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Evaluation of Patients With Chest Pain and Normal Coronary Angiograms
Leonard Schwartz, MD;
Martial G. Bourassa, MD
Arch Intern Med. 2001;161:1825-1833.
INTRODUCTION
Over 1 million coronary angiograms are performed in North America annually,
and a significant number are interpreted as normal. In the Coronary Artery
Surgery Study Registry of the 1970s, normal angiograms were found in 19% of
patients,1 and the prevalence may not have
changed in the current era of more sophisticated noninvasive testing. A recent
study found that 19% of patients had no arteriographic evidence of disease.2 For women selected for angiography, a normal result
is found 3 times more frequently than for men.1-2
Further elucidation of the diagnosis in a patient population of this size
is of obvious importance. However, correctly investigating and managing the
treatment for such patients can be challenging. On the one hand, a potentially
serious, yet manageable condition must not be overlooked. On the other hand,
excessive anxiety over a problem that may not exist or may not be serious
must not be created. Therefore, the finding of a normal angiogram in a patient
with chronic chest pain in whom coronary disease was suspected prior to the
procedure must lead to a thorough investigation (Figure 1). The pathophysiologic features, investigation, and treatment
of chest pain in these patients are the subject of this review.
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Figure 1. Decision algorithm for a patient
presenting with chest pain and a purported normal coronary angiogram.
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ARE THE CORONARY ANGIOGRAMS TRULY NORMAL?
In an important minority of patients, definite coronary abnormalities
may account for the presence of angina pectoris and myocardial ischemia in
spite of what may have been interpreted initially as a normal coronary angiogram.
Possibilities include large-vessel coronary vasospasm, missed coronary artery
lesions, congenital coronary anomalies, and myocardial bridges.
Large-Vessel Coronary Vasospasm
There seems to be less interest today in large-vessel coronary vasospasm
than there was in the 1960s and early 1970s. The reason for this may be a
true decrease in prevalence as a result of more attention to coronary risk
factors or the more liberal use of calcium channel blockers. It is also possible,
however, that cases are going undetected.3
Angina due to vasospasm often occurs at rest, and good exercise tolerance
is maintained. Thus, the history differs from that of classic Heberden angina
and may be dismissed as not "organic."
Ergonovine testing was very popular in the late 1970s and early 1980s,4-7 but today
it is rarely performed. It has proven to be very useful in the diagnosis and
care of patients with possible spasm and has enhanced our knowledge of the
pathophysiologic mechanisms of myocardial ischemia. Two large series established
the safety and utility of the test.8-9
Bertrand et al8 performed it on a wide spectrum
of patients including a large subset with fixed coronary disease and did not
encounter serious complications. The series by Harding et al9
included more than 3000 patients with normal or near normal coronary angiograms;
complications occurred in only 11 patients (0.37%) and there were no deaths.
A positive test result requires findings of a segmental reversible narrowing
of at least a 75% diameter stenosis and chest pain. An example of angiographically
documented spasm induced by the administration of 0.25 mg of intravenous ergonovine
maleate is shown in Figure 2. In
controls, up to an 18% diffuse diameter reduction can occur without ST-segment
shift or chest pain.10 If there is no chest
pain, one is less certain about the diagnosis. Conversely, chest pain without
angiographic coronary spasm does not constitute a positive test result. Patients
with esophageal disease can experience chest pain with the administration
of intravenous ergonovine.11 With these criteria
for a positive test result (ie, chest pain and angiographic spasm) ergonovine
provocation has excellent predictive accuracy for the diagnosis of coronary
spasm with a sensitivity of 91% to 100% and a specificity of 93% to 96%.4-7 It is
safe and inexpensive, and in patients with possible coronary vasospasm, it
is important to establish the diagnosis for at least 2 reasons. First, coronary
vasospasm is a common cause of sudden death in patients with structurally
normal hearts, and the risk can be reduced with appropriate calcium channel
blocker therapy.12 Second, there are therapeutic
implications. ß-Blockers may be ineffective and possibly even detrimental
in patients with vasospasm,13 presumably by
unmasking  -adrenergic vasoconstriction. Calcium channel blocking drugs
are the pharmacological approach of choice, and in patients with refractory
vasospasm, more so than in patients with fixed coronary disease, therapy with
a combination of calcium channel blocking drugs (for example, diltiazem and
nifedipine) may be effective when a single agent has failed.14
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Figure 2. A, Right coronary angiogram in
the 60° left anterior oblique view with mild midvessel narrowing. B, Severe
midvessel spasm (arrow) immediately following the administration of 0.25 mg
of intravenous ergonovine maleate.
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Missed Coronary Artery Lesions
The introduction of selective coronary angiography by Sones and Shirey15 represents one of the major advances in the management
of ischemic heart disease. Angiographic findings have been consistent and
reliable in predicting mortality.16 Relatively
modest angiographic progression is a strong independent predictor of coronary
events.17 Coronary angiography permits a safe,
rapid, and cost-effective method of visualizing the entire large and medium
vessel coronary tree.
However, coronary angiography has limitations and pitfalls. Angiographic
autopsy discrepancies were the subject of studies in the early 1970s.18-19 Later, Glagov et al20
clarified that one of the mechanisms for the discrepancy was because compensatory
enlargement of atherosclerotic coronary arteries may keep pace with plaque
growth and maintain vessel lumen. Over the last 20 years, intravascular ultrasound
(IVUS) and more critically reviewed angiography have permitted the identification
of certain troublesome angiographic lesions and patterns that may lead to
the erroneous conclusion that an angiogram is normal. These include the following:
Diffuse Disease
Diffuse disease can reduce coronary flow reserve and cause angina; yet
the lumen can remain constant, be apparently preserved, and be misinterpreted
as an inherently small lumen artery. Nissen and colleagues21
found that two thirds of angiographically normal segments were abnormal on
IVUS, and one third of these showed diffuse concentric disease. Diffuse disease
should be suspected when reviewing an angiogram if there is any irregularity
or if the ongoing branches are larger in diameter than the proximal arteries. Figure 3 shows a smooth left main coronary
artery, which, however, is of smaller diameter than either of its branches,
and IVUS confirmed diffuse left main stem disease.
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Figure 3. A, Left coronary angiogram in
a 30° right anterior oblique, 30° cranial projection demonstrating
a diffusely narrowed left main coronary artery (arrow) with a diameter smaller
than either the left anterior descending artery or the circumflex artery.
B, Intravascular ultrasound image of the left main coronary artery (arrow)
demonstrating a 61% area stenosis (2.9F, 30-MHz Ultracross Catheter, Boston
Scientific Corporation, Boston, Mass). Reproduced with the permission of Canadian Journal of Cardiology (1999;15:297-302).
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Eccentric Plaques
Intravascular ultrasound studies have also shown that eccentric plaques
may go undetected in angiographic studies.21
Such lesions may only lighten the contrast column without apparent diameter
reduction if the slit is viewed in its widest diameter.
Flush Occlusions
Flush occlusions may go undetected unless all segments of the myocardium
are reviewed for matching blood supply. They may also be missed if longer
cinecoronary angiography runs have not been performed to permit sufficient
time for distal segments to opacify in a retrograde fashion by collaterals.
Vessel Foreshortening
It may be difficult to visualize some foreshortened segments, which
are sometimes surprisingly long. When such segments are identified they can
usually be "unforeshortened" with unconventional oblique angulations or continuous
rotational views.22
Aorto-ostial Lesions
Aorto-ostial lesions can exist alone and can represent aortic rather
than coronary disease. The tendency to use smaller French-size diagnostic
catheters may result in their passage through and beyond an ostial lesion
with failure to opacify the diseased segment. When in doubt, sinus flushes
should be performed.
Branch Ostial Lesions
Branch ostial lesions can be difficult to detect and may represent a
challenge to identify. Atherosclerosis has a propensity for bifurcation locations,
possibly because of high sheer stress. Right coronary artery branches at the
crux and proximal left anterior descending (LAD) branches are notoriously
difficult to visualize and ostial lesions of these branches may be overlooked.
Overlapping Side Branches
Overlapping side branches on occasion may obscure a field of interest,
and multiple oblique views may be required. Figure 4 illustrates such a case.
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Figure 4. A, Left coronary angiogram in
a 50° left anterior oblique, 30° cranial projection (arrow). B, Left
coronary angiogram in a 30° right anterior oblique, 30° caudal projection
(arrow). C, Localized left anterior descending artery stenosis (arrows; inset,
magnified section) is shown in a 30° right anterior oblique, 80° caudal
projection. The lesion is located just beyond the origin of a septal perforator
that hides the lesions in other views (A and B).
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Disease of the Left Main Coronary Artery
Disease of the left main coronary artery can be underestimated or go
totally undetected.23 The greatest discrepancy
between angiographic findings and pathologic features occurs in left main
stem disease.24 The study by Glagov et al20 was based on an examination of the left main coronary
artery. On average, it is less than 1 cm long, arises slightly posteriorly,
and the true ostium can be identified only in a left anterior oblique view.
It then courses anteriorly and inferiorly and is least foreshortened in a
straight or slightly angulated anteroposterior view. A combination of these
views may be required to exclude disease.
When the angiograms have been read as normal and yet the clinician suspects
(based on a classic history or documented ischemia) that a significant stenosis
may have gone undetected, then further investigation should be considered.
The potential usefulness of IVUS imaging is shown in Figure 5. Coronary angiography in this case was performed because
of unstable angina and continued rest pain. On first examination, the angiogram
was read as normal. However, on review there were 3 contentious areas that
were clarified with IVUS imaging, and the final diagnosis was moderate coronary
atherosclerosis, possibly with superimposed coronary spasm. Physiological
assessment of borderline or angiographically obscure lesions or segments can
also be performed using Doppler flow or pressure wires and pharmacological
coronary arteriolar vasodilation (usually with the administration of intracoronary
adenosine) to measure coronary flow reserve.25
This has proven to be reliable in longitudinal studies in which coronary angioplasty
was performed or withheld based on flow reserve measurements.26
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Figure 5. Left coronary angiogram in a 60°
left anterior oblique, 30° caudal projection and the intravascular ultrasound
images of 3 segments. A, Ultrasound image of the mid–left anterior descending
artery just beyond the origin of the diagonal branch (arrow) showing an eccentric
plaque with a 47% area and 27% diameter stenosis. B, Ultrasound image of the
proximal left anterior descending artery (arrow) showing a fibrous eccentric
plaque with a 51% diameter and 30% area stenosis. The angiogram shows a lighter
dye column in this segment. C, Origin of the diagonal branch with an apparent
angiographic narrowing (arrow) but patent on intravascular ultrasound imaging
(3.2F, 30-MHz, Ultracross Catheter, Boston Scientific Corporation, Boston,
Mass).
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It is important clinically to detect mild to moderate atherosclerotic
lesions on a coronary angiogram for at least 2 reasons. First, it has been
clearly shown that it is often the mild or moderate lesions that are the most
vulnerable to plaque rupture and account for up to two thirds of the cases
of acute coronary syndromes.27-28
The milder lesions are often softer, lipid-rich plaques and more prone to
disruption. Angiography cannot predict future sites of coronary occlusion,
but a recent study suggested that IVUS may have this potential. The results
of an initial baseline IVUS and angiogram with a second angiogram triggered
by a clinical event showed that large eccentric plaques with echolucent zones
had an increased risk of producing a subsequent acute coronary event even
though the lumen was intact at the initial study.29
Second, serial angiographic follow-up studies in patients with completely
normal coronary arteries indicate that new development of atherosclerosis
over a 4- to 5-year period is very unusual, whereas patients with mild coronary
atherosclerosis usually show a rate of disease progression that is not notably
different from that of patients with significant coronary artery disease.30-31
Congenital Coronary Anomalies
There are other instances where the findings of an angiographic study
may be incorrectly read as normal. Congenital anomalies of the coronary arteries
may be overlooked and certain variations may result in ischemia in the absence
of coronary atherosclerosis. The importance of their detection is also underlined
by their association with sudden death that often occurs in younger people.32 The most important anomaly for this review is the
origin of the circumflex artery arising from the right coronary artery or
right sinus of Valsalva. Its relevance relates to 3 factors: first, it is
the most frequent anomaly, with a prevalence in angiographic findings of 0.45%33; second, it is the only one in which the anomalous
vessel is associated with a greater frequency of disease than is the case
for nonanomalous arteries32; third, it can
easily go undetected if one mistakes an intermediate branch or a diagonal
branch for the circumflex artery or assumes that it is congenitally absent.
Other anomalies are less frequent and less likely to be missed; however, they
may be associated with myocardial ischemia in the absence of atherosclerotic
narrowing. These include the left coronary artery arising from the right sinus
of Valsalva or the right coronary artery proper and the right coronary artery
arising from the left sinus of Valsalva.33
Congenital large coronary arteriovenous or cardiopulmonary fistulae are usually
obvious, but subtle ones can be missed as can arteriocameral fistulae connecting
coronary arteries with cardiac chambers.34
They may cause ischemia by a "steal" phenomenon and are suggested when there
is rapid opacification of the left ventricular chamber during coronary angiography.
Myocardial Bridges
Finally, patients with myocardial bridges but with otherwise normal
coronary angiograms may have angina. These bridges consist of segments of
the LAD artery that course from their subepicardial surface location into
the myocardial tissue and then back out. Transient systolic constriction occurs,
which resolves during diastole. The overall incidence at coronary angiography
is approximately 1%. Chest pain is frequent, and there is electrocardiographic
and metabolic evidence that if there is greater than a 75% diameter systolic
compression, ischemia may occur during tachycardia.35
Flow reduction may even extend into diastole if the compression is severe.36 Surgical decompression is effective treatment,37 and more recently, stent implantation in 3 patients
with persistent and severe angina normalized hemodynamic abnormalities and
coronary flow reserve and resulted in clinical improvement.38
IS THERE A NONCORONARY CARDIAC CAUSE OF ISCHEMIC CHEST PAIN?
Several cardiovascular diseases can contribute to or cause myocardial
ischemia in the absence of coronary disease. The most important are valvular
heart disease, cardiomyopathy, and hypertension. Valvular heart disease, particularly
aortic stenosis and aortic regurgitation, is associated with impaired coronary
flow reserve39 and increased myocardial oxygen
requirements, and angina is a frequent presenting symptom. Angina may occur
with all forms of cardiomyopathy but most frequently occurs in the hypertrophic
syndromes in which myocardial oxygen supply balance is particularly tenuous.40 The importance of this syndrome for this review is
that, clinically, the diagnosis is often missed. The diagnosis is made on
the basis of the echocardiogram, but if the disease is not suspected, echocardiography
may not be performed. Chest pain is also a frequent complaint in patients
with dilated cardiomyopathy, and it is usually ischemic in origin.41 The most frequent entity associated with chest pain
and normal coronary angiograms is hypertension. In one study of 41 patients
with hypertension and normal coronary angiograms, 15 (37%) of the 41 patients
had chest pain.42 The suggested mechanisms
included increased left ventricular mass, medial arteriolar hypertrophy,43 diastolic dysfunction, and impaired coronary vasodilation.44
IS THERE A NONCARDIAC CAUSE OF CHEST PAIN?
Almost any condition can mimic angina pectoris. Pain characteristics
may be helpful in excluding other syndromes. However, even after a careful
history, 2 areas remain diagnostic challenges: the distal esophagus and the
musculoskeletal system.
The Distal Esophagus
There are several reasons why esophageal pain may be mistaken for cardiac
pain. The distal esophagus and the heart share a common afferent nerve supply;
hence, pain location and radiation may be identical.45
Certain types of exertion, particularly those that increase intra-abdominal
pressure, may precipitate esophageal pain. Therapy with nitroglycerine may
relieve esophageal spasm. The reproduction of chest pain with intravenous
ergonovine, which was thought to be pathognomonic of coronary spasm, has now
been shown to occur with esophageal motor disorders.11
In addition, patients with documented coronary artery spasm often have esophageal
spasm as well, suggesting a unifying mechanism, and both can be provoked by
hyperventilation.46 Cardiac and esophageal
disease also share risk factors such as obesity and smoking. Acid reflux may
reduce the angina threshold in patients with established coronary disease.47
The causes of esophageal pain are reflux esophagitis, esophageal motility
disorders consisting of high-amplitude, long-duration contractions (also called
spasm), and hernia incarceration. The classic esophageal pain syndrome is
easily identifiable: it is felt as a heartburn moving toward the pharynx,
sometimes accompanied by pharyngeal burning and dysphagia, and it is aggravated
by the supine position, particularly nocturnally. The diagnosis can be confirmed
with a barium swallow and endoscopy. In more difficult cases, manometry, acid
perfusion studies, ambulatory 24-hour pH monitoring, and provocative tests
may be necessary. If the patient's typical pain syndrome can be reproduced
with the administration of either intravenous ergometrine or intravenous methacholine
chloride, with simultaneous abnormalities in manometric measurements such
as high-amplitude and long-duration contractions, or with acid perfusion of
0.1-M hydrochloric acid into the midesophagus, then the diagnosis of an esophageal
rather than cardiac disorder is fairly certain.
Chest Pain of Musculoskeletal Origin
The thoracic compartment is a complex structure consisting of 24 ribs,
12 vertebrae, 12 chondrosternal joints, 14 costochondral joints (these 26,
all synchondroses), in total 38 costovertebral and costotransverse joints
(all synovial lined), 2 sternoclavicular joints, 1 manubriosternal joint,
and 1 xiphisternal joint as well as intercostal muscles, ligaments, tendons,
and a complex nerve supply. In a consecutive series of patients presenting
to cardiologists with suggestive cardiac pain, 10% had a costosternal syndrome.48
Given the elaborate anatomy described above, perhaps it is surprising
that chest wall pain is not even more common. Chest wall pain differs from
other causes of chest pain by the presence of findings on musculoskeletal
examination and physical examination and provocation of the pain by simple
maneuvers whereby the diagnosis can often be made at the bedside without the
need for further testing. On occasion, ancillary investigations such as rib
radiography and cervical and thoracic spine radiography, computed tomography,
and magnetic resonance imaging may be helpful.
Pain arising from the shoulder and cervical and thoracic spine may be
referred to the chest wall with the same nerve supply and may be associated
with deep or myofascial tenderness.49 The C5-C6
and C6-C7 syndromes are not only associated with tenderness on palpation of
the anterolateral corners of the bordering vertebrae, but also with points
of referred tenderness over the anterior chest.50
Costochondritis is a self-limited inflammatory disorder of unknown etiology
that may recur. Because it most often affects the upper costal cartilages,
it is often mistaken for cardiac disease. Diffuse tenderness invariably occurs
over the involved costochondral or costosternal joints without swelling, and
the pain can usually be reproduced by palpation of the chest wall.48
The fibrositis syndrome (or fibromyalgia or the myofascial syndrome)
is a poorly understood disorder that occurs much more frequently in women
than in men and is a common cause of chest wall pain.49
There is no objective evidence of inflammation, and there is unrestricted
movement of joints. It is characterized by tender "trigger" points that may
cause pain at a distant site. Although chest pain in this syndrome often occurs
with exertion, it is almost always with the use of the arms rather than the
legs, in contrast to angina in which the opposite is true.
CHEST PAIN WITH A BROAD SPECTRUM OF POSTULATED MECHANISMS: SYNDROME
X
The term syndrome X arose from a publication
by Arbogast and Bourassa51 in 1973. They described
10 patients (whom they called group X) who had normal
coronary angiograms but had chest pain typical of angina. They compared these
patients to 11 patients with coronary disease and angina. The response to
rapid atrial pacing of the patients with syndrome X was normal with increased
cardiac index, decreased left ventricular end diastolic pressure, and an improved
ventricular function, in contrast to the patients with coronary disease whose
ventricular function deteriorated. Both groups behaved similarly metabolically,
either decreasing lactate extraction or frankly producing lactate. In spite
of this, a diagnosis of true ischemia was questioned by the authors and has
been questioned since by others who have shown, in contrast to the study of
Arbogast and Bourassa,51 a nonischemic pattern
of myocardial substrate uptake and utilization both at rest and in response
to pacing.52 Follow-up observations of these
patients suggested a benign condition compared with other syndromes causing
ischemia.53
More than 20 years after the initial publication, little more definitive
information is known about patients with this syndrome. Many theories of cardiac
syndrome X have evolved through the years, some of which will be reviewed
here. One theory will not apply to all patients, and the theories overlap.
Much is speculative because this entity seems to defy scientific testing.
Impaired Coronary Flow Reserve
Early on, it was postulated that coronary flow reserve was impaired
in syndrome X, and in the absence of large-vessel disease, it was thought
that the abnormality resided at an arteriolar level. Normally, coronary flow
increases by severalfold with exercise, and this can be measured invasively
with Doppler velocity flow wires or noninvasively with positron emission tomography.
In a series of well-selected patients with syndrome X, the coronary flow reserve
ratio was 2.72 ± 1.39 vs 5.22 ± 1.26 in "controls" (ie, patients
with transplants) (P<.01).54
In this study, 40 of the 53 patients with syndrome X had a flow reserve of
less than 3.5, while this was true of only 1 of 20 controls. A lower than
normal resting microvascular tone may also contribute to impaired reserve
by allowing little room for further vasodilation. Using positron emission
tomography and intravenous dipyridamole in 17 patients, Geltman et al55 found that in 8 of them, coronary flow reserve was
normal, but in the other 9, resting flow was higher and maximal flow was lower
than normal, thus reducing coronary flow reserve. Thus, modulation of microvascular
tone may be disturbed in some patients with this syndrome.
Microvascular Spasm
The problem at the level of the resistance arterioles may be microvascular
spasm. Hackett et al56 were able to provoke
typical angina with the administration of intracoronary ergonovine in 5 patients
who had normal coronary angiograms, suggesting that they had ergonovine-induced
and, presumably, spontaneous microvascular spasm. Egashira and colleagues57 found that the mean increase in acetylcholine-induced
coronary flow was lower in 9 patients with syndrome X than in 10 controls
in spite of comparable large-vessel dilation with the administration of acetylcholine.
Thus, impaired nitric oxide release at a microvascular level might induce
vasospasm in these patients, although vascular hyperreactivity is another
possible mechanism.
Patchy Prearteriolar Vasoconstriction
A theory developed by Maseri and colleagues58
suggests that the problem may be located in the prearteriolar vessels. These
authors postulated that there is patchy constriction of prearteriolar vessels
resulting in downstream release of adenosine. Local adenosine accumulation
might stimulate afferent cardiac nerves and produce anginalike chest pain
without any true ischemia. Aminophylline is an antagonist of adenosine P1 receptors, and in one double-blind crossover study, pretreatment with
aminophylline was effective in reducing ischemia and chest pain and extending
exercise test duration in patients with syndrome X.59
Disease of the Small Arteries
Small arteries account for 40% of coronary vascular resistance, with
the remainder at the arteriolar level. In some patients, pathological disease
of small arteries may be an explanation for syndrome X, but these vessels
are too small for the measurement capability of angiography, which is generally
considered to be 0.5 mm or larger. They can be assessed indirectly by observing
and measuring the speed of dye flow.
Slow dye flow with normal epicardial arteries has been observed in separate
series of patients with syndrome X. In one report, 10 of 143 patients with
syndrome X showed this slow dye flow, and results of left ventricular biopsies
in all 10 showed small artery thickening and lumen reduction.60
Mosseri and colleagues61 described 16 cases
of syndrome X, all of which demonstrated slow flow of the dye column. Right
ventricular biopsy specimens from these patients showed evidence of intramural
coronary artery fibromuscular hyperplasia and swollen capillaries and a relative
lack of capillaries. Strauer62 performed endomyocardial
biopsies on 220 patients with angina and normal coronary arteriograms: 85
of the biopsy specimens showed evidence of small-artery vasculitis and a variety
of collagen vascular diseases such as systemic immune complex vasculitis,
scleroderma, and periarteritis, and the remaining 135 showed evidence of systemic
hypertension and hypertensive hypertrophy of the small arteries. Therefore,
a diligent search for systemic evidence of vasculitis or immune complex disease
would be appropriate in normotensive patients with this syndrome.
Occult Large-Vessel Disease
Results of an IVUS study of 30 patients with syndrome X emphasize the
heterogeneity of the syndrome.63 This study
included performing resting IVUS imaging of all 3 coronary arteries and exercise
IVUS imaging in the artery that showed the most abnormal resting IVUS finding.
Three patterns evolved: (1) a normal IVUS finding (12 patients); (2) atheromatous
plaque (10 patients); and (3) marked intimal thickening with no plaque (8
patients). The patients with a normal IVUS finding (pattern 1) showed coronary
vasodilation with exercise, and the patients with plaque or intimal thickening
(patterns 2 and 3) showed vasoconstriction with exercise. Thus, patients with
syndrome X may have subtle large-vessel disease, which may account for their
stress-induced angina.
Pain Due to Excessive Adenosine Effect Without Ischemia
There is growing proof that one mediator of cardiac pain is adenosine,
which activates ventricular sympathetic afferents. Intracoronary adenosine
administration causes chest pain in patients with typical angina.64 Aminophylline seems to have a dual action in the
myocardial microvascular circulation: it blocks adenosine P1 pain
receptors on afferent sympathetic nerve fibers but also competitively blocks
dipyridamole-induced inhibition of cellular adenosine reuptake.65
Intravenous aminophylline is instantaneously effective in relieving the pain
that may occur with dipyridamole perfusion testing. This suggests that the
fault for some patients might be an aberration of adenosine metabolism resulting
in adenosine accumulation in the absence of ischemia.
Psychological Disorders
Psychosocial problems are common in patients with noncardiac chest pain.
Wielgosz et al66 found a high incidence of
hypochondriasis in patients with chest pain and normal coronary angiograms.
Beitman et al67 reported a 34% incidence of
panic disorders among patients with normal coronary angiograms. In a group
of patients with chest pain who were referred for myocardial stress scintigraphy
and had a negative scan result, 56% met the criteria for panic disorder.68 Finally, among 441 consecutive patients consulting
the emergency department of a cardiology hospital with a chief complaint of
chest pain, 25% met structured interview criteria for panic disorder.69 In these patients, simple reassurance may not be
sufficient to relieve the patient's anxiety, and referral to a mental health
professional may be required.
Hormonal Deficiency
In contrast to the sex distribution of coronary heart disease, most
patients with syndrome X (almost 80%) are women and most are hypoestrogenic.
It has been postulated that this syndrome represents a generalized alteration
of vasomotor control (including dysfunction of the coronary microvasculature)
due to ovarian hormonal deficiency. In a double-blind, crossover, placebo-controlled
trial, there was a significant reduction of chest pain episodes in these patients
with the application of estradiol-17ß patches for 8 weeks, although there
was no change in exercise test duration.70
Other Theories and Contributing Factors
Forty-one patients with chest pain and normal coronary arteriograms
had platelet hyperaggregability in response to adenosine diphosphate or epinephrine
stimulus,71 but the clinical relevance of this
in vitro observation requires confirmation. Abnormal endothelial function
has received increased attention of late, since at a large-vessel and arteriolar
level, endothelial function is important in maintaining coronary flow reserve.
Hyperlipidemia, aging, diabetes, smoking, and lack of physical exercise alters
endothelial function72 and may contribute to
ischemia and angina in the absence of angiographic coronary disease.
Therapeutic Implications
From all of this chaos, how can one develop an investigative and therapeutic
management plan for a patient in whom this syndrome is suspected? Risk factor
modification where indicated should be initiated. Normalizing lipid levels
improves positron emission tomography perfusion abnormalities.73
Estrogen replacement may improve symptoms if the patient is a woman and is
hypoestrogenic.70 Nicotine discontinuation
may ameliorate symptoms. Exercise training enhances endothelial function.74
L-arginine (a precursor of endothelial-derived nitric oxide) therapy
and dietary supplementation represent a new approach to treating endothelial
dysfunction and have been shown to improve endothelial-dependent vasodilation
in patients with syndrome X75 and in patients
with coronary disease. In a study by Lerman et al,76
L-arginine dietary supplementation for 6 months improved coronary small-vessel
endothelial function and symptoms.
Nitrates may not only be ineffective but may even reduce coronary flow.
One study showed that treadmill performance became worse with sublingual isosorbide
dinitrate therapy in patients with syndrome X in contrast to improvement in
patients with coronary disease.77 As discussed
above, theophylline preparations have been used with some success,59 but before attempting a novel therapeutic approach
such as this, one should be cognizant of the variable nature of the symptoms
in this syndrome.
CONCLUSIONS
How does the clinician approach the treatment of a patient with normal
coronary angiograms in whom angina and coronary disease were suspected prior
to angiography? First, the angiograms should be reviewed critically for any
possibly missed or undercalled lesions. If the history suggests vasospastic
angina, ergonovine testing should be considered. If ischemia is documented
on stress-induced myocardial scintography and there is mild or moderate coronary
disease or segments that are not well visualized, then a restudy with IVUS
imaging or flow reserve measurements could be pursued. A cardiac echocardiogram
is mandatory because it is an excellent screening tool for excluding other
cardiac causes of angina. If symptoms suggest, a noncardiac cause of chest
pain should be investigated, and finding the cause may be relatively easy
as in the case of costochondral or costosternal syndromes or more labor intensive
as in the case of esophageal motility disorders. Finally, many patients' conditions
will remain undiagnosed, and they will be labeled as having syndrome X, a
heterogeneous chest pain syndrome often of undetermined etiology. In these
patients, risk factors for coronary disease should be appropriately treated,
which will improve vascular function. In general, antianginal medications
should be avoided since they are usually ineffective and may, as in the case
of nitrates, even worsen exercise intolerance and symptoms. Patients who show
scintigraphic or echocardiographic signs of myocardial ischemia should be
observed more closely and have their clinical status reevaluated whenever
appropriate. However, the diagnostic label of coronary disease should be avoided.
On the contrary, reassurance should be given because their risk of ever developing
coronary disease is minimal. In fact, the long-term prognosis of patients
with truly normal coronary angiograms and chest pain for whom other causes
have been excluded is excellent and may even exceed that of the general population.78
AUTHOR INFORMATION
Accepted for publication March 13, 2001.
Corresponding author and reprints: Leonard Schwartz, MD, Toronto
General Hospital, EN 13-204, 200 Elizabeth St, Toronto, Ontario, Canada M5G
2C4 (e-mail: leonard.schwartz{at}uhn.on.ca).
From the University of Toronto and the Toronto General Hospital, University
Health Network, Toronto, Ontario (Dr Schwartz), and the University of Montreal
and Montreal Heart Institute, Montreal, Quebec (Dr Bourassa).
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