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CLINICIAN UPDATE
Pathophysiology and Management of Patients With Chest Pain
and Normal Coronary Arteriograms (Cardiac Syndrome X)
Juan Carlos Kaski, MD, DSc
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P
atients with cardiac syndrome
X (CSX)—typical chest pain
and
electrocardiographic
changes suggestive of myocardial ischemia despite normal coronary arteriograms–represent a diagnostic
and therapeutic riddle. CSX is not
associated with an increased mortality or an increased risk of cardiovascular events, but it often severely impairs quality of life and represents a
substantial cost burden to the healthcare
system. This syndrome of chest pain
with normal coronary arteries encompasses a variety of pathogenic subgroups
and is predominantly seen in postmenopausal women. Lack of understanding of
the syndrome by the cardiovascular physician not infrequently results in discounting
the clinical problem. Treatment remains
elusive, but management strategies can
improve the patient’s quality of life and
reduce the financial burden imposed on
health services.
Case Report: A 55-year-old white
female pharmacist underwent diagnostic coronary arteriography for the assessment of typical exertional chest
pain, which had started 18 months
previously and had gradually become
more frequent and severe despite treatment with oral and sublingual nitrates
and atenolol (50 mg daily). Central
chest pain and dyspnea occurred at rest
and with emotional stress and responded rather poorly to sublingual
nitrate administration. ECG exercise
stress test was positive (Figure 1), and
transient perfusion defects were found
on thallium-201 dipyridamole testing
(Figure 2). She had long-lasting excruciating chest pain after dipyridamole infusion. Risk factors included a family
history of coronary artery disease, a lowdensity lipoprotein-cholesterol level of
4.2 mmol/L, a high-density lipoproteincholesterol level 0.9 mmol/L, menopausal status, a previous history of
smoking, body-mass index of 28 kg/m2,
and raised high-sensitivity C-reactive
protein levels (3.8 mg/L). Coronary arteries and left ventricular function were
completely normal. Coronary intravascular ultrasound showed no significant
subangiographic disease. After reassurance by her cardiologist, all cardiac medications were discontinued. Symptoms
continued to deteriorate over the ensuing
months, however, to the point that she
was unable to work and required help
with her supermarket shopping and
household tasks. She was referred to our
CSX clinic for treatment.
Esophageal manometry and pH
measurements showed 4 asymptomatic
episodes of gastroesophageal reflux
without associated ECG changes. Specialist psychological assessment revealed no abnormalities. Coronary artery spasm and musculoskeletal
conditions were ruled out as the cause
of her symptoms. Transient ST-segment
depression and chest pain detected during ambulatory monitoring were usually
associated with tachycardia (Figure 3). It
was noted that 20% of the episodes of
ST-segment depression occurred with a
heart rate ⬍80 bpm. Brachial artery
flow-mediated dilatation was reduced
to 1.3%, indicating systemic endothelial dysfunction. Dobutamine stressechocardiogram showed no regional
wall motion abnormalities despite the
occurrence of ST-segment depression
and chest pain. Treatment was initiated
with diltiazem 360 mg daily, simvastatin 40 mg daily, imipramine 50 mg
daily, and sublingual nitrates. An exercise program was devised for this
patient, and she received advice regarding diet and lifestyle changes. The
patient decided against estrogen replacement therapy.
Clinical Results: Symptoms improved significantly over an 8-month
period and the patient was able to
return to work. Improvements were
observed in body mass index (23
kg/m2), high-density lipoprotein-cho-
From the Coronary Artery Disease Research Unit, Cardiological Sciences, St George’s Hospital Medical School, London, UK.
Correspondence to Prof J.C. Kaski, Head, Cardiological Sciences, Director, Coronary Artery Disease Research Unit, Department of Cardiovascular
Medicine, St George’s Hospital Medical School, Cranmer Terrace, London SW17 0RE, United Kingdom. E-mail [email protected]
(Circulation. 2004;109:568-572.)
© 2004 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/01.CIR.0000116601.58103.62
568
Kaski
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Figure 1. Positive exercise stress test response with horizontal ST-segment depression associated with typical central chest pain. Chest pain subsided gradually after
exercise (some chest discomfort persisted for 12 minutes), and ST-segment depression returned to baseline levels within 5 minutes.
lesterol level (1.3 mmol/L), lowdensity lipoprotein-cholesterol level
(2.8 mmol/L), and flow-mediated dilatation (4.2%). Exercise test was
borderline positive, with up-sloping
ST-segment depression but without
chest pain (peak heart rate 158 bpm,
peak blood pressure 180/88 mm Hg;
stage 4 Bruce protocol).
Background
Although patients with typical exertional chest pain and positive exercise
tests usually have obstructive coronary
artery disease, particularly when risk
factors are present, approximately 20%
of these patients have normal coronary
arteriograms.1 These individuals are
considered to have CSX, for which
there is no universally accepted defini-
Cardiac Syndrome X
569
tion. Most cardiologists agree that, in
addition to typical chest pain and ECG
changes (or other evidence of a cardiac
involvement such as myocardial perfusion abnormalities), the coronary angiogram should be completely normal.1,2
Even this stringent angiographic criterion
has limitations, as coronary arteriography
provides no information regarding early
atherosclerotic events within the arterial
wall.
Patients with systemic hypertension,
left ventricular hypertrophy, and diabetes mellitus are excluded from CSX,
as it is assumed that the cause for their
angina is known. Consideration
whether or not such exclusions are
justifiable is beyond the scope of this
manuscript. Patients with coronary artery spasm and those with objectively
documented extracardiac causes for
the pain (such as chest wall syndrome,
psychological disturbances, and esophageal spasm) are also excluded.1
Despite intense investigation over
the past 30 years regarding the pathogenesis of CSX, many fundamental
questions remain unanswered. Among
these, the following feature prominently: (1) Is the chest pain cardiac in
origin?; (2) Is it caused by myocardial
ischemia?; (3) Are other mechanisms
involved?; and (4) What are the respective roles of microvascular dysfunction and reduced pain threshold?
Pathogenesis
Coronary Microvascular
Dysfunction (Microvascular
Angina)
Figure 2. Short and long axis 201-thallium scintigraphy images showing transient perfusion defects in the septal region of the left ventricle after dipyridamole infusion.
Excruciating chest pain and ST-segment changes suggestive of myocardial ischemia
were observed immediately after dipyridamole.
Microvascular angina (reduced coronary microvascular dilatory responses
and increased coronary resistance)3
has been consistently found in CSX
patients and suggested as a cause for
regional myocardial blood flow abnormalities and heterogeneous myocardial
perfusion. Endothelial dysfunction,
with reduced bioavailability of endogenous NO and increased plasma levels
of endothelin-1 (ET-1), may explain
the abnormal behavior of the coronary
microvasculature in CSX.4 – 6 Transient
myocardial perfusion defects have
been reported in areas supplied by
570
Circulation
February 10, 2004
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Figure 3. Continuous 2-channel ambulatory ECG monitoring during the patient’s daily
activities. Episodes of typical transient ST-segment depression were observed during
monitoring and were commonly associated with increased heart rate and chest pain.
Episodes of chest pain usually lasted longer than episodes of ST-segment depression.
arteries showing endothelial dysfunction4 and increased levels of ET-1 correlated with impaired coronary microvascular dilator responses in patients
with chest pain and normal coronary
arteries.7 Moreover, a lower NO/ET-1
ratio has been found in CSX patients
compared with control subjects.8
Endothelial dysfunction in CSX appears to be multifactorial and linked to
risk factors such as smoking, obesity,
hypercholesterolemia, and inflammation.1 High plasma C-reactive protein
levels, a marker of inflammation, have
been shown to correlate with disease
activity9 and endothelial dysfunction.
CSX patients with multiple risk factors
often have subangiographic coronary
atheroma that may further impair endothelial function. Insulin resistance
has also been suggested to have a
major pathogenic role.10
Given the high prevalence (approximately 70% in most series) of postmenopausal women in the CSX population,
estrogen deficiency has been suggested
as a pathogenic agent acting via endothelium-dependent and endotheliumindependent mechanisms.11 Impaired
endothelial function in postmenopausal
CSX patients is improved by the administration of 17␤-estradiol.11
ischemia could be its pathogenic
mechanism. However, this mechanism
has proven elusive, as ischemia is objectively documented in only a minority (approximately 25%) of patients.1,2
Evidence of myocardial ischemia in
these patients derives from myocardial
perfusion studies, from investigations
using metabolic markers such as myocardial lactate and isoprostane production, and from coronary sinus blood
oxygen and pH changes. Studies using
myocardial-perfusion MRI12 and 31Phosphorus nuclear magnetic resonance13 have provided fresh evidence
for myocardial ischemia in CSX patients. Because many authors question
the role of myocardial ischemia in
CSX based on its good prognosis, the
poor response to nitrates in many
cases, the normal results of stress
echocardiography, and the absence of
objective markers of ischemia in many
CSX patients, non-ischemic mechanisms have been proposed to explain
the occurrence of CSX, including autonomic nervous system dysfunction14,15 and increased pain perception.16 Negative findings regarding
ischemia, however, may be due to
dilution of study groups by subjects
with non-cardiac chest pain and to poor
sensitivity of diagnostic techniques.
Myocardial Ischemia
Abnormal Pain Perception
From the initial description of CSX, it
has been speculated that myocardial
Increased pain perception is common
in patients with CSX, but the reason
Figure 4. Interrelations between chest pain
and microvascular dysfunction are important
in the pathogenesis of CSX and are likely to
determine the patient’s clinical presentation.
A given patient with markedly increased
pain sensitivity (y axis, arbitrary severity
scale 1 to 10) may develop chest pain in
response to algogenic cardiac (and probably also non-cardiac) stimuli even in the
absence of major coronary microvascular
dysfunction or myocardial ischemia. Adenosine and potassium release have been suggested to cause chest pain and ECG
changes in CSX patients. Endothelin-1 and
the autonomic nervous system modulate
pain threshold. Patients with both marked
microvascular dysfunction (x axis) and
reduced pain threshold will be highly symptomatic and are also likely to have objective
evidence of myocardial ischemia. Patients
with intermediate degrees of chest pain
sensitivity and microvascular dysfunction
may have no ischemia or this may be undetectable; the latter depending on the sensitivity of the diagnostic tools employed for
investigation and the severity and location of
ischemia. Variable interactions between pain
threshold and microvascular dysfunction
can explain the heterogeneous pathogenesis of CSX. Both pain threshold and microvascular dysfunction have ample gradation
spectra regarding severity and are also
modulated by factors such as endothelial
dysfunction, inflammation, autonomic influences, and psychological mechanisms,
among others.
remains elusive. Potassium and adenosine release, as well as abnormalities
in the central modulation of pain perception, have been suggested to play a
role.16 Greater and more extensive cortical activation, particularly of the right
insula, suggesting abnormal handling
of afferent stimuli by the central nervous system is seen in CSX patients as
compared with controls.16 CSX patients may thus have an ineffective
thalamic gate that would allow inadequate cortical activation by afferent
stimuli from the heart, resulting in
increased pain perception16. Auto-
Kaski
Cardiac Syndrome X
571
nomic nervous system imbalance with
increased adrenergic activity and impaired parasympathetic tone could explain both increased pain sensitivity
and endothelial dysfunction.14 –16 Possible interactions between pain threshold and microvascular dysfunction in
CSX are presented in Figure 4.
Psychiatric Morbidity
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CSX patients have high rates of psychiatric morbidity17; approximately
30% have a treatable psychiatric disorder and another 30% have psychological problems, factors that probably
contribute to the continuing symptoms
characteristic of the condition. Psychiatric morbidity varies in different series depending on the referral sources
of these patients and may, particularly
in anxiety disorders, be secondary to
inappropriate reassurance about often
disabling cardiovascular symptoms,
uncertainty as to the nature of the
condition, and failure of conventional
treatments to improve quality of life.
Prognosis and Management
With the exception of patients who
present with left bundle branch block
and subjects with microvascular angina secondary to serious systemic
diseases (such as amyloidosis or myeloma), prognosis is good regarding
survival and left ventricular function in
patients with CSX.1,2 Quality of life,
however, is poor in a large proportion
of CSX patients.
Treatment is a challenging and often
frustrating exercise for both patients
and physicians. Kaski and Valenzuela
Garcia18 have reviewed treatment options available for CSX, and American
Heart Association/American College
of Cardiology treatment guidelines
are available for management of CSX
in the context of the acute coronary
syndrome.19 Successful management
usually depends on identifying the prevailing pathogenic mechanism and tailoring the intervention to the individual patient. Advice on lifestyle
changes and risk factor management–in particular aggressive lipid
lowering therapy with statins—should
Figure 5. Practical algorithm for management of patients with cardiac syndrome X.
ACEi indicates angiotensin-converting enzyme inhibitors; CAD, coronary artery disease;
HT, hormone therapy; IVUS, intravascular ultrasound; LVH, left ventricular hypertrophy;
MVA, microvascular angina; SCS, spinal cord stimulation; and TENS, transcutaneous
electrical nerve stimulation.
be considered vital components of any
therapeutic strategy. A multidisciplinary approach is required in most
cases. Figure 5 depicts an algorithm
used in our institution for the management of CSX patients. Briefly, antianginals such as calcium antagonists and
␤-adrenergic blockers are useful in
patients with documented myocardial
ischemia or abnormal myocardial perfusion. Sublingual nitrates are effective in 50% of CSX patients.2 Little
evidence is available in relation to the
efficacy of nicorandil, ␣-adrenergic
blockers, trimetazidine, and angiotensin-converting enzyme inhibitors in
this setting.
vasculature. Controlled clinical trials
have suggested, however, that the risk
of developing cardiovascular disease
and breast cancer increases in women
taking hormone therapy (HT). Thus,
although HT has potential cardiovascular benefits, it can also cause harm.23
The US Preventative Services Task
Force has suggested that routine postmenopausal HT should not be advised
for the prevention of chronic conditions,23 and women should take an
active part in decisions regarding HT.
These recommendations apply also to
CSX patients. However, HT may be
useful in specific cases where a direct
relationship exists between estrogen
deficiency and CSX symptoms.
Analgesic Intervention
Analgesic intervention with imipramine,20 an antidepressant with analgesic properties, and with aminophylline,21,22 an antagonist of adenosine
receptors, has been shown to improve
symptoms in patients with chest pain
and normal coronary arteriograms.
Transcutaneous electrical nerve stimulation and spinal cord stimulation can
offer good pain control. As with other
interventions in CSX, studies in larger
numbers of patients are lacking.
Psychological Intervention
Psychological intervention may be
beneficial for a substantial number of
patients, whether or not organic factors
are involved.24 Studies support the role
of a structured cognitive behavioral
approach to the management of CSX
patients with non-ischemic chest
pain,24 and this treatment is more
likely to be effective if it is begun early
after diagnosis.
Physical Training
Hormone Therapy
Hormone therapy improves chest pain
and endothelial function in women
with CSX.11 Estrogens antagonize the
effects of ET-1 and dilate the coronary
As a result of physical deconditioning
and low pain threshold, CSX patients
have an impaired exercise capacity.25
Physical training improves pain
threshold and endothelial function and
572
Circulation
February 10, 2004
delays the onset of exertional pain in
patients with typical chest pain and
normal coronary arteries.25
6.
Summary and Final
Considerations
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Controversy surrounds the pathogenesis
and management of CSX patients. Although the majority of these patients has
non-ischemic mechanisms and increased
pain sensitivity, only a minority has documented myocardial ischemia. Identification of the prevailing mechanism is
important for rational management. A
multidisciplinary approach and a genuine, sympathetic appreciation by the
physician of the devastating effect of
CSX on the patient’s quality of life
usually have a positive therapeutic
impact.
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Pathophysiology and Management of Patients With Chest Pain and Normal Coronary
Arteriograms (Cardiac Syndrome X)
Juan Carlos Kaski
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Circulation. 2004;109:568-572
doi: 10.1161/01.CIR.0000116601.58103.62
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