Myocardial
infarction is ischemic necrosis due to occlusion of coronary artery by thrombus
or subintimal hemorrhage at the site of atheromatous narrowing.
Less often, complete occlusion by intimal plagues or by hemorrhage
into a plague is responsible/ Coronary vasoconstriction
or spasm may be intense and prolonged and has been proved to result in
myocardial infarction in a small number of cases.
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Foam
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cell
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formation
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Adherence
and
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aggregation
of
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platelets
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Adherence
and
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entry
of
leukocytes
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T
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cell
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activation
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VSMC,
vascular smooth muscle cell migration.
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The location and
extent of infarction depend upon the anatomic distribution of the vessel, the
site of current and previous occlusions, and the adequacy of collateral
circulation. Thrombosis occurs most commonly in the anterior descending branch
of the left coronary artery, resulting in infarction of the anterior left
ventricle. Occlusion of the left circumflex artery produces anterolateral infarction. Right coronary thrombosis leads to
infarction of the posteroinferior portion of the left
ventricle and might involve the right ventricular myocardium.
The hemodynamic findings are related directly to the extent of necrosis or scarring of the myocardium. In mild infarction, toe hemodynamics may be normal. With more severe disease, there may be a raised left ventricular end-diastolic pressure with associated increase in the pulmonary artery diastolic pressure, decreased cardiac output, and decreased ejection fraction. When the patient is hypotensive or in shock, the cardiac output is considerably reduced in conjunction with evidences of left ventricular failure and a high left ventricular filling pressure. The “wedge” and left ventricular diastolic pressure may be raised, with no abnormality in the right ventricular diastolic pressure or the right atrial pressure; thus, the superior Vena cava or right atrial pressures are often misleading because they do not reflect left ventricular events. They are, however, valuable if the pressures are very low, indicating the possibility of hypovolemia; the response to volume loads may be helpful in producing an increased cardiac output. The presence of a large V wave in the pulmonary wedge pressure pulse is helpful in diagnosing acute mitral insufficiency due to papillary muscle dysfunction in patients who abruptly worsen, with development of cardiac failure. Similarly, raised oxygen content in the right ventricle under similar circumstances helps in diagnosis of perforated ventricular septum.
Clinical
Findings
A.
Symptoms:
CLINICAL
History: Most patients with
angina pectoris report of retrosternal chest
discomfort rather than frank pain. The former is usually described as a
pressure, heaviness, squeezing, burning, or choking
sensation. Anginal pain may be localized primarily in
the epigastrium, back, neck, jaw, or shoulders.
Typical locations for radiation of pain are arms, shoulders, and neck.
Typically, angina is precipitated by exertion, eating, exposure to cold, or emotional stress. It lasts for approximately 1-5
minutes and is relieved by rest or nitroglycerin.
Chest pain lasting only a few seconds is not usually angina pectoris. The
intensity of angina does not change with respiration, cough, or change in
position. Pain above the mandible and below the epigastrium is rarely anginal in
nature.
Ask
patients about the frequency of angina, severity of pain, and number of nitroglycerin pills used during angina
episodes.
Angina
decubitus is a variant of angina pectoris that occurs
at night while the patient is recumbent. Some have suggested that it is induced
by an increase in myocardial oxygen demand caused by expansion of the blood
volume with increased venous return during recumbency.
The
Canadian Cardiovascular Society grading scale is used for classification of
angina severity, as follows:
Class I -
Angina only during strenuous or prolonged physical
activity
Class II -
Slight limitation, with angina only during vigorous physical
activity
Class III -
Symptoms with everyday living activities, ie, moderate
limitation
Class IV -
Inability to perform any activity without angina or angina at rest, ie, severe limitation
The New
York Heart Association classification is also used to quantify the functional
limitation imposed by patients' symptoms, as follows:
Class I -
No limitation of physical activity (Ordinary physical activity does not cause
symptoms.)
Class II -
Slight limitation of physical activity (Ordinary physical activity does cause
symptoms.)
Class III -
Moderate limitation of activity (Patient is comfortable at rest, but less than
ordinary activities cause symptoms.)
Class IV -
Unable to perform any physical activity without discomfort, therefore severe
limitation (Patient may be symptomatic even at rest.)
Unstable
angina is defined as new-onset angina (ie, within 2 mo
of initial presentation) of at least class III severity, significant recent
increase in frequency and severity of angina, or angina at
rest.
Physical:
For most
patients with stable angina, physical examination findings are normal.
Diagnosing secondary causes of angina, such as aortic stenosis, is important.
A positive
Levine sign (characterized by the patient's fist clenched over the sternum when
describing the discomfort) is suggestive of angina
pectoris.
Look for
physical signs of abnormal lipid metabolism (eg, xanthelasma, xanthoma) or of
diffuse atherosclerosis (eg, absence or diminished
peripheral pulses, increased light reflexes or arteriovenous nicking upon ophthalmic examination, carotid
bruit).
Examination
of patients during the angina attack may be more helpful. Useful physical
findings include third and/or fourth heart sounds due to LV
Pain produced by chest wall
pressure is usually of chest wall origin.
1. Premonitory
pain-Over one-third of patients
give a history of alteration the pattern of angina, sudden onset of typical or
atypical angina, or unusual "indigestion" felt in the
chest.
2. Pain of
infarction-This may begin during rest
(even in sleep) or activity. It is similar to angina in location and radiation
but is more severe, does not subside with rest, and builds up rapidly or in
waves to maximum intensity in the space of a few minutes or longer.
Nitroglycerin has little effect. The pain may last for hours if unrelieved by
narcotics and is often unbearable. Patients break out in a cold sweat, feel weak
and apprehensive; and move about, seeking a position of comfort. They prefer not
to lie quietly. Lightheadedness, syncope, dyspnea,
orthopnea, cough, wheezing, nausea and vomiting, or
abdominal bloating may be present singly or in any
combination.
3. Painless
infarction-In
5-15%
of cases, pain is absent or minor and is overshadowed by the immediate
complications, notably acute pulmonary edema or rapidly developing heart
failure, profound weakness, shock, syncope, or cerebral
thrombosis.
B. Signs: Physical findings
are highly variable; the presence of rales, gallop
rhythm, tachycardia, arrhythmia or bradycardia, and
hypotension correlate well with hemodynamic and clinical evidences of the
severity of the attack and the extent of the necrosed
myocardium.
1. Shock. Shock may be
described as a systolic blood pressure below
80
mm Hg; (or slightly higher with
prior hypertension) along with gray facial color, mental dullness, cold clammy
skin, peripheral cyanosis, decreased urine output, tachycardia or bradycardia, and weak pulse. Shock is present only in severe
attacks (incidence about 8-14%). Shock may be caused primarily
by the pain rather than the hemodynamic effects of the infarction; if so,
distinct improvement occurs within
30-60
minutes after relief of pain and administration of oxygen.
2. Cardiac
effects-In the severe attack, the
first and second heart sounds are faint, are often indistinguishable on
auscultation, and assume the so-called "tic-tac" quality. Gallop rhythm,
distended neck veins, and basal rales are often
present. Acute pulmonary edema or progressive congestive failure may dominate
the picture. In less severe attacks, examination is normal or there may be
diminished intensity of the first sound or low systolic blood pressure;
arrhythmia, hypoxemia, radiologic evidence of pulmonary venous congestion, and
echocardiographic evidence of left ventricular
distention may be present. Pericardial friction rub appears in
20% of
cases between the second and fifth days; it is often transient or intermittent
and is rarely of clinical significance unless the patient is taking
anticoagulants, in which case a large hemorrhagic effusion may
develop.
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The presence of
right ventricular failure with raised venous pressure disproportionate to left,
ventricular failure in the presence of an inferior myocardial infarction should
make one consider right ventricular infarction. In the usual case of severe left
ventricular failure followed by right ventricular failure, the former dominates.
When the reverse is true, right ventricular infarction associated with
enlargement and hypokinesis of the right ventricle may
be present. The ventricular septum and the posterior left and right ventricles
are usually infarcted.
3. Fever-Fever-is absent at the
onset (in contrast to acute pericarditis) and during
prolonged shock. It usually rises to
37.8-39.4 °C – rarely to
40.6 °C—within
24
hours and persists for 3-7
days
(rarely longer).
C. Laboratory
Findings: Leukocytosis of 10-20 thousand cells/mL
usually develops on the second day and disappears in
1
week. The sedimentation rate is normal at onset, rises on the second or third
day, and remains elevated for
1-3
weeks. SGOT activity increases in
6-12
hours, reaches a peak in 24—48
hours,
and returns to normal in
3—5
days. Serum lactic acid dehydrogenase may remain
elevated for 5-7
days.
Serial determinations are helpful in equivocal instances. Creatine phosphokinase (CPK) isoenzyme activity may
increase earliest (especially -the MB isoenzyme,
derived almost exclusively from the myocardium), and, when determined
every
2
hours, gives an estimate of the magnitude of the infarction, although for
diagnosis, CPK determination every
6—12 hours is
adequate.
D.
Electrocardiography: Electrocardiographic changes
do not correlate well with the clinical severity of the infarction. The
characteristic pattern consists of specific changes that undergo a stereotyped
"evolution
''
over a matter of weeks in the average case. At the onset there
are elevation of ST segment and T wave and abnormal Q waves; fee ST segment
progressively returns to the baselines as T waves become symmetrically inverted.
An unequivocal electrocardiographic diagnosis of infarction can only be made in
the presence of all
3
abnormalities. Serial ST-T changes alone are compatible with but not diagnostic
of infarction. The characteristic changes are not seen in the presence of left
bundle branch block or when a previous infarct has permanently altered fee ECG. Even in these instances an ECG taken early in an attack often shows ST segment
displacement.
Chest radiograph findings are
usually normal in patients with angina pectoris. However, they may show cardiomegaly in patients with previous MI, ischemic cardiomyopathy, pericardial effusion, or acute pulmonary
edema. Calcification of coronary arteries frequently
correlates with major coronary artery disease.
These test
results must be interpreted in the context of the likelihood of the presence of
coronary artery disease determined from the patient's history and physical
examination findings. In a population with low prevalence, the predictive
abilities of these tests are low; however, in patients with a high likelihood of
coronary artery disease, the predictive value is much
higher.
Stress
echocardiography can be used to evaluate segmental wall motion during exercise.
It detects changes in regional wall motion that occur during myocardial
ischemia. Normal myocardium becomes hyperdynamic
during exercise; ischemic segments become hypokinetic
or akinetic.
Stress
echocardiography has the advantage of simultaneous evaluation of LV
It is also
helpful for localizing ischemia and evaluating its
severity.
Signs of
severe coronary artery disease during exercise stress echocardiography include
LV LV
A major
problem with stress echocardiography is the technical difficulty with obtaining
adequate images in some patients.
Thallium
Tl 201 and technetium Tc 99m
sestamibi are the most frequently used myocardial
perfusion scintigraphy tests. These tests are
especially useful in patients with baseline ECG
abnormalities, to localize the region of ischemia, and as prognostic indicators.
The presence of increased lung uptake upon thallium imaging is associated with a
poor prognosis. Increased lung uptake, together with poststress dilation of the LV
Differential
Diagnosis
In acute pericarditis, fever often precedes fee onset of pain, which
may be predominantly pleuritic and is significantly
relieved by breath-holding and leaning forward and made worse by swallowing. The
friction rub appears earlier, is louder, is heard over a greater area, and is
more persistent than in infarction, and a pleuropericardial rub is often present. There are no QRS changes, and ST elevation and T wave inversion are more
widespread, without reciprocal changes (except in aVR). SGOT and LDH are rarely elevated.
Dissection of fee
aorta causes violent chest pain feat is often of maximum severity at onset. It
typically spreads up or down fee chest and back over a period of hours. Changes
in pulses, changing aortic murmurs, and left pleural effusion or cardiac tamponade are distinctive features. Blood pressure does not
fall early. Syncope or neurologic abnormalities are common. Electrocardiographic
changes are not diagnostic of infarction unless fee coronary ostia arc involved in fee proximal
dissection.
Acute pulmonary
embolism may cause chest pain indistinguishable from myocardial infarction as
well as hypotension, dyspnea, and distended neck
veins, but fee ECG, regardless of coronarylike changes, will often show right axis deviation
or right ventricular conduction defect early in fee course of fee acute process.
SGOT and LDH are often
elevated, as in myocardial infarction. The myocardial band isoenzyme of CPK is not elevated
in acute pulmonary embolism. If the attack is not fatal, pulmonary infarction
may follow, frequently causing pleuritic pain, hemoptysis, and localized lung findings. Thrombophlebitis is often found when careful examination is
made of the legs, the groins, and the lower abdomen.
Cervical or thoracic spine
disease produces sudden, severe chest pain similar to myocardial infarction; but
orthopedic measures give relief and the ECG is
normal.
Reflux esophagitis may simulate the pain of infarction, and the T
waves may be flat or even inverted during the attack, but there is no
hypotension or subsequent fever, leukocytosis, or
increase in sedimentation rate, SGOT, LDH, or CPK.
Acute pancreatitis and acute
cholecystitis may superficially mimic infarction by
causing ST-T changes; Q wave abnormalities are rare. A past history of
gastrointestinal symptoms, present findings in the abdomen, jaundice, elevated
serum amylase, and x-ray findings differentiate these. Most helpful is the
absence of diagnostic serial electrocardiographic changes and absence of
elevated CPK-MB;
Spontaneous pneumothorax, mediastinal
emphysema, preemptive herpes zoster, and severe psychophysiologic cardiovascular reactions may have to be
differentiated from myocardial infarction.
Complications
Congestive heart failure and
shock may be present at onset of infarction or may develop insidiously or
abruptly following an arrhythmia or pulmonary embolization. Sedation and weakness may mask the presence of
dyspnea and orthopnea.
Distension of neck veins, persistent basal rales,
gallop rhythm,
the
appearance of the murmur of mitral insufficiency, abnormal cardiac pulsations,
an enlarging tender liver, and peripheral edema should besought daily. If
increasing cardiac failure or evidence of poor cardiac output develops, a
Swan-Ganz flow-directed balloon catheter should be
inserted to determine precisely the hemodynamic abnormalities and to assist in
treatment. Portable chest
x-ray films to recognize pulmonary venous congestion are desirable. If
anticoagulants are not given, pulmonary embolism secondary to phlebitis of the
leg or pelvic veins occurs in 5-10% of patients during
the acute and convalescent stage.
Arrhythmias occur commonly
after myocardial infarction and are thought to be the cause of death in
about
40% of
patients. The mechanism is either cardiac arrest or ventricular fibrillation;
the former occurs following shock or heart failure, and the latter is more apt
to be a primary event (although it can be secondary). Continuous monitoring has
revealed a higher incidence of ventricular tachycardia, complete atrioventricular block, and other less serious arrhythmias
than was formerly suspected. The appearance of left anterior hemiblock, especially combined with right bundle branch
block, often precedes the development of complete atrioventricular block and requires insertion of a
prophylactic pacemaker. Ventricular premature beats often precede more serious
arrhythmias in late or secondary but may not in early
or primary ventricular fibrillation. Atrial
arrhythmias are less common and often transient, as is the case with atrial fibrillation. The prompt recognition of arrhythmias
is essential in order to initiate treatment.
Cerebrovascular accident may
result from a fall in blood pressure associated with myocardial infarction or
from embolism secondary to a mural thrombus. It is advisable to take an ECG in all patients with "cerebrovascular accident."
Recurrent
myocardial infarction or extension of the infarction occurs in about
5% of
patients during recovery from the initial attack.
Rupture of the
heart is uncommon. When it occurs, it is usually in the first
week.
Perforation of the
ventricular septum is rare, characterized by the sudden appearance of a loud,
harsh systolic murmur and thrill over the lower left parastemal area or apex and acute heart failure. This must
be distinguished from mitral insufficiency caused by papillary muscle infarction
or dysfunction. The diagnosis may sometimes be made by passing (at the bedside)
a pulmonary artery flow-directed catheter and noting the size of the v wave in
the wedged position and the oxygen content in the right ventricle.
Two-dimensional echocardiography may demonstrate the perforation of the
ventricular septum and so obviate the need for catheterization. Both lesions may
precipitate cardiac failure and require cardiac surgery when the patient's
condition has stabilized in weeks or months and right and left heart
catheterization reveals a significant hemodynamic lesion. 'Emergency surgical
repair is sometimes required but has a high mortality rate. An effort should be
made to delay surgery for at least a month.
Ventricular
aneurysm and peripheral arterial embolism may occur early or not for months
after recovery. The spectrum of ventricular aneurysm is now recognized to extend
from frank outpocketing of an area of myocardium with
well-demarcated paradoxic pulsations to localized poor
contraction or irregular pulsation seen on cineangiography. Approximately 20% or patients
develop some form of aneurysm or left ventricular hypokinesis, recognized clinically by abnormal paradoxic precordial pulsations
and proved by gated pool scintigraphy, 2-dimensional
echocardiography, cinefluoroscopy, or left ventricular
cineangiography. Some of these patients develop
refractory cardiac failure and benefit from surgical
excision.
The shoulder-hand
syndrome is a rare preventable disorder caused by prolonged immobilization of
the arms and shoulders, possibly due to "reflex sympathetic
dystrophy.'' Early pain and
tenderness over the affected shoulder are followed by pain and swelling and
weakness of the hand, with excessive or deficient sweating. Oliguria, anuria, or, rarely,
tubular necrosis may result if shock persists.
TREATMENT
Medical Care: The main goals of
treatment in angina pectoris are to relieve the symptoms, slow the progression
of disease, and reduce the possibility of future events, especially MI and
premature death.
General
measures
Smoking cessation results in a
significant reduction of acute adverse effects on the heart and may reverse, or at least slow, atherosclerosis. Strongly
encourage patients to quit smoking, and take an active role in helping them to
achieve this goal.
Treat risk factors, including
hypertension, diabetes mellitus, obesity, and hyperlipidemia.
Several clinical trials have
shown that in patients with established coronary artery disease, reduction of
low-density lipoprotein (LDL) level with a beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitor (ie, statin) is associated with significant reductions in both
mortality rate and major cardiac events.
These benefits are present
even in patients with mild-to-moderate elevations of LDL cholesterol level.
Recent trials with
cholesterol-lowering agents have confirmed the benefits of the therapeutic LDL lowering in older persons.
Angiographic studies
demonstrate that a reduction of the LDL level in
patients with coronary artery disease could cause slowing of progression,
stabilization, or even regression of coronary artery
lesions.
A recent study demonstrates a
significant reduction of symptomatic myocardial ischemia in patients with
unstable angina or non–Q-wave infarction with the administration of a statin during the early acute phase.
In a more recent study of
10,001 patients with stable coronary artery disease, an aggressive
cholesterol-lowering approach with atorvastatin 80 mg
daily (mean cholesterol level of 77 mg/dL) compared to
a less-aggressive approach with atorvastatin 10 mg
daily (mean cholesterol level of 101 mg/dL) resulted
in a 2.2% absolute reduction and a 22% relative reduction in the occurrence of a
first major cardiovascular event (defined as death from coronary heart disease;
nonfatal, non–procedure-related myocardial infarction; resuscitation from
cardiac arrest; or fatal or nonfatal stroke).This occurred with a greater
incidence of elevated aminotransferase levels with the
aggressive cholesterol-lowering approach (1.2% vs
0.2%, p<0.001).
On the basis of several recent
studies that have demonstrated the benefits of more aggressive LDL-lowering therapies in high-risk patients with coronary
artery disease, the Committee of the National Cholesterol Education Program
recently made the following modifications to the Adult Treatment Panel III (ATP
III) guidelines.
In high-risk patients, a serum
LDL cholesterol level of less than 100 mg/dL is the goal.
In very high-risk patients, an
LDL cholesterol level goal of less than 70 mg/dL is a therapeutic option. Patients in the category of very
high risk are those with established coronary artery disease with one of the
following: multiple major risk factors (especially diabetes), severe and poorly
controlled risk factors (especially continued cigarette smoking), multiple risk
factors of the metabolic syndrome (especially high triglyceride levels [>200
mg/dL] plus non-HDL
cholesterol level [>130 mg/dL] with low HDL cholesterol level [<40 mg/dL]), and patients with acute coronary syndromes.
For moderately high-risk
persons (2+ risk factors), the recommended LDL
cholesterol level is less than130 mg/dL, but an LDL cholesterol level of 100 mg/dL
is a therapeutic option.
Some triglyceride-rich
lipoproteins, including partially degraded very LDL
levels, are believed to be independent risk factors for coronary artery disease.
In daily practice, non-HDL cholesterol level (ie, LDL + very LDL cholesterol [total cholesterol - HDL cholesterol]) is the most readily available measure of
the total pool of these atherogenic lipoproteins.
Thus, the ATP III has identified non-HDL cholesterol
level as a secondary target of therapy in persons with high triglyceride levels
(>200 mg/dL). The goal for non-HDL cholesterol level (for persons with serum triglyceride
levels >200 mg/dL) is 30 mg/dL higher than the identified LDL
cholesterol level goal.
Patients with established
coronary disease and low HDL cholesterol levels are at
high risk for recurrent events and should be targeted for aggressive nonpharmacological (ie, dietary
modification, weight loss, physical exercise) and pharmacological
treatment.
A recent study demonstrated
that in patients with established coronary artery disease who have low HDL and low-risk LDL levels, drug
therapy with medications that raise HDL cholesterol
levels and lower triglyceride levels but have no effect on LDL cholesterol levels (eg, gemfibrozil) could significantly reduce the risk of major
cardiac events.
Currently, the accepted
approach to the management of patients with coronary artery disease and low
HDL levels is as follows:
In all persons with low HDL cholesterol levels, the primary target of therapy is to
achieve the ATP III guideline LDL cholesterol level
goals with diet, exercise, and drug therapy as needed.
After reaching the targeted
LDL level goal, emphasis shifts to other issues. That
is, in patients with low HDL cholesterol levels who
have associated high triglyceride levels (>200 mg/dL), the secondary priority is to achieve the non-HDL cholesterol level goal of 30 mg/dL higher than the identified LDL
cholesterol level goal. In patients with isolated low HDL cholesterol levels (triglycerides <200 mg/dL), drugs to raise the HDL
cholesterol level (eg, gemfibrozil, nicotinic acid) can be
considered.
Exercise training results in
improvement of symptoms, increase in the threshold of ischemia, and improvement
of patients' sense of well-being. However, before enrolling a patient in an
exercise-training program, perform an exercise tolerance test to establish the
safety of such a program.
Consider enteric-coated
aspirin at a dose of 80-325 mg/d for all patients with stable angina who have no
contraindications to its use. In patients in whom aspirin cannot be used because
of allergy or gastrointestinal complications, consider clopidogrel.
Although early observational
studies suggested a cardiovascular protective effect with the use of hormone
replacement therapy, recent large randomized trials failed to demonstrate any
benefit with hormone replacement therapy in the primary or secondary prevention
of cardiovascular disease.
In fact, these studies even
demonstrated an increased risk of coronary artery disease and stroke in patients
on hormone replacement therapy.
The Women's Health Initiative
study demonstrated that the use of hormone replacement therapy for 1 year in
10,000 healthy postmenopausal women is associated with 7 more instances of
coronary artery disease, 8 more strokes, 8 more pulmonary emboli, 8 more
invasive breast cancers, 5 fewer hip fractures, and 6 fewer colorectal
cancers.
Based on these data, the risks
and benefits of hormone replacement therapy must be assessed on an individual
basis for each patient.
Sublingual nitroglycerin has been the mainstay of treatment for angina
pectoris. Sublingual nitroglycerin can be used for
acute relief of angina and prophylactically before
activities that may precipitate angina. No evidence indicates that long-acting
nitrates improve survival in patients with coronary artery disease.
Beta-blockers are also used
for symptomatic relief of angina and prevention of ischemic events. They work by
reducing myocardial oxygen demand and by decreasing the heart rate and
myocardial contractility. Beta-blockers have been shown to reduce the rates of
mortality and morbidity following acute MI.
Long-acting heart rate–slowing
calcium channel blockers can be used to control anginal symptoms in patients with a contraindication to
beta-blockers and in those in whom symptomatic relief of angina cannot be
achieved with the use of beta-blockers, nitrates, or both. Avoid short-acting
dihydropyridine calcium channel blockers because they
have been shown to increase the risk of adverse cardiac
events.
Anginal symptoms in
patients with Prinzmetal angina can be treated with
calcium channel blockers with or without nitrates. In one study, supplemental
vitamin E added to a calcium channel blocker significantly reduced anginal symptoms among such patients.
In patients with syndrome X
and hypertension, ACE inhibitors may normalize thallium perfusion defects and
increase exercise capacity.
Surgical Care:
Revascularization therapy
(ie, coronary revascularization) can be considered in
patients with left main artery stenosis greater than
50%, 2- or 3-vessel disease and LV dysfunction (ejection fraction, <45%),
poor prognostic signs during noninvasive studies, or
severe symptoms despite maximum medical therapy. The 2 main coronary
revascularization procedures are percutaneous transluminal coronary angioplasty, with or without coronary
stenting, and coronary artery bypass
grafting.
Patients with 1- or 2-vessel
disease and normal LV
Patients with single-vessel
disease and normal ventricular function treated with percutaneous transluminal coronary
angioplasty show improved exercise tolerance and fewer episodes of angina
compared with those who receive medical treatment. However, no difference in the
frequency of MI or death has been shown between these two
groups.
Patients with significant left
main coronary artery disease, 2- or 3-vessel disease and LV dysfunction,
diabetes mellitus, or lesions anatomically unsuitable for percutaneous transluminal coronary
angioplasty have better results with coronary artery bypass grafting. The
overall operative mortality rate for coronary artery bypass grafting is
approximately 1.3%. The rate of graft patency 10 years after surgery is less
than 50% for vein grafting, although more than 90% of grafts using internal
mammary arteries are patent at 10 years. In recent years, interest has increased
regarding surgery without cardiopulmonary bypass (ie,
off-pump) in an attempt to avoid the morbidity associated with cardiopulmonary
bypass. A recent randomized study demonstrated that off-pump coronary surgery
was as safe as on-pump surgery and caused less myocardial damage. However, the
graft-patency rate was lower at 3 months in the off-pump group than in the
on-pump group.
Recently, laser transmyocardial revascularization has been used as an
experimental therapy for the treatment of severe, chronic, stable angina
refractory to medical or other therapies. This technique has been performed with
either an epicardial surgical technique or by a percutaneous approach. In both approaches, a series of transmural endomyocardial channels
are created to improve myocardial perfusion. The surgical transmyocardial revascularization technique has been
associated with symptomatic relief for end-stage chronic angina in the short
term. However, no published data address the long-term efficacy of surgical
transmyocardial revascularization. Nonetheless, this
technique appears to provide at least symptomatic relief for end-stage chronic
angina in the short term.
Diet: A diet low in
saturated fat and dietary cholesterol is the mainstay of the Step I and Step II
diet from the American Heart Association.
Activity: The level of
activity that aggravates anginal symptoms is different
for each patient. However, most patients with stable angina can avoid symptoms
during daily activities simply by reducing the speed of
activity.
MEDICATION
The goals of pharmacotherapy
are to reduce morbidity and to prevent complications.
Drug Category: Antiplatelet agents -- Prevent thrombus
formation by inhibiting platelet aggregation. Aspirin is proven beneficial in
primary and secondary prevention of coronary artery disease. In patients with
aspirin intolerance, use clopidogrel. Clopidogrel is also used in combination with aspirin after
coronary stent placement. Recently, clopidogrel use in
addition to aspirin has been shown to be significantly superior to aspirin alone
in patients with acute coronary syndrome without ST-segment elevation
MI.
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Drug Name
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Aspirin
(Bayer, Empirin, Anacin) -- Prevents platelet
aggregation by irreversible cyclooxygenase inhibition
with subsequent suppression of thromboxane A2.
Antiplatelet effect can last as long as 7 d.
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Adult Dose
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81-325 mg PO qd
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Pediatric Dose
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Not established
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Contraindications
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Documented
hypersensitivity; liver damage; hypoprothrombinemia;
vitamin K deficiency; bleeding disorders; asthma
Because of association with Reye syndrome, do not use in children (<16 y) with flu |
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Interactions
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Antacids
and urinary alkalinizers may decrease effects;
corticosteroids decrease salicylate serum levels;
anticoagulants may cause additive hypoprothrombinemic
effects and increased bleeding time; may antagonize uricosuric effects of probenecid
and increase toxicity of phenytoin and valproic acid; doses >2 g/d may potentiate
glucose-lowering effect of sulfonylurea drugs
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Pregnancy
|
D - Unsafe in pregnancy
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Precautions
|
May
cause transient decrease in renal function and aggravate chronic kidney disease;
avoid use in patients with severe anemia, history of
blood coagulation defects, or taking anticoagulants; adverse effects include
prolonged bleeding time, rhinitis, asthma, urticaria,
and exacerbation of gout; monitor BP, BUN, and uric acid level; consider
discontinuing 7 d before surgery
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|
Drug Name
|
Clopidogrel
(Plavix) -- Selectively inhibits ADP binding to
platelet receptor and subsequent ADP-mediated activation of GPIIb/IIIa complex, thereby inhibiting platelet aggregation.
Consider in patients with contraindication to aspirin.
|
|
Adult Dose
|
75 mg PO qd
|
|
Pediatric Dose
|
Not established
|
|
Contraindications
|
Documented
hypersensitivity; active pathological bleeding
|
|
Interactions
|
Naproxen
associated with increased occult GI blood loss; prolongs bleeding time; safety
of coadministration with warfarin not established
|
|
Pregnancy
|
C
- Safety for use during pregnancy has not been established.
|
|
Precautions
|
Caution
in patients at increased risk of bleeding from trauma, surgery, or other
pathological conditions; caution in patients with lesions with propensity to
bleed (eg, ulcers); adverse effects include rash,
diarrhea, purpura, GI
ulcers, neutropenia, and rare cases of agranulocytosis; consider discontinuing 7 d before
surgery
|
Drug Category:
Beta-adrenergic blocking agents -- Work by competing with endogenous
catecholamines for beta-adrenergic receptors. Reduce
myocardial oxygen consumption via several effects, including decrease in resting
and exercise heart rates and reductions in myocardial contractility and afterload. Classified as nonselective, beta-1 selective, and having intrinsic sympathomimetic effects.
|
Drug Name
|
Metoprolol
(Lopressor, Toprol XL) --
Selective beta1-adrenergic receptor blocker that decreases automaticity of
contractions. Is lipophilic and penetrates CNS.
|
|
Adult Dose
|
50-200 mg PO bid
|
|
Pediatric Dose
|
Not established
|
|
Contraindications
|
Documented
hypersensitivity; uncompensated CHF; bradycardia; asthma; cardiogenic
shock; AV conduction abnormalities
|
|
Interactions
|
Aluminum
salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may
decrease bioavailability and plasma levels, possibly resulting in decreased
pharmacologic effects; sparfloxacin, phenothiazines, astemizole,
calcium channel blockers, quinidine, flecainide, and contraceptives may increase toxicity; may
increase toxicity of digoxin, flecainide, clonidine,
epinephrine, nifedipine, prazosin, verapamil, and lidocaine
|
|
Pregnancy
|
B
- Usually safe but benefits must outweigh the risks.
|
|
Precautions
|
Beta-adrenergic
blockade may mask signs and symptoms of acute hypoglycemia and may decrease clinical signs of
hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism,
including thyroid storm; monitor patient closely and withdraw drug slowly;
during IV administration, carefully monitor BP, heart rate, and ECG; adverse effects include hypotension, decreased libido,
impotence, lethargy, depression, and decreased HDL;
may cause less bronchial tree and arterial smooth muscle
constriction
|
|
Drug Name
|
Atenolol
(Tenormin) -- Selectively blocks beta-1 receptors with
little or no effect on beta-2 receptors. Is hydrophilic and does not penetrate CNS.
|
|
Adult Dose
|
50-200 mg PO qd
|
|
Pediatric Dose
|
Not established
|
|
Contraindications
|
Documented
hypersensitivity; CHF; pulmonary edema; cardiogenic shock; AV
conduction abnormalities; heart block (without pacemaker)
|
|
Interactions
|
Aluminum
salts, barbiturates, calcium salts, cholestyramine,
NSAIDs, penicillins, and
rifampin may decrease effects; haloperidol, hydralazine, loop diuretics, and MAOIs may increase toxicity
|
|
Pregnancy
|
C
- Safety for use during pregnancy has not been established.
|
|
Precautions
|
Beta-adrenergic
blockade may hide symptoms of acute hypoglycemia and
mask signs of hyperthyroidism; abrupt withdrawal may exacerbate symptoms of
hyperthyroidism and cause thyroid storm; monitor patients closely and withdraw
drug slowly; adverse effects include bradycardia,
hypotension, decreased libido, impotence, and decreased HDL; beta1-selective blockers may cause less bronchial tree
and arterial smooth muscle constriction; titrate dose carefully to level of
patient tolerance and effectiveness
|
|
Drug Name
|
Propranolol
(Inderal) -- Nonselective
beta-blocker that is lipophilic (penetrates CNS).
Although generally short-acting agent, long-acting preparations also available.
|
|
Adult Dose
|
IR:
40-160 mg PO bid
SR: 60-320 mg |
|
Pediatric Dose
|
Not established
|
|
Contraindications
|
Documented
hypersensitivity; history of bronchospasm;
uncompensated CHF; bradycardia; cardiogenic shock; AV
conduction abnormalities
|
|
Interactions
|
Aluminum
salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may
decrease effects; calcium channel blockers, cimetidine, loop diuretics, and MAOIs may increase toxicity; may increase toxicity of hydralazine, haloperidol, benzodiazepines, and phenothiazines
|
|
Pregnancy
|
C
- Safety for use during pregnancy has not been established.
|
|
Precautions
|
Beta-adrenergic
blockade may mask signs of acute hypoglycemia and
hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism,
including thyroid storm; withdraw drug slowly and monitor closely; adverse
effects include bronchial constriction, Raynaud
phenomenon, hypotension, decreased libido, impotence, lethargy, depression, and
decreased HDL; caution in Wolff-Parkinson-White
syndrome and renal or hepatic dysfunction
|
Drug Category: Calcium
channel blockers -- Reduce transmembrane flux of
calcium via calcium channels. Cause smooth muscle relaxation, resulting in
peripheral arterial vasodilation and afterload reduction. Indicated when symptoms persist despite
treatment with beta-blockers or when beta-blockers are contraindicated. Also indicated in patients with Prinzmetal
angina with or without nitrates.
|
Drug Name
|
Amlodipine
(Norvasc) -- During depolarization, inhibits calcium
ions from entering slow channels and voltage-sensitive areas of vascular smooth
muscle and myocardium.
|
|
Adult Dose
|
5-10 mg PO qd
|
|
Pediatric Dose
|
Not established
|
|
Contraindications
|
Documented
hypersensitivity; severe CHF; sick sinus syndrome;
second- or third-degree AV block; hypotension (<
|
|
Interactions
|
Fentanyl
may increase hypotensive effects; may increase
cyclosporine levels; H2 blockers (eg, cimetidine) may increase toxic effects
|
|
Pregnancy
|
C
- Safety for use during pregnancy has not been established.
|
|
Precautions
|
Severe
aortic stenosis, CHF,
hepatic dysfunction; adverse effects include headache, edema, flushing, palpitation, drowsiness, and
fatigue
|
|
Drug Name
|
Diltiazem
(Cardizem CD, Dilacor) --
During depolarization, inhibits calcium ions from entering slow channels and
voltage-sensitive areas of vascular smooth muscle and myocardium.
|
|
Adult Dose
|
IR:
120-360 mg PO divided tid/qid
SR: 120-480 mg |
|
Pediatric Dose
|
Not established
|
|
Contraindications
|
Documented
hypersensitivity; severe CHF; sick sinus syndrome;
second- or third-degree AV block; hypotension (<
|
|
Interactions
|
May
increase carbamazepine, digoxin, cyclosporine, and theophylline levels; when administered with amiodarone, may cause bradycardia
and decrease in cardiac output; when given with beta-blockers may increase
cardiac depression; cimetidine may increase levels
|
|
Pregnancy
|
C
- Safety for use during pregnancy has not been established.
|
|
Precautions
|
Caution
in impaired renal or hepatic function; may increase LFT levels, and hepatic injury may occur; adverse effects
include constipation, AV conduction block, worsening of heart failure,
peripheral edema, bradycardia, and AV dissociation
|
|
Drug Name
|
Verapamil
(Calan, Covera) -- During
depolarization, inhibits calcium ion from entering slow channels or
voltage-sensitive areas of vascular smooth muscle and myocardium.
|
|
Adult Dose
|
IR:
80-120 mg PO tid/qid
SR: 120-240 mg |
|
Pediatric Dose
|
Not established
|
|
Contraindications
|
Documented
hypersensitivity; severe CHF; sick sinus syndrome;
second- or third-degree AV block; hypotension (<
|
|
Interactions
|
May
increase carbamazepine, digoxin, theophylline, and
cyclosporine levels; amiodarone can cause bradycardia and decrease in cardiac output; when
administered concurrently with beta-blockers may increase cardiac depression;
cimetidine may increase levels
|
|
Pregnancy
|
C
- Safety for use during pregnancy has not been established.
|
|
Precautions
|
Hepatocellular
injury may occur; transient elevations of transaminases with and without concomitant elevations in
alkaline phosphatase and bilirubin have occurred (elevations have been transient and
may disappear with continued treatment); monitor liver function periodically;
adverse effects include constipation, AV dissociation, worsening heart failure,
bradycardia, negative inotropism, and hypotension
|
Drug Category:
Short-acting nitroglycerins -- Suitable for
immediate relief of exertional or rest angina. Can also be used for prophylaxis several minutes before planned
exercise to avoid angina. Reduce myocardial oxygen demand by reduction of
LV
|
Drug Name
|
Nitroglycerin
(Nitrostat, Nitro-bid, Nitrol) -- Causes relaxation of vascular smooth muscle by
stimulating intracellular cyclic GMP production.
Result is decrease in BP.
|
|
Adult Dose
|
0.3-0.6
mg SL prn
0.4 mg metered-dose spray 0.1-0.8 mg/h patch TD qd |
|
Pediatric Dose
|
Not established
|
|
Contraindications
|
Documented
hypersensitivity; severe anemia; shock; postural
hypotension; head trauma; closed-angle glaucoma; cerebral hemorrhage; hypertrophic obstructive cardiomyopathy
|
|
Interactions
|
Concurrent
sildenafil (Viagra) may cause severe hypotension and
death; aspirin may increase serum concentrations; calcium channel blockers may
cause markedly symptomatic orthostatic hypotension (dose adjustment of either
agent may be necessary)
|
|
Pregnancy
|
C
- Safety for use during pregnancy has not been established.
|
|
Precautions
|
Caution
in coronary artery disease and low systolic BP; adverse effects include
hypotension, flushing, headache, light-headedness, and tolerance (8- to 12-h
nitrate-free interval is most effective method to prevent development of
tolerance); high IV doses may cause methemoglobinemia,
heparin resistance, and ethanol intoxication; ischemia may worsen upon
withdrawal
|
Drug Category: Long-acting
nitroglycerins -- Reduce LV preload and afterload by venous and arterial dilation, which
subsequently reduces myocardial oxygen consumption and relieves angina. Also
cause dilation of epicardial coronary arteries, which
is beneficial in patients with coronary spasm. In addition, nitroglycerin has antithrombotic and antiplatelet effects in patients with angina pectoris. No
evidence suggests that nitrates improve survival or slow progression of coronary
artery disease.
|
Drug Name
|
Isosorbide
(Isordil, ISMO) -- Relaxes
vascular smooth muscle by stimulating intracellular cyclic GMP. Decreases
|
|
Adult Dose
|
Isosorbide
dinitrate:
2.5-10 mg SL prn IR 10-30 mg PO bid/tid SR 80-120 mg PO qd IR Isosorbide mononitrate: 10-20 mg PO bid SR 30-120 mg |
|
Pediatric Dose
|
Not established
|
|
Contraindications
|
Documented
hypersensitivity; severe anemia; closed-angle
glaucoma; postural hypotension; head trauma; cerebral hemorrhage
|
|
Interactions
|
Alcohol
may cause severe hypotension and cardiovascular collapse; aspirin may increase
serum concentrations and actions; calcium channel blockers may increase
symptomatic orthostatic hypotension (adjust dose of either agent); may decrease
effects of heparin
|
|
Pregnancy
|
C
- Safety for use during pregnancy has not been established.
|
|
Precautions
|
Tolerance
to vascular and antianginal effects of nitrates may
develop; minimize tolerance by using smallest effective dose or pulse therapy
(intermittent dosing) or by alternating with other coronary vasodilators (take
last daily dose of short-acting agent no later than 7 pm); caution when
administering to patients with glaucoma
|
Drug Category: Angiotensin-converting enzyme inhibitors
-- Recently shown to reduce rates of death, MI, stroke, and need for
revascularization procedures in patients with coronary artery disease or
diabetes mellitus and at least one other cardiovascular risk factor,
irrespective of the presence of hypertension or heart failure.
|
Drug Name
|
Ramipril
(Altace) -- Prevents conversion of angiotensin I to angiotensin II, a
potent vasoconstrictor, resulting in lower aldosterone
secretion.
|
|
Adult Dose
|
2.5-5
mg
|
|
Pediatric Dose
|
Not established
|
|
Contraindications
|
Documented
hypersensitivity; history of angioedema
|
|
Interactions
|
May
increase digoxin, lithium, and allopurinol levels; probenecid may
increase levels; coadministration with diuretics
increases hypotensive effects; NSAIDs may reduce hypotensive
effects
|
|
Pregnancy
|
C
- Safety for use during pregnancy has not been established.
|
|
Precautions
|
Category
D in second and third trimesters of pregnancy; adverse effects include
persistent cough, angioedema, hypotension, and prerenal azotemia; caution in
renal impairment, valvular stenosis, or severe CHF
|
Drug Category:
Anti-ischemic agents, miscellaneous -- Ranolazine elicits action unlike beta-blockers, calcium
antagonists, or nitrates. It does not affect hemodynamics or contractile and conduction
parameters.
|
Drug Name
|
Ranolazine
(Ranexa) -- Cardioselective
anti-ischemic agent (piperazine derivative) that
partially inhibits fatty acid oxidation. Also inhibits late sodium current into
myocardial cells and prolongs QTc interval. Indicated
for chronic angina unresponsive to other antianginal
treatments. Used in combination with amlodipine,
beta-blockers, or nitrates. Unlike beta-blockers, calcium channel blockers, and
nitrates, does not reduce blood pressure or heart rate. Effect on angina rate or
exercise tolerance appears to be smaller in women than in men. Absorption is highly variable but unaffected by food.
|
|
Adult Dose
|
500
mg PO bid initially; if necessary, may increase to 1000 mg
|
|
Pediatric Dose
|
Not established
|
|
Contraindications
|
Documented
hypersensitivity; preexisting QT prolongation; hepatic
impairment (Child-Pugh class A [mild], B [moderate], or C [severe]);
QT-prolonging drugs (see Interactions); potent or moderate CYP4503A inhibitors
(eg, ketoconazole, diltiazem)
|
|
Interactions
|
CYP4503A
and P-gp substrate; potent CYP3A inhibitors (eg, ketoconazole at 200 mg bid)
increase levels approximately 3.2-fold, moderate CYP3A inhibitors (eg, diltiazem at 180-360 mg/d)
increase levels approximately 1.8- to 2.3-fold, and verapamil (a CYP3A and P-gp
inhibitor) increases levels approximately 2-fold; caution with other P-gp inhibitors (eg, ritonavir, cyclosporine); toxicity may occur when coadministered with other drugs that increase QTc interval (eg, class I and III
antiarrhythmic agents, certain macrolide and quinolone
antibiotics, phenothiazines, TCAs)
Inhibits CYP4503A, CYP 4502D6, and P-gp; may increase plasma levels of digoxin, simvastatin, dextromethorphan, TCAs, and antipsychotics |
|
Pregnancy
|
C
- Safety for use during pregnancy has not been established.
|
|
Precautions
|
Causes
dose-related QTc-interval prolongation (obtain
baseline and follow-up ECGs to monitor for torsades de pointes and potential for sudden death; mild and
moderate hepatic impairment increases QTc interval
compared with normal hepatic function at same plasma level; increases blood
pressure by approximately
|
FOLLOW-UP
Deterrence/Prevention:
Coronary atherosclerosis is
the main preventable cause of mortality in the United
States
Smoking cessation is the
single most effective preventive intervention to reduce coronary atherosclerosis
prevalence. It has been associated with a coronary artery disease reduction of
7-47% in primary prevention settings.
Aggressive treatment of
diabetes mellitus, hypertension, LV
The most important recent
development in coronary atherosclerosis risk modification is the introduction of
inhibitors of beta-hydroxy-beta-methylglutaryl
coenzyme A reductase. Reductions of total and LDL cholesterol levels by 25% and 35%, respectively, can
achieve a similar reduction in rates of total and coronary mortality, MI, and
need for coronary revascularization.
Complications:
Complications of angina
pectoris include unstable angina, MI, and death.
Prognosis:
Important prognostic
indicators in patients with angina pectoris include LV
Critical lesions of left main
and proximal left anterior descending coronary arteries are associated with a
greater risk. Mortality rates are also directly associated with the number of
epicardial arteries involved.
Unstable angina, recent MI, or
both is a sign of atherosclerotic plaque instability, which is a strong
predictor of increased risk of short-term coronary events.
A number of signs during noninvasive testing are predictive of a higher risk of
coronary events, including ST-segment depression of more than
2 mm at a low workload,
ST-segment depression that persists for more than 5 minutes after termination of
exercise, and failure of blood pressure to rise or an actual drop in blood
pressure.
Patients who continue to smoke
after an MI have a 22-47% increased risk of reinfarction and death.
In general, Prinzmetal angina and syndrome X are associated with
excellent long-term prognoses.
Patient Education:
Educating patients about the
benefits of smoking cessation, a low-cholesterol diet, physical activity, and
periodic screening for diabetes mellitus and hypertension is the prime component
of a long-term management plan.
For excellent patient
education resources, visit eMedicine's Circulatory
Problems Center, Cholesterol Center, Heart Center, and Statins Center. Also, see eMedicine's patient education articles Angina Pectoris, High
Cholesterol, Understanding Your Cholesterol Level, Lifestyle Cholesterol
Management, Understanding Cholesterol-Lowering Medications, Chest Pain, Coronary
Heart Disease, and Heart Attack.
MISCELLANEOUS
Medical/Legal Pitfalls:
In patients with stable angina
pectoris, even the most carefully performed history and physical examination
have limitations. Classification of these patients solely on the basis of
history and physical examination findings may lead to serious mistakes. Some
type of stress testing is usually indicated to confirm the diagnosis and quantitate the severity of ischemia.
In women, elderly persons, and
diabetic patients, coronary artery disease may manifest with atypical
presentations other than angina pectoris, such as silent ischemia or infarction.
Physicians should use a careful approach when evaluating these
patients.
·
LITERATURE
·
Allen KB,
Dowling
RD
·
Ambrosio G,
Betocchi S, Pace L, et al: Prolonged impairment of
regional contractile function after resolution of exercise-induced angina.
Evidence of myocardial stunning in patients with coronary artery disease.
Circulation 1996 Nov 15;
94(10): 2455-64.
·
Cannon CP, Braunwald E, McCabe CH, et al: Intensive versus moderate
lipid lowering with statins after acute coronary
syndromes. N Engl J
Med 2004 Apr 8; 350(15): 1495-504.
·
Gibbons RJ,
Balady GJ, Bricker JT, et
al: ACC/AHA 2002 guideline update for exercise testing: summary article: a
report of the American College of Cardiology/American Heart Association Task
Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing
Guidelines). Circulation 2002 Oct 1; 106(14): 1883-92.
·
Grundy SM, Cleeman JI, Merz CN, et al: Implications of
recent clinical trials for the National Cholesterol Education Program Adult
Treatment Panel III Guidelines. J Am Coll Cardiol 2004 Aug 4; 44(3): 720-32.
·
Lanza
GA
·
National
Cholesterol Education Program: Executive Summary of The
Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment
of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001 May 16; 285(19): 2486-97.
·
Piatti P,
Fragasso G, Monti LD, et al:
Endothelial and metabolic characteristics of patients with angina and angiographically normal coronary arteries: comparison with
subjects with insulin resistance syndrome and normal controls. J Am Coll Cardiol 1999 Nov 1; 34(5):
1452-60.
·
Scandinavian
Simvastatin Survival Study Group: Randomised trial of
cholesterol lowering in 4444 patients with coronary heart disease: the
Scandinavian Simvastatin Survival Study (4S). Lancet
1994 Nov 19; 344(8934): 1383-9.
·
Shepherd J,
Blauw GJ, Murphy MB
·
Yusuf S, Zhao F,
Mehta SR, et al: Effects of clopidogrel in addition to
aspirin in patients with acute coronary syndromes without ST-segment elevation.
N Engl J Med 2001 Aug
16; 345(7): 494-502.
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