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Angina pectoris caused by coronary microvascular spasm

Author: Mohri, Masahiro; Koyanagi, Masamichi; Egashira, Kensuke; Tagawa, Hirofumi; et al


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Abstract (Abstract): Research results indicate that coronary microvascular spasm and resultant
myocardial ischemia may be the cause of chest pain in a subgroup of patients with microvascular
angina.

Abstract: Microvascular angina can occur during exercise and at rest. Reduced vasodilator
capacity of the coronary microvessels is implicated as a cause of angina during exercise, but the
mechanism of angina at rest is not known. Our aim was to test the hypothesis that primary
hyperconstriction (spasm) of coronary microvessels causes myocardial ischaemia at rest.
Acetylcholine induces coronary artery spasm in patients with variant angina. We tested the effects
of intracoronary acetylcholine at graded doses in 117 consecutive patients with chest pain (at
rest, during exertion, or both) and no flow-limiting (>50%) organic stenosis in the large epicardial
coronary arteries. We also assessed the metabolism of myocardial lactate during acetylcholine
administration in 36 of the patients by measurement of lactate in paired blood samples from the
coronary artery and coronary sinus vein.
Of the 117 patients, 63 (54%) had large-artery spasm, 29 (25%) had microvascular spasm, and 25
(21%) had atypical chest pain. The 29 patients with microvascular spasm developed angina-like
chest pain, ischaemic electrocardiogram (ECG) changes, or both spontaneously (two patients) or
after administration of acetylcholine (27 patients) without spasm of the large epicardial coronary
arteries. Testing of paired samples of arterial and coronary sinus venous blood showed that
lactate was produced during angina attack in nine of 11 patients with microvascular spasm. There
was more women (p<0.01) and fewer coronary risk factors (p<0.01) in patients with
microvascular spasm than in those with large-artery spasm.
Coronary microvascular spasm and resultant myocardial ischaemia may be the cause of chest
pain in a subgroup of patients with microvascular angina.

Full text: Headnote


Summary
Background Microvascular angina can occur during exercise and at rest. Reduced vasodilator
capacity of the coronary microvessels is implicated as a cause of angina during exercise, but the
mechanism of angina at rest is not known. Our aim was to test the hypothesis that primary
hyperconstriction (spasm) of coronary microvessels causes myocardial ischaemia at rest.
Methods Acetylcholine induces coronary artery spasm in patients with variant angina. We tested
the effects of intracoronary acetylcholine at graded doses in 117 consecutive patients with chest
pain (at rest, during exertion, or both) and no flow-limiting (>50%) organic stenosis in the large
epicardial coronary arteries. We also assessed the metabolism of myocardial lactate during
acetylcholine administration in 36 of the patients by measurement of lactate in paired blood
samples from the coronary artery and coronary sinus vein.
Findings Of the 117 patients, 63 (54%) had large-artery spasm, 29 (25%) had microvascular
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spasm, and 25 (21%) had atypical chest pain. The 29 patients with microvascular spasm
developed angina-like chest pain, ischaemic electrocardiogram (ECG) changes, or both
spontaneously (two patients) or after administration of acetylcholine (27 patients) without spasm
of the large epicardial coronary arteries. Testing of paired samples of arterial and coronary sinus
venous blood showed that lactate was produced during angina attack in nine of 11 patients with
microvascular spasm. There was more women (p<001) and fewer coronary risk factors (p<001) in
patients with microvascular spasm than in those with large-artery spasm.
Interpretation Coronary microvascular spasm and resultant myocardial ischaemia may be the
cause of chest pain in a subgroup of patients with microvascular angina.
Lancet 1998; 351: 1165-69 See Commentary page 1144
Introduction
Angina pectoris occurs in patients with angiographically normal or slightly diseased coronary
arteries and no coronary artery spasm. Such patients have a generic diagnosis of microvascular
angina or syndrome X.1,2 Blunted coronary-vasodilator responses to metabolic and
pharmacological stimuli have been shown in selected cases of microvascular angina.3-6
Inadequate microvascular dilation in response to increased demand for myocardial oxygen could
account for exercise-induced myocardial ischaemia in these patients.4,7 A large proportion of
patients with syndrome X, however, have angina at rest.8 We postulate that primary
microvascular hyperconstriction (spasm) could be the cause of myocardial ischaemia in this group
of patients.
Acetylcholine can induce coronary artery spasm with high sensitivity and specificity in patients
with variant angina caused by spasm of the large epicardial arteries.9,10 The aim of our study
was to test the hypothesis that myocardial ischaemia might result from spasm of the coronary
microvessels in a subgroup of patients with microvascular angina. Because visualisation of
spasms of the coronary microvessels by conventional arteriography is difficult, we examined
whether intracoronary administration of acetylcholine induced chest pain, ischaemic ST changes,
or both without spasm of the epicardial artery in patients who had a history of chest pain and
angiographically normal or slightly diseased coronary arteries. We also assessed the metabolism
of myocardial lactate during acetylcholine administration.
Methods
The study protocol was approved by the Institutional Human Research Committee of Kyushu
University. We obtained written informed consent from each patient before enrolment.
Between September, 1994, and January, 1997, consecutive patients admitted to our department
for chest pain underwent diagnostic coronary arteriography. Cardiac catheterisation was done in
the fasting state after administration of oral diazepam 5 mg. All cardiovascular drugs, apart from
sublingual nitroglycerin, were discontinued at least 24 h before study entry. We obtained baseline
angiograms of the right and left coronary arteries by the Judkins technique. If atherosclerotic
coronary stenosis of greater than 50% luminal diameter reduction was not observed in any
epicardial coronary artery, a bipolar-pacing catheter was advanced to the right ventricle to
prevent bradycardia during infusion of acetylcholine. We excluded patients with acute myocardial
infarction, hypertrophic cardiomyopathy, severe valvular disease, severe angina or congestive
heart failure in whom cardiovascular medications could not be withdrawn, and with chronic renal
failure requiring haemodialysis.
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Graded acetylcholine doses of 10 (mu)g, 30 (mu)g, and 100 (mu)g were infused over 30 s into the
left coronary artery of eligible patients. This regimen induces coronary spasm with greater than
90% specificity and sensitivity in patients with variant angina, but does not cause angina,
ischaemic ST-T change, or epicardial coronary spasm in individuals with atypical chest pain.9,11
We ensured that the catheter was positioned so that the drug was not preferentially directed to
the left anterior or circumflex artery by injecting a small amount of contrast medium. 1 min after
each dose of acetylcholine had been administered, systemic arterial pressure, heart rate, and 12lead electrocardiogram (ECG) trace were recorded and coronary arteriography undertaken.
If angina, ischaemic ECG change, or coronary artery spasm did not occur, we administered the
next dose of acetylcholine after an interval of 2 min. If 100 (mu)g acetylcholine injected into the
left coronary artery did not induce angina, ECG changes, or coronary spasm, we infused
acetylcholine into the right coronary artery at graded doses of 5 (mu)g, 15 (mu)g, and 50 (mu)g.
Whenever angina, ischaemic ECG changes, or coronary spasm occurred, administration of
acetylcholine was stopped and arterial pressure, 12-lead ECG trace, and coronary cineangiogram
were recorded and 1 mg isosorbide dinitrate was administered. After completion of acetylcholine
testing, we administered isosorbide dinitrate into the right and left coronary arteries (I mg for
each artery). Coronary angiograms of the right and left coronary arteries were obtained in
multiple projections to assess the severity of organic coronary artery stenosis.

Biplane coronary
cineangiograms in the right and left anterior projections were recorded with a Siemens
cineangiographic system (Siemens Bicor &Hicor, Erlangen, Germany). An enddiastolic frame was
selected and the lumen diameter of the large epicardial coronary artery was measured with a
validated densitometric analysis system.12 Reproducibility between and within observers is high
with this system (r=096 and r=098, respectively). We defined coronary spasm of the epicardial
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coronary arteries as reduction in diameter of greater than 75% compared with the diameter
recorded after intracoronary administration of isosorbide dinitrate.11,13 We measured the luminal
diameter in five segments of the right coronary artery (proximal, middle, and distal segments,
posterolateral and posterior descending branches) and ten segments of the left coronary artery
(left main trunk, proximal, middle and distal left anterior descending artery, first and second
diagonal branches, proximal and distal circumflex artery, obtuse marginal and posterolateral
branches). Each measurement of luminal diameter was done three times and the average value
for each segment was used for the analysis.
The standard 12-lead ECG was continuously monitored throughout the study and the trace
recorded at 25 mm/s at baseline, after administration of each dose of acetylcholine, and after
administration of isosorbide dinitrate. We defined ischaemic ECG changes as a transient ST
segment shift of 0.1 mV or greater in at least two leads. Transient ECG changes that were
observed shortly after coronary arteriography were not taken to be positive. The level of ST
segment was measured at 80 ms after the J point above or below the isoelectric line. We
measured systemic-arterial pressure via the Judkins cathether.
The risk factors for coronary atherosclerosis were: hypercholesterolaemia (serum total cholesterol
>569 mmol/L); current smoking habit; hypertension (> 140/90 mm Hg); diabetes mellitus (fasting
blood glucose >778 mmol/L or positive glucose test); and family history of ischaemic heart
disease. Leftventricular hypertrophy was defined as interventricular septal, posterior, or both wall
thickness of greater than 12 mm by echocardiography.
Coronary sinus catheterisation for the measurements of lactate concentrations was attempted
prospectively from May, 1996. We inserted a 6F coronary sinus catheter via the femoral vein. To
measure lactate concentration, we collected paired samples of 2 mL blood from the coronary
artery and coronary sinus vein at baseline, 1 min after the administration of each dose of
acetylcholine before coronary arteriography, and after administration of isosorbide dinitrate.
Lactate concentration was immediately measured with a calibrated automatic lactate analyser
(2300 Stat Plus, YSI, Yellow Spring, OH, USA). Comparisons of continuous and discrete variables
between the groups were done by Kruskal-Wallis test and z test, respectively. A p value less than
005 was significant.
Results
We enrolled 117 consecutive patients (58 men, 59 women, median age 63 [IQR 54-68] years) with
chest pain at rest, on exertion, or both and no flow-limiting (>50%) organic stenosis of the large
epicardial coronary arteries. We classified the patients as having large-artery spasm,
microvascular spasm, or atypical chest pain. 63 (54%) patients had large-artery spasm-ie,
coronary artery spasm in one or more of the large epicardial coronary segments, spontaneously
(six patients) or after intracoronary administration of acetylcholine (57 patients). 29 (25%)
patients had microvascular spasmie, angina-like chest pain, ischaemic ECG changes, or both,
which developed spontaneously or after administration of acetylcholine but without spasm of the
large epicardial coronary arteries. The remaining 25 patients with atypical chest pain did not have
angina, ischaemic ECG changes, or coronary artery spasm.
The clinical characteristics of the patients are shown in table 1. There was no significant
difference in age or type of chest pain between patients with large-artery spasm, microvascular
spasm, and atypical chest pain. There was a larger proportion of men than women in the group of
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patients with large-artery spasm (p<001). All but one of the female patients with microvascular
spasm were postmenopausal and none had received hormone replacement therapy.
Hypercholesterolaemia and current smoking were more common in patients with large-artery
spasm than in those with microvascular spasm or atypical chest pain. By contrast, there were no
between-group differences in the rate of positive exercise testing (chest pain >0.1 mV STsegment depression), hypertension, diabetes, and family history of ischaemic heart disease or
left-ventricular hypertrophy. Patients with microvascular spasm had fewer coronary risk factors
than those with large-artery spasm (p<0.01) and a similar number of risk factors as patients with
atypical chest pain.

Acetylcholine induced
modest constriction of the large epicardial coronary artery in the group of patients with
microvascular spasm and in those with atypical chest pain. However, the maximum percentage
decrease in lumen diameter of the large epicardial coronary arteries caused by administration of
acetylcholine was 57 (39-62)% in patients with microvascular spasm, which was similar to that in
patients with atypical chest pain (55 [46-61]%) and significantly less than that in those with largeartery spasm (90 [80-99]%, p<0.0001).
Of the 29 patients with microvascular spasm, two spontaneously developed their typical chest
pain during catheterisation, which was associated with ST elevation in one patient and ST
depression in the other. The remaining 27 patients developed angina, ischaemic STsegment
changes, or both after acetylcholine infusion in the absence of angiographically confirmed
coronary artery spasm. In these patients, angina, ST-segment changes, or both occurred after
administration of acetylcholine at 5 (mu)g in one patient, at 10 jig in two patients, at 30 (mu)g in
five patients, and at 100 jig in 19 patients. Overall in the microvascular spasm group, angina was
noted in 27 (93%) patients, ischaemic ECG changes in 24 (83%) patients, and both symptoms and
ECG changes in 20 (69%) patients. 25 of 27 patients reported that the chest pain they developed
during cardiac catheterisation was similar to previous pain. Nine patients had documented
ischaemic ECG changes during spontaneous angina attacks before the study, and in seven of
them administration of acetylcholine induced ischaemic ECG changes (figure 1).

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