring have more
advanced CHD with frequent evidence of multivessel
disease (10).
The exact reasons for the development of angina
during some episodes of myocardial ischemia and the
absence of symptoms during other episodes are not
known. Some mechanisms include:
1) inability to reach pain threshold during an episode
of ischemia,
2) lesser severity and shorter duration of ischemic
episodes,
Asymptomatic patients
3) presence of higher threshold for pain,
The prevalence of asymptomatic but significant
coronary disease in the general population can be
estimated from data of screening studies and studies
evaluating autopsy findings in people not known to
having had coronary disease. Between 2 and 4 percent
of apparently healthy asymptomatic middle-aged man
have a significant coronary disease. The prevalence
may be up to 10 percent in asymptomatic men with 2
or more coronary risk factors (smoking, obesity,
family history of heart disease, age over 45, diabetes,
hypertension, and hypercholesterolemia). The data on
women are inconclusive because of a higher incidence
of false positive electrocardiograms.
4) generalized defective perception of painful stimuli,
58
5) presence of a defective anginal warning system,
6) higher beta-endorphin levels (11,12), and
7) higher production of anti-inflammatory cytokines
which block pain transmission pathways and
increase the threshold for nerve activation.
Autonomic neuropathy involving cardiac afferent
nerves in diabetes mellitus might account for the
higher incidence of silent ischemia in diabetics
(13).
The exact mechanism that plays a role in silent
ischemia is dependent upon a variety of factors such as
age, ethnic background, presence of diabetes or other
J. Boras, N. Brkljačić, A. Ljubičić, S. Ljubić / SILENT ISCHEMIA AND DIABETES MELLITUS
cause of autonomic neuropathy, prior MI, prior
coronary artery bypass graft (CABG), use of certain
drugs, etc.
Myocardial ischemia occurs when there is an
imbalance between myocardial oxygen supply and
demand. Myocardial oxygen demand is dependent
upon heart rate, myocardial contractibility, afterload
(systolic blood pressure) and ventricular wall tension
(preload). For clinical purposes, heart rate, systolic
blood pressure and calculated double product (HR x
systolic BP) are the most important determinants of
myocardial oxygen demand.
Atherosclerotic coronary disease is the most
common underlying cause responsible for myocardial
ischemia (even in early stages before the lesion
becomes occlusive). Changes in vasomotor tone
(vasospasm) may also play a role. When
atherosclerosis produces critical stenotic lesion (50%70% luminal narrowing), there is a threshold point
beyond which an increase in myocardial oxygen
demand may result in myocardial ischemia (ischemic
threshold). The ischemic threshold varies from patient
to patient and can even change in a given patient based
upon a variety of factors (e.g., time of the day, level of
mental stress, physical activities and neurohormonal
status).
The pathophysiological mechanisms responsible for
the genesis of silent myocardial ischemia remain
unresolved. It has been suggested that primary
reduction in coronary blood flow plays a dominant
role; most silent ischemic episodes occur during
minimal or no physical activity (13,14,16) and
ambulatory monitoring studies have shown relatively
small increases in the heart rate immediately preceding
silent ischemic episodes, which is in contrast to the
prominent increases during exercise testing (14,15).
Other reports suggest that increased myocardial
oxygen demand for any cause plays a major role in the
pathogenesis of silent ischemia (16,17). The majority
of patients who experience silent myocardial ischemia
during daily life have evidence of inducible ischemia
during exercise test that is primarily due to an increase
in myocardial demand (15,16). Several factors, such as
mental stress and intrinsic physiologic changes due to
circadian rhythm, are associated with significant
Diabetologia Croatica 39-2, 2010
hemodynamic changes that raise myocardial oxygen
demand (24). Associated with mental stress induced
myocardial ischemia are wall motion abnormalities,
which can be prevented by atenolol therapy (as the
result of lower rate-pressure product) and by
nifedipine (coronary vasoconstriction and decrease in
myocardial blood flow also occur).
Most episodes of silent ischemia are preceded by an
increase in oxygen demand (only 20%-30% are due to
reduced coronary flow secondary to vasospasm or
other factors) (18). Silent myocardial ischemia has a
bimodal distribution, with a peak between 6.00 a.m.
and noon. It may be related to one or more
physiological changes (15,23) such as increased heart
rate and blood pressure, elevated catecholamine levels,
elevated coronary vasomotor tone, enhanced platelet
aggregation, and decreased intrinsic fibrinolytic
activity. Asymptomatic nocturnal ST segment changes
are almost invariably an indicator of two- or threevessel CAD or the left main coronary artery stenosis.
SILENT ISCHEMIA AND DIABETES
MELLITUS
Coronary artery disease is the major cause of
morbidity and mortality in patients with diabetes
(19,20). More than half of all diabetic patients die
from coronary artery insufficiency (21,22). CAD is
usually more advanced at the time of diagnosis and has
unfavorable prognosis in diabetic patients (23,24).
Later diagnosis of CAD may be explained by the
presence of SMI. Angiographically proved SMI is
more frequent in patients with diabetes than in
nondiabetic patients (probably because of diabetic
neuropathy). SMI has a prevalence between 10% and
20% in diabetic patients versus 1% to 4% in
nondiabetic patients (25,26). Traditional and emerging
cardiac risk factors have not been associated with
abnormal stress tests, although cardiac autonomic
dysfunction was found to be a strong predictor of
ischemia.
Scognamiglio et al. (27) performed detection of
coronary disease in asymptomatic patients with type 2
diabetes mellitus. They found that two risk groups (≥2
vs. 0 or 1 risk factors) had equivalent rates of an
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J. Boras, N. Brkljačić, A. Ljubičić, S. Ljubić / SILENT ISCHEMIA AND DIABETES MELLITUS
abnormal stress test (60%) and of significant coronary
disease on angiography (65%). The patients with ≥2
risk factors had more severe coronary disease with
significant higher rates of three-vessel disease (33%
vs. 8%), diffuse disease (55% vs. 18%) and vessel
occlusion (31% vs. 4%). Janand-Delenne et al. (28)
performed a 1-year study to estimate the prevalence of
SMI in type 1 and 2 diabetic patients and to define the
high-risk diabetic population by systematically testing
patients with no symptoms of CAD. The results
showed that SMI with significant lesions occurred in
20.9% of type 2 diabetic male patients who were
completely asymptomatic for CAD. They recommend
routine screening for male patients in whom the
duration of type 2 diabetes is more than 10 years or
even less when more than one cardiovascular risk
factor are present.
The Detection of silent myocardial Ischemia in
Asymptomatic Diabetics (DIAD) study (29) was
designed to determine the prevalence of inducible
myocardial ischemia in asymptomatic patients with
type 2 diabetes using adenosine-stress single-photon
emission-computed tomography (SPECT) myocardial
perfusion imaging as well as clinical and laboratory
predictors of abnormal test results. A total of 22% of
patients had silent ischemia. The strongest predictors
for abnormal tests were abnormal Valsalva (lower
Valsalva heart rate ratio), male sex and diabetes
duration. Selecting only the patients who met the
American Diabetes Association guidelines (those who
have two or more additional CAD risk factors), they
would have failed to identify 41% of patients with
silent ischemia. Traditional cardiac risk factors or
inflammatory and prothrombotic markers were not
associated with abnormal stress tests, although cardiac
autonomic dysfunction was a strong predictor of
ischemia.
Autonomic neuropathy is a serious and common
complication of diabetes. About 20% of asymptomatic
diabetic patients have abnormal cardiovascular
autonomic function (30,31). The risk of cardiovascular
autonomic neuropathy depends on the duration of
diabetes and the degree of glycemic control. The main
consequences are dysfunctional heart rate control,
abnormal vascular dynamics and cardiac denervation,
60
which have become clinically overt as exercise
intolerance (32), orthostatic hypotension (33),
intraoperative cardiovascular lability and SMI.
Cardiovascular autonomic neuropathy may provoke
ischemic episodes by upsetting the balance between
myocardial supply and demand. Instead of typical
angina, patients often complain of shortness of breath,
diaphoresis or profound fatigue. Silent ischemia
delays treatment of acute coronary events and makes it
more difficult to monitor anti-ischemic treatment or
determine whether restenosis has occurred after
coronary intervention.
It is presently recommended that baseline
determination of cardiovascular autonomic function
be performed upon diagnosis in type 2 diabetes and
within 5 years of diagnosis in type 1 diabetes, followed
by yearly repeated tests (34).
DIAGNOSIS
No single diagnostic test is ideal in screening patients
for asymptomatic CHD. Due to the relatively low
pretest likelihood of the disease, the predictive
accuracy of any screening test is low and generally
requires confirmation by further testing (35).
Exercise ECG testing has been widely used in
screening for asymptomatic CHD. Although an
abnormal ECG response predicts a high risk of
subsequent coronary and cardiac death in patients with
known CHD (36-38), it has a low predictive value in
subjects without known disease.
Exercise treadmill test (ETT) and ambulatory
(Holter) monitoring are the most readily available and
frequently used tests to identify silent ischemia in
clinical practice.
Exercise testing
Exercise testing is the most suitable laboratory
diagnostic test do document SMI in asymptomatic
individuals (i.e. patients with no history of CHD) and
in those with a history of CHD or exertional angina.
J. Boras, N. Brkljačić, A. Ljubičić, S. Ljubić / SILENT ISCHEMIA AND DIABETES MELLITUS
Conventional ST segment analysis during the test is
moderately sensitive in detecting CHD. It has low
specificity because of an unacceptably high rate (10%35%) of false positive responses (asymptomatic
persons and women) (39). The diagnosis of
myocardial ischemia by ETT in asymptomatic persons
must be confirmed by radionuclide imaging
techniques (e.g., thallium perfusion scintigraphy or
exercise ventriculography) before the subject is
labeled as having silent ischemia (40).
phenothiazines). Pharmacological stress tests with
dipyridamole or adenosine plus thallium scintigraphy
or dobutamine stress echocardiography can be used in
those patients who are unable to ambulate or exercise
(e.g., due to advanced peripheral vascular disease)
(Table 1).
Table 1. Diagnostic modalities for detection and
evaluation of silent myocardial ischemia
Exercise treadmill test
Holter monitoring
Holter monitoring is the second most frequently used
diagnostic test for silent ischemia. The advantage is
providing long-term ECG recording of ischemic and
arrhythmic events while patients are engaged in
routine daily activities out of hospital (41). Episodes
of transient ischemia during Holter monitoring are
diagnosed by the sequence of ECG changes that
include a flat or downsloping ST depression of at least
1 mm, with gradual onset and offset that lasts at least
one minute (42). One potential limitation to the use of
outpatient Holter monitoring is the marked day to day
variability in frequency and duration of ST depression
and ischemic episodes (43). The ST depression
recorded during Holter monitoring and other
simultaneous objective evidence of ischemia by
perfusion scintigraphy, radionuclide cardioangiography and hemodynamic monitoring show an
excellent correlation.
Exercise test remains the preferred diagnostic
modality for initial identification of patients with silent
ischemia. Only a small fraction of patients with
negative finding on exercise testing will demonstrate
evidence of ischemia on Holter monitoring.
Nuclear and echocardiographic imaging studies
Nuclear imaging tests such as stress thallium
scintigraphy or exercise radionuclide ventriculography
are recommended for the evaluation of silent ischemia
in patients who have an abnormal baseline ECG (e.g.,
left ventricular hypertrophy or stain, bundle branch
block, preexcitation syndrome) or those who receive
drugs that produce repolarization changes (digoxin,
Diabetologia Croatica 39-2, 2010
Continuous ECG (Holter) monitoring
Exercise myocardial perfusion scintigraphy
Radionuclide angiocardiography
Pharmacological stress scintigraphy
Hemodynamic monitoring
PROGNOSIS AND THERAPY
Episodes of myocardial ischemia, regardless of
whether they are symptomatic or asymptomatic, are of
prognostic importance in patients with CAD. As such,
myocardial ischemia, as opposed to symptoms alone,
has been identified as a valid therapeutic target. In
asymptomatic patients, the presence of exerciseinduced ST segment depression has been shown to
predict a four- to fivefold increase in cardiac mortality
(30).
The Lipid Research Clinics Coronary Primary
Prevention Trial (asymptomatic hypercholesterolemic
men) and the Multiple Risk Factor Intervention Trial
(MRFIT) (asymptomatic middle-aged men with two or
more coronary risk factors) found significant
association between exercise test-induced silent
ischemia and mortality (6,7). A study by Laukkanen et
al. also demonstrated the relationship between CHD
risk in patients with silent ischemia and coronary risk
factors; exercise-induced silent ischemia was
associated with an increase in mortality and the risk of
any acute coronary event was 5.9- and 3-fold in those
who smoked; 3.8- and 1.9-fold in hypercholesterolemic subjects; and 4.7- and 2.2-fold in
hypertensive patients (44). These associations were
weaker and not significant in men without these risk
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factors. The Heart and Soul study suggested the
presence of ischemia rather than that of angina to
determine the outcome (45). In the Psychophysiologic
Investigations of Myocardial Ischemia study, the
presence of mental stress-induced ischemia, as
established by new or worsened wall motion
abnormalities on radionuclide imaging, significantly
predicted death during an average follow-up of 5.2
years (46).
The exact reason for the adverse prognosis associated
with silent ischemia is not known. It is possible that
repeated episodes of silent ischemia could lead to
progressive fibrosis and the development of left
ventricular dysfunction, and to life-threatening
arrhythmias, especially in patients with an electrical
substrate for arrhythmias.
Treatment without revascularization
Pharmacological agents that reduce or abolish
episodes of symptomatic ischemia, i.e. nitrates, betablockers and calcium antagonists, also reduce or
abolish episodes of silent ischemia.
As increased myocardial oxygen demand appears to
be the primary reason for the development of silent
ischemia, beta-blockers and heart rate reducing
calcium channel blockers are the first choice.
Combination therapy is necessary when monotherapy
with beta-blockers does not effectively suppress silent
ischemia. One of the most favored combinations is a
long acting beta-blocker and long acting nitrate
preparation. The elimination of ST segment depression
on Holter monitoring is frequently used to evaluate the
effect of this therapy, but the marked variability in the
number and duration of ischemic episodes as detected
with this technique may confound the accurate
assessment of prescribed therapy (13).
Two studies with mental stress management showed
that a program of stress management reduced the
frequency of ischemic events, particularly among
patients with a higher frequency of ischemic episodes
(≥4/hour) (47), and had a significantly lower number
of coronary events at two years (48).
62
Hyperlipidemia is associated with endothelial
dysfunction, which promotes the development of
atherosclerosis and can also cause unopposed
vasoconstriction or established coronary stenoses,
thereby triggering silent or overt ischemia. A study
with lovastatin (49) showed that after six months of
therapy there was a significant reduction in the number
of episodes of ST segment depression and abolished
ST segment depression in a higher percentage of
patients (65% vs. 10% in the placebo group).
Treatment with revascularization
There are limited data evaluating the efficacy of
coronary revascularization in the treatment of silent
ischemia. However, the data available suggest that
revascularization may improve patient outcomes. The
NIH-sponsored Asymptomatic Cardiac Ischemia Pilot
(ACIP) study (50,51) illustrated that CABG more
effectively suppressed ischemia than PTCA (both on
ambulatory ECG and on ETT); that mortality after one
and two years was lower in patients undergoing
revascularization compared to those with Holter
guided therapy or medical therapy guided by relief of
angina; and that the rates of combined end points of
death, myocardial infarction or recurrent
hospitalization at one and two years were lower in
patients undergoing revascularization compared with
those undergoing either form of medical therapy.
CONCLUSION
Silent myocardial ischemia is defined as the presence
of objective evidence of myocardial ischemia in the
absence of chest discomfort or other anginal
equivalents. Most silent ischemic episodes occur
during minimal or no physical exertion. SMI is
associated with an increase in coronary risk that may
be reversible with appropriate therapy. The risk of
silent ischemia is increased substantially in patients
with diabetes, particularly if they have other risk
factors. Exercise treadmill test (ETT) and ambulatory
(Holter) monitoring are the most readily available and
frequently used tests to identify silent ischemia in
clinical practice. Therapy for asymptomatic episode is
equal as for the symptomatic one.
J. Boras, N. Brkljačić, A. Ljubičić, S. Ljubić / SILENT ISCHEMIA AND DIABETES MELLITUS
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