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Induction of coronary artery spasm by intracoronary acetylcholine: Comparison with intracoronary ergonovine
Induction of coronary artery spasm by intracoronary acetylcholine: Comparison intracoronary ergonovine
with
To investigate the mechanism of coronary spasm, we compared the action of acetylcholine with that of ergonovine in 11 patients with vasospastic angina (group 1) and in 15 patients with chest pain (group 2). Coronary arteriography was performed immediately after the patients received intracoronary injections of titrated increments of each agent. In the patients in group 1 occlusive or near-occlusive (99% luminal narrowing) coronary spasm associated with angina and ischemic electrocardiographic ST changes was noted in nine of 11 patients receiving acetylcholine and in all 11 patients receiving ergonovine. The region and the degree of the most severe coronary spasm on coronary arteriograms evoked by the two agents were the same in nine of the 11 patients in group 1. In the other two patients in group 1, spontaneous focal coronary spastic stenosis in the baseline coronary arteriogram was relieved by the intracoronary injection of acetylcholine, and a focal coronary occlusive spasm in the same region was induced repeatedly by the subsequent intracoronary injection of ergonovine (paradoxic phenomenon). In contrast, occlusive or near-occlusive coronary spasm was not induced by either agent in any patient in group 2. These results suggest that the two provocative tests for coronary spasm that involve acetylcholine and ergonovine are clinically useful in the diagnosis of vasospastic angina, but testing with intracoronary ergonovine is needed when a spontaneous focal coronary spasm is relieved by the intracoronary injection of acetylcholine. The results also indicate that in many patients with vasospastic angina, nonspecific hypersensitivity to acetylcholine or ergonovine in a definite region of the coronary arteries generally plays an important role in the induction of coronary spasm. This theory alone, however, is not sufficient to explain the paradoxic phenomenon observed in a few patients with vasospastic angina. (AM HEART J 1992;124:39.)
Yukisono Suzuki, MD, Shingo Tokunaga, MD, Shigeru Ikeguchi, MD, Shinji Miki, MD,” Tomoyuki Iwase, MD,” Tetsuya Tomita, MD,” Tomoyuki
Murakami, MD,” and Chuichi Kawai, MD.” Kyoto, Japan
Coronary artery spasm is widely recognized as the cause of variant angina.l However, the true mechanism of coronary artery spasm remains unclear. Various agents and stimuli can provoke coronary artery spasm.2-7 Ergonovine is most commonly used to induce coronary spasm in vivo by intravenous or intracoronary injection.” Recently Yasue et a1.greported that intracoronary injection of acetylcholine was useful in the induction of coronary artery spasm. Some in vitro experiments have elucidated and compared the vasoactive properties of various agents.l@r” In the clinical setting, however, no such comparison
has been reported. The aim of this study is to compare the action of acetylcholine with that of ergonovine in provoking coronary artery spasm in vivo and to clarify the mechanism of coronary artery spasm.
From the Cardim ascular Department, Third Division of Internal Medicine.
10 men and one woman with a mean age of 54 years, ranging from 43 to 76 years (Table I). Eight patients had fixed coronary stenosis with 25 % to 90 % luminal narrowing, and three had no fixed coronary stenosis. The patients in group 1 were divided into active-disease and inactive-disease groups. The active-disease group con-
Received Reprint Kyotn Japan. -1/l/37350
for publication -quests. Universit>
Chuichi Hospital,
Aug.
Ijinkai aKyoto
:X1, 1990;
Takeda General Hospital University Hospital.
accepted
Kawai. MD, Third Division 5-l Kawaracho, Shogoin.
Dec.
and
12, 1991.
of Internal Sakyo-ku,
Medicine, Kynto 606,
METHODS Patients.
We studied 26 patients. Eleven had a history of typical vasospasticangina (chestpain at rest early in the morning). Transient ST segmentelevation or depression occurring spontaneously at rest was documented with standard 1%lead electrocardiogramsor Holter electrocardiograms in six patients before cardiac catheterization (cases1, 2, 3, 8, 9, and 11). This group (group 1) included
39
40
Suzuki
et al.
American
Table I. Clinical findings and results of intracoronary vasospastic angina (group 1) Coronary
Disease Case
artcry -
inject,ion
Sex
Sitfxl dose CF.&
c
and ergonovine Ach
strnosis
Age Csrll
UCtiL~it)
of acetylcholine
pain
Chest
in patients
Heart
with
test
KG: ST segment change (mV, leadi
-
STl.Of V,-VC; STl.l* II, III, aVF
(‘A(; --~ __.~S6: 99’,
1 2
A A
52/M
S6: 75’,
7.5’ /
44/M
Normal
Normal
Li2,5 R/s
20/10
:3
I
47/M
s13: 50’,
I,/50
“oil0
4
A
56/M
s7: 25’, s13: 50’, s1,2,3: SO’,
s1,2: ‘Ii’ UC <
R/25
7ilU
I
63/M
Normal
Normal
L/50
6ilO
I I
43/F 52/M
Sll: 75(, S6: 5O’c
Normal S6: 50 I’,
L/100 L/25
0 5ilO
8
A
.56/M
x/10
ST0.41 II, III, aVp
A
76/M
s2: SO’, S6: 50’, S6: 50°C
R/25
9
s2: 25’1 S6: 75”c S6: 50’~
Lb5
ill0
STO.l, V;-VI-;
Sll: 75°C
57/M
Sll: 75’, s13: 90’, s1,2: 25’,
S6,ll: s13:
R/50
lO/lO
STO.lt II, III, aVk
Sl:
SO’,
s2:
loo’,
I
10
A
11
44/M
r,/lO
July 1992 Journal
STO.4, I. II, III, aVl aVF, Vd-Vtj ST0.21 II, III, aVF ST0.2t I. aVI,, VS-VI; No change ST0.41 VI-V;, STO.lj aV1
Sl: 75”, s2: loo”,
si: loo’, s1:i: loo’, Sl: 75’1 <
S’), -. 100’ / 57: 75f, S8,Y: 100 I( Sll: 501, S6,7.8: 75’< s9: 99’c
(I))
Sl: 75’, s”:
loo’, 75’ lOO’((
s13: 90’1
s1.2: 25’,
R/50
S2: 7si,
0
No change
s2: 50”,
JPI,: 75 ( / Ach.
Acetylcholine;
EM.
artery: ST!, ST segment Wry;
ST!,
ST segment
ergonovine;
C, control; coronary I, inactive
elevation; S. depression:
NTC. artery disease;
nitroglycerin: ECG. electrocardiogram; segment according to the reporting II. diffuse luminol narrowing.
sisted of six patients in whom angina had occurred during the 4 days before the provocation test, and the inactivedisease group consisted of five patients in whom angina had not occurred for at least 7 days before the provocation test. Fifteen patients in the control group (group 2) were examined because they were experiencing chest pain. This group included nine men and six women with a mean age of 54 years, ranging from 39 to 69 years (Table II). Group 2 was subdivided into groups 2A and 2B on the basis of the type of chest pain. The nine patients in group 2A had atypical chest pain and a history that was not suggestive of vasospastic angina. The six patients in group 2B had chest pain resembling angina. Twelve patients in group 2 had normal coronary arteriograms, and three had fixed coronary stenosis of 25 % to 50% luminal narrowing. Fully informed consent was obtained in writing from each patient. Procedures. All medications were discontinued for at least 24 hours before the procedures were begun, but the patients were allowed to use sublingual nitroglycerin. No patient took nitroglycerin during the 2 hours before a procedure. One patient in group 1 (case 6) had mistakenly taken 30 mg diltiazem and 5 mg nicorandil the previous evening. Cardiac catheterization was performed in the morning with the femoral puncture method. First, simultaneous biplane left ventricular cineangiography was performed. Second, control coronary arteriograms of the left
CAG. coronary arteriogram; system of the .4merican Heart
A, active disease: L, left coronary Association; R. right cormar~ nr-
coronary artery and the right coronary artery in the right anterior oblique projection and in the left anterior oblique projection were obtained with a biplaned cineangioiystem. A temporary pacemaker was inserted into the right ventricle, and the pacing rate was set at 50 beats/min. Selection of the right or left coronary artery for provocative tests. In six patients in group 1, whose angina attacks were documented by electrocardiograms, the coronary artery was chosen for testing on the basis of previous regional electlvcardiographic localization of myocardial ischemia during an angina attack. In the other five patients in group 1, whose angina attacks were not documented by electrocardiograms, the process of selection of the right or left coronary artery for provocative testing was as follows. First, the patients were asked to describe the details of their angina attacks. When near-syncope was recognized during an attack, the right coronary artery was chosen. Next, t,he left ventriculogram that was recorded before baseline coronary arteriography was examined carefully. When anterior wall motion of the left ventricle was judged to be slightly hypokinetic, the vasospastic angina-related coronary artery was believed to be the left coronary artery. When inferior wall motion of the left ventricle was judged to be slightly hypokinetic, the vasospastic angina-related coronary artery was believed t,o be the right coronary artery. This method was useful in the determination of’
Volume Number
124 1
Acetycholine
EM
nnsl-
(pg)
(‘host
pain
5/10
test
ECG: ST segment change f m V, lead)
lo/lo
ST0.6’ ST0.4f
v,-vs II, III,
“/lO
ST0.2+
VI-V6
9/10
STO.3:
II, III,
10
5110
STO.l,
Vty
10
8/10 4/10
ST0.3f STO.l/
I, v2-vI; aVL
10
5/10
ST0.3,
I, VI-VI;
.5
7/10
ST0.2;
Vs-VG
IO
2OilO
STO.21
II, III,
10
6/10
STO.15f
:10 5
II, III.
aVF
aVF
aVF aVF
CAG S6: 9gc,, Sl: 25’, s2: lOO@, s7: 50’; s13: loo’; Sl: 25? s2: loot;’ s7,8: 5O’c s9: loo’, S7,ll: 1OO’r SG: 75’; S7.8: 305 s9: loo”;’ Sl: 50’; s2: 99°F s3: 50”,, S6,ll: 75”~’ s13: 99’c Sl: 75’,’ s2: loo’; Sl: 5O’c s2: 99’; 4PL: 75’,;8
which coronary artery was responsible for vasospastic angina. We also examined the baseline coronary arteriogram carefully to determine whether focal stenosis or diffuse coronary segmental constriction caused by coronary spasm was present. When this angiographic finding was recognized in the right or left coronary arteriogram, either the right or left coronary artery was judged to be spastic, and this spastic coronary artery was chosen for testing. The above-mentioned three methods were used for the selection of the left or right coronary artery for the provocation test. The left coronary artery was judged to be the cause of vasospastic angina in two patients (cases 5 and 7) on the basis of slight hypokinesis of the anterior wall of the left. ventricle and in one patient (case 6) on the basis of spastic coronary artery. The right coronary artery was implicated in one patient by both a history of near-syncope during an atI ack and the spastic right coronary artery (case 4) and in another patient by only the spastic right coronary artery (case 10). As a result six left coronary arteries and five right coronary arteries were selected for provocative tests in group 1. These three points were also considered in the selection of the left or the right coronary artery for provocative tests in all 15 patients in group 2. One patient (case 15) had an episode of near-syncope during an attack, but there were no abnormal findings in the others. The left coronary artery was selected for provocative testing in 12 of the 15 patients in group 2. In bhe ot,her three patients, including case 15, t.he right coronary artery was selected for provocation test,ing.
versus ergorbne
in coronary spasm
41
Provocative tests. First, acetylcholine was injected in incremental doses of 50 and 100 pg in 5 ml 0.9 CCsaline solution into the left coronary artery (25 pg acetylcholine was injected first if the patient was suspected of definitely having vasospastic angina), and doses of 25 fig and 50 pg acetylcholine were injected into the right coronary artery. Patients were asked to report any chest pain and to grade it from 1 to 20 points. Ten points was considered to be equal to the intensity of the usual angina1 pain. A standard 12. lead electrocardiogram was recorded every minute. One minute after each injection coronary arteriograms were obtained, and subsequent injection of acetylcholine was done. The time interval between each injection was 2 minutes. The administration of acetylcholine was stopped when angina or ischemic ST changes appeared on the electrocardiogram, and coronary arteriography was performed immediately. When coronary artery spasm induced by acetylcholine did not disappear spontaneously within 3 minutes, 0.1 mg nitroglycerin was injected into the coronary artery, coronary arteriography was performed, and the Judkins catheter was removed. The sheath was left in the femoral artery, and the patient was moved to the observation room near the catheterization laboratory. For 2 hours the patient was carefully observed, the blood pressure was monitored, and a standard 12-lead electrocardiogram was recorded. The patient then returned to the catheterization laboratory, and the test of coronary artery spasm induced by ergonovine was started. When coronary artery spasm was not induced by acetylcholine or disappeared spontaneously, the intracoronary injection of nitroglycerin was not done, and intracoronary ergonovine injection was started 3 minutes after the last coronary arteriogram was t,aken. Baseline coronary arteriography was first performed in the same plane as in the acetylcholine provocat,ion test. Ergonovine in 0.9”; saline solution was slowly injected into the same coronary artery into which acetylcholine had been injected in titrated, l-minute increments of 1,5,10, and 30 pg that were diluted in volumes of 10 ml 0.9”, saline solution, as reported by Hackett et al.” At least 3 minutes were allowed to elapse between increments. Patients were asked to report any chest pain and to grade it from 1 to 20 points. A grading of 10 points was considered to be equal to the intensity of the usual angina1 pain. A standard 12-lead electrocardiogram was recorded every minute. If any chest pain or ischemic ST changes on the electrocardiogram occurred, coronary arteriography was performed. It was also performed after each increment of ergonovine was administered. The administration of ergonovine was stopped when angina or ischemic ST changes appeared on the electrocardiogram, and coronary arteriography was performed again. After the ergonovine provocation test was performed, an intracoronary injection of 0.1 mg nitroglycerin was given, and a final coronary arteriogram was performed. In seven of the 11 patients in group 1, the ergonovine provocation test was performed 2 hours after the intracoronary injection of nitroglycerin in the acetylcholine provocation test. In three patients (cases 5, 6, and 11) the ergonovine provocation test was performed 3 minutes after
42
Suzuki
et al.
Amencan
Hean
July 1992 Journal
Fig. 1. Left coronary arteriogram of patient 1 in group 1. Baseline arteriogram shows 75(, stenosis of proximal portion of left anterior descending art,ery (A). Injection of 25 pg acetylcholine into left coronary artery induced 99 ‘:; stenosis at this site (B). Coronary spasm was relieved by an intracoronary injection of nitroglycerin. Two hours later, injection of ergonovine (cumulative dose 6 Fg) into left coronary artery induced 99 “I stenosis at same site of left anterior descending artery (C). After intracoronary inject ion ot‘ nitroglycerin, spasm disappeared, but 75 “; stenosis remained in proximal portion of left anterior descending artery (D).
the acetylcholine provocation test, because the coronary artery spasm induced by acetylcholine disappeared spontaneously in one patient (case 5), and coronary artery spasm had not been induced by acetylcholine in the other patients (cases 6 and 11). In one patient (case 3) the ergonovine provocation test was performed 7 days after the acetylcholine provocation test. In all patients in group 2 the ergonovine provocation test was performed 3 minutes after the acetylcholine provocation test without any intracoronary injection of nitroglycerin. The diameter of the coronary arteries was measured with calipers at end diastole from 35 mm cineangiograms that were projected on a 28 x 20 cm screen. The measurement was performed in the same projection of coronary arteriography at each stage in the acetylcholine or ergonovine provocation test. The percentage of luminal narrowing of the coronary arteries was classified according to the reporting system of the American Heart Association.l” Diffuse luminal narrowing of the coronary arteries was recorded as “D.”
RESULTS
The results are summarized in Tables I and II. Group 1. Acetylcholine-induced coronary spasm occurred in nine of the 11 patients. Complete occlusion was demonstrated in seven patients, and 99 ‘, luminal narrowing of the coronary artery was demonstrated in two patients. Coronary spasm involved coronary segments with fixed stenosis in six of the seven patients. The cumulative dose of acetylcholine required for provocation of spasm was 26 to 75 pg. Acetylcholine-induced coronary spasm was associated with chest pain in all nine cases(grade 3 to 20); seven patients had ST elevation and two patient,s had ST depression. Ergonovine-induced coronary spasm occurred in all 11 patients. Complete occlusion was demonstrated in seven patients, and 99 c( luminal narrowing of the coronary artery was demonstrated in four
Volume Number
124 1
Acet~~cholinc
versus ergonovine
in coronar
spa:sm
43
Fig. 2. Left coronary arteriogram of patient 6 in group 1. Baseline arteriogram shows75% stenosisof proximal portion of left circumflex artery and no stenosisof left anterior descendingartery (A). Injection
ofacerylchofine (cumulative dose150pg) into left coronary artery did not induce spasm,and improvement of luminal narrowing in proximal portion of left circumflex artery (50[;. stenosis)is seen(8). Injection of 10pg ergonovineinto left coronary artery wasthen performed, and complet,eocclusionsare shownat proximal portions of left circumfiex artery and left anterior descendingartery (C). After an intracoronary in.jection of nitroglycerin, spasmsdisappeared,left coronary artery wasgenerally dilated, and there wasno stenosisin left circumflex artery or in left anterior descendingartery (0).
patients. The cumulative dose of ergonovine required for the provocation of’ spasm was 6 to 46 /lg. Ergonovine-induced coronary spasm was associated with chest. pain (grade 2 to 20) and with ST elevation in six patients and ST depression in five patients. In all except two paGents in group 1, the regions of occlusive (100 “C obstruction) or near-occlusive (99 5’0
luminal narrowing) spasm induced by acetylcholine were the same as those induced by ergonovine. That is, complete agreement (loo’> vs loo”, or 99‘1 vs 99 c,t) was obtained in six of nine patients, and nearly complete agreement (lOO”( vs 99(‘( 1 was obtained in
three patients, but electrocardiographic
changes dur-
ing attacks induced by acetylcholine were essentially the same as those induced by ergonovine in only seven of nine patients in group 1.
In three of six patients
in the acbive-disease group,
complete agreement of coronary spasm and electro-
cardiographic change between two provocation tests was obtained (cases 1,2, and 4). In contrast, complete agreemtint of coronary spasm and electrocardiographic change between two provocation tests was obtained in only one of five patients in the inactivedisease group (case 10). A typical case (case 1) is shown in Fig. 1. Near-occlusive spasm (99 % luminal narrowing) in the proximal portion of the left anterior descending coronary artery was induced by the intracoronary injection of acetylcholine, and focal coronary spasm in the same portion was repeatedly induced by the intracoronary injection of ergonovine. In two patients in group 1 (cases 6 and 11) the coronary artery response to the intracoronary injection of acetylcholine was quite different from the response to the intracoronary injection of ergonovine. One patient belonged to the inactive-disease group (case 6) and the other to the active-disease group (case 11). In
44
Suzuki
et al.
Table II. Clinical pain (group 2)
Group 2A 1 43/M ‘2 65/M
American
findings
Normal Normal
and results
Normal Normal
L/100 L/l00
of intracoronary
0 0
injection
No change No change
3 4
68/F
SG: 50’;
S6: 50°C
52/F
Normal
Normal
L/100 R/50
5
45/F
Normal
Normal
L/l00
6
39/M 64/M
Normal Normal
Normal Normal
L/100 L/l00
8 69/M 59/F 9 Group 2B 10 51/M
s1:3: 25rct Normal
s13: 25(‘. Normal ’
L/l00 L/l00
Normal
Normal
L/100
11
60/M
Normal
Normal
L/100
Discomfort 0
12 13 14
44/F 54/M 52/F
Normal Normal Normal
Normal s2: 25’r Normal
L/100 R/50 L/100
0 11 0
Biphasic T vr-v:j No change No change No change
15
51/M
Normal
Normal
R/50
5/10
No change
7
Ikxvnfort.
Chest discomfort.
Ot.her abbreviations
0 0 Discomfort 0 Discomfort 0 7/1O
No change
of acetylcholine
S6: 50’, s7: SO’,
and ergonovine
30 30
No change
S6: 50’, Sl,2,3,4:
30 30
No change
75”r (D) Normal
:10
No change No change No change No change No change
-
Normal S6,8: 5O’r 511,13: 50’, 513: 25’, Normal
30 30 30 :30
S6: 50’, s1.3: 751, S6: Sh’,
30
Normal s1,2,3: SO’< L-33,7: 50’, S8: ‘is’, 7, 50’ , h.3:
0 0 0 0 Discom fort 0 I) 0 0
in patients
No change No change
July 1992 Journal
with chest
S6:
50’,
S6:
“5’ -,
,
No change No change
s7: 50’ / SC? W’, 51,2: X’,
iLo change
Normal
No change No change
Normal S6.8: 2h”, s11.13: 25’ s1:3: SO’, Normal
No change No change No change
:30
Discom fort 0
30 30 30
0 0 0
No change No change No change
9/10
No change
30
Heart
No change
as in Table I.
case 6 focal spastic 75”O luminal narrowing of segment 13 in the left circumflex artery on the baseline coronary arteriogram decreased to 50 “;# luminal narrowing after the intracoronary injection of acetylcholine. Three minutes later the intracoronary injection of ergonovine induced occlusive spasm of the proximal portions of both the left circumflex artery and the left anterior descending artery (Fig. 2). The attack was associated with chest pain and ST elevation on the electrocardiogram. This paradoxic phenomenon was also demonstrated in case 11. Focal spastic 75’, luminal narrowing of segment 2 in the right coronary artery on the baseline coronary arteriogram decreased to 50’, luminal narrowing after the intracoronary injection of acetylcholine. Angina and ischemic electrocardiographic ST changes were not recognized. Three minutes later the intracoronary injection of ergonovine induced near-occlusive spasm of the same region of segment 2 in the right coronary artery. The attack was associated with chest pain and ST elevation on the elect.rocardiogram. Group 2. In all 15 patients chest pain associated with ischemic ST changes on the electrocardiogram
was not. induced by the intracoronary injection 01’ acetylcholine or ergonovine, but chest pain or chest discomfort was reported by five patients. Luminal narrowing of the coronary arteries of 90”;) or more was not induced. The cumulative dose of acetylcholine was 75 to 150 ~g and that of ergonovine was 46 P%. In group 2A acetylcholine induced 75’( luminal narrowing of a coronary art,ery in one patient and 25’l, to 50“;’ in three patients. In the remaining five patients there was no change. Ergonovine induced 25’C’ to 50’ ( luminal narrowing of a coronary arteq in five patients. In the remaining four patients there was no change. In group 2B acet,ylcholine induced 75”; luminal narrowing of a coronary artery in three patients and 25”, to 50 “(’ in two patients. In the remaining patient there was no change. Ergonovine induced 75’; luminal narrowing of a coronary artery in one patient and 25’, to 50’( in four patients. In the remaining patient there was no change. In all patients in group 2, except in the five patients who showed no response on coronary arteriograms to the intracoronary injection of the two agents, CONnary vasoconst.riction tended to occur in the same
Volume Number
124 1
regions after either provocation. However, the grade of coronary vasoconstriction differed, and both the region and the grade after acetylcholine injection were the same as that after ergonovine injection in only one patient (case 1). DISCUSSION Comparison of various pharmacologic agents for induction of coronary spasm. Several pharmacologic
agents have been used to induce coronary spasm, but there have been no detailed descriptions of coronary arteriography during coronary artery spasms induced by these agents except for a few incomplete studies that compared histamine with ergonovine (Kaski et a1.r7) and dopamine with ergonovine (Crea et, al.“). Acetylcholine has recently been introduced for the induction of coronary artery spasm.g Shibat,a et a1.18compared the acetylcholine and ergonovine provocation tests and found false-negative result,s with the ergonovine test, but they used intravenous and not intracoronary injections of ergonovine, and they did not state whether the coronary spasms induced by acetylcholine and by ergonovine were in the same segment. In our present study occlusive or near-occlusive (2-99’ ( luminal narrowing) coronary spasm was not induced by intracoronary injection of acetylcholine or ergonovine in the patients in group 2, but occlusive or near-occlusive coronary spasm with angina was induced in the same regions of the coronary arteries in all but two patients (cases6 and 11) in group 1. In these nine patients ergonovine-induced electrocardiographic changes occurred basically in the same leads in which acetylcholine-induced attacks were documented, except in one patient (case 8). In this patient bilateral coronary artery spasm was suspected, although a left coronary arteriogram was not obtained. The int.racoronary injection of ergonovine may have affected not only the directly injected right coronary artery but also the opposite left coronary artery through the coronary vein. In the cLinica setting the intracoronary injection of acetylchoine or ergonovine is considered to be useful for the induction of coronary art,ery spasm, but a subsequent intracoronary injection of ergonovine is needed when a spontaneous focal coronary spasm is relieved by the intracoronary injection of acetylcholine. The paradoxic phenomenon may be due to the fl,llowing: (1) an agent factor (that is, either a difference between acetylcholine and ergonovine in their ability to induce coronary spasm or the occurrence of endothelium-dependent relaxation induced by acetylcholine) or (2) a coronary arterial wall factor (that is. either the response of a local vascular smooth
Acetycholirw
L’ersus ergonoL:ine in coronary
spasm
45
muscle to the vasoconstrictive agents or the production, release, and diffusion of an endothelium-dependent relaxation factor in the local vascular endothelium). It can easily be predicted that coronary spasm will be induced by the intracoronary injection of either acetylcholine or ergonovine in patients with extremely active vasospastic angina. However, the paradoxic phenomenon cannot be explained by disease activity alone, because only one patient (case No. 6) had inact,ive disease and the other (case No. 11) had active disease. The exact mechanism of this phenomenon remains unknown. Of considerable interest is the observation that the focal spastic coronary segment in which ergonovine-induced coronary spasm is subsequently demonstrated can exhibit vasodilation in responseto the endothelium-dependent relaxation factor induced by the intracoronary injection of acetylcholine. Mechanism of coronary artery spasm. The mechanism of the induction of coronary artery spasm by the intracoronary injection of acetylcholine remains unclear. Ludmer et al.“O performed intracoronary injections of acetylcholine in patients with coronary atherosclerosis and frequently noted vasoconstriction. They reported that vasoconstriction induced by acetylcholine occurred both early and late in the course of coronary atherosclerosis, and they suggested that the abnormal vascular response to acetylcholine represented a defect in endothelial vasodilator function, which was important in the pat.hogenesis of coronary spasm. Yasue et al.” proposed that a direct cholinergic muscarinic effect of acetylcholine caused the coronary spasm in patient,s with variant angina and suggested that the coronary arteries involved in spasm might have atherosclerosis with dysfunctional endothelium. Miwa et al. l4 also postulated that the coronary arteries in patients with variant, angina were supersensitive to acetylcholine and suggested that they had a malfunctioning endothelium that could not produce sutlicient protective factors against spasm, such as prostaglandin 12 or other endothelium-derived relaxing factors. These reports indicate that coronary spasm may result, from dysfunctional endothelium that, cannot release endothelium-dependent relaxing factor. In their experiment,al study, however, Bossaller et al.“’ reported that impaired cholinergic responses in atherosclerotic arteries reflected a muscarinic defect and not an inability of the endothelium to release endothelial factor or of smooth muscle to respond to it. In two of our patients in group 1 the paradoxic phenomenon was observed, and this phenomenon was considered to be related to the endothelium-dependent, relaxing factor induced
46
Suzuki
et al.
by acetylcholine. Thus the mechanism of coronary artery spasmcaused by the intracoronary injection of acetylcholine is not explained simply by impaired endothelium-dependent relaxation induced by coronary atherosclerosis. The mechanism of the induction of coronary artery spasm by ergonovine also remains unclear, although ergonovine has been the most commonly used agent, to provoke coronary spasm in vivo. Some experimental studies have indicated that ergonovine acts mainly through serotogenic receptors and that there is some relationship between the hypercontraction of smooth muscle induced by ergonovine and the atherosclerotic change in coronary arteries.‘l, I53l6 Kawachi et al.‘l reported that endothelial denudation and a long-term high-cholesterol diet in dogs resulted in a regional atherosclerotic change and that smooth muscle in atherosclerotic arteries becan& hypersensitive to ergonovine. They suggested that coronary spasm induced by ergonovine in humans was related to the presence of atherosclerotic changes in coronary arteries. In vivo studies, however, have not confirmed these results. Hackett et. a1.8reported that the intracoronary injection of ergonovine induced localized coronary spasm and postulated that local arterial hyperactivity was the cause of spasm in patients with variant angina. In our study both acetylcholine and ergonovine induced coronary artery spasm in the same region of the coronary arteries in all patients except two in group 1. Although seven patients in group 1 had received intracoronary injections of nitroglycerin 2 hours earlier, coronary artery spasm was repeatedly documented after the intracoronary injection of ergonovine in all seven patients. In contrast, mild (Zc’;’ to 50’0 luminal narrowing) or moderate (75”~ luminal narrowing) coronary vasoconstriction was frequently induced by intracoronary acetylcholine or ergonovine in patients in group 2, but the grade of coronary vasoconstriction induced by the two agents differed in many patients in group 2. Our results indicate that nonspecific hypersensitivity to various agents (i.e., acetylcholine and ergonovine) located in definite regions of the coronary arteries in many patients with vasospastic angina generally plays an important role in the induction of coronary artery spasm, but this theory alone is not sufficient to explain the paradoxic phenomenon. Limitations of this study. This study has two limitations. One is the study population. Vasospastic angina was definitely diagnosed in only six patients in group 1. In the remaining five patients angina attacks were first demonstrated in the catheterization laboratory, although the patients had a history of typical
American
Heart
July 1992 Journal
vasospastic angina. In all five patients, however. the character of the attack in t,he cathet,erizat,ion laboratory was the same as that of usual at.tacks, and the ergonovine provocation test (the standard method for the diagnosis of vasospastic angina) documented coronary spasm in these five patients. Group 2 COG sisted of patient,s with chest pain, and the results of acetylcholine and ergonovine provocation tests were generally reasonable. In some patients, however (cases4, 10, Il. 13, and 14). 75 ‘; luminal narrowing of the coronary arteries without an angina attack or ischemic ST changes in the elect.rocardiogram wa:, induced by the intracoronary inject,ion of acetylcholine or ergonovine. This moderate coronary vasoct )ilstriction was more common in group 2B than in group 2A. An int.ermediat,e stage between normal and typ ical vasospastic angina is possibly present. Some pa tients in group 2B may have t,he intermediate stage. Further follow-up study is needed tc~ romfirm 1hi:, hypothesis. The second limitation is the methodology of the angina provocation test. Intracoronary injection 01’ ergonovine was performed after that of acetylcholinr on the same day in all but, one patient. Therefore thud response of the coronary artery to intracoronary ?I gonovine was affected by endotheliun-derived relax ing factor induced by acetylcholine and by intracol.~ onary nitroglycerin injected for the relief of coronar>’ artery spasm that did not disappear spontaneous11 To reduce the effect of t,hese fact.ors we did the ergonovine provocation test 2 hours after the acetJ.1 choline provocation test. Actually, the baseline ctii’ onary arteriograms taken immediately before the C”I gonovine provocation test were nearly the same ah those taken before the acetylcholine provocation ?esi REFERENCES
A, Severi S, De Nes M, 1,‘Abbate A. Marzilli M, Baii estra A. Parodi 0, Biagini A, Distante A. “Variant angina”: one aspect of a continuous spectrum of vasospastic mpocardial i-chemia. Am .I Cardiol 1978;42:1019-36. Schroeder .JS. Bolen JL. Quint RA. Provocation of coronar> spasm with ergonovine maleate: new test with results in 57 patients undergoing coronary arteriography. .4m .J (‘artlioi 1977;40:4R7-91. Heulper FA. Proudfit WI,, Razavi M. Shirey El<, Greentitreet K, Sheldon WC. Ergonovine maleate provocative test for car onary artery spasm. Am J Cardiol 1978;41:6:1 l-40. Ginsburg R, Bristow MR, liantrowitz N, Haim 1)s. Harrison LX. Histamine provocation of clinical corcrnar?; artery spasm: implications concerning pathogenesis of’ variant angina p”~’ toris. AM HEAK’I‘ J 1981;102:819-38. Crea F, C’hierchia S, Eiaski JC. Davies GJ. Margonato A. Mi ran DO. Rlaseri A. I’rovtrcat ion of’ cnronarv hpasm hy dopam ine in patients with active variant angina pectoris. Circulation I I)Hfi:74:“lil’-‘I. Yasue H, Nagao M, Omote S, Takizawa A, Miwa li. Tanaka S. Coronary arterial spasm and Prinzmetal’s variant form 1)f’ angina induced by hyperventilation and Trii-buffer infusirjn I’irrulatitrn 1978:.58:.X-62.
1. Maseri
2.
:I
4
5
fi.
Volume
124
Number
1
7. Waters DD, Szlachcic d, Bonan R, Miller DD, Dauwe F, Theroux P. Comparative sensitivity of exercise, cold pressor, and ergonovine testing in provoking attacks of variant angina in patients with active disease. Circulation 1983;67:310-5. 8. Hackett D, Larkin S. Chierchia S, Davies G, Kaski JC, Maseri A. Induction of coronary artery spasm by a direct local action cut’ ergonovine. Circulation 1987;75:577-82. 9. Yasue H, Horio Y. Nakamura N. Fujii H, Imoto N, Sonoda R, Kuzivama K. Obata K. Morikami Y. Kimura T. Induction of coronarv artery spasm by acetylcholine in patients with variant angina: possible role of the parasympathetic nervous system in the pathogenesis of coronary artery spasm. Circulation 19Rti:i?:~%i6-63. lti. ‘l‘oda N. Isolated human coronary arteries in response to vasoconstrictor substances. Am J Physiol 1983;245:H937-41. 11. Kawach: Y, Tomoike H, Maruoka Y, Kikuchi Y, Araki H, Ishii Y.,‘l’anaka K, Nakamura M. Selective hypercontraction caused hy ergonovine in the canine coronary artery under conditions of induced atherosclerosis. Circulation 1984;69:441-50. 12. Kalsnee S. Richards R. Coronary arteries of cardiac patients are hyperactive and contain stores of amines: a mechanism for CI )ronary spasm. Science 1984;223:1435-7. 13 American Heart Association committee report.. A reporting s;;stem on patients evaluated for coronary artery disease. Circulatinn 1976;51:5-40. 14. Miwa K. Goto M, Lee .JD, Matsuyama F, Schimizu H, Kato T, H ara A, Uakamura T. Supersensitivity of coronary arteries in variant angina to spasm induced by intracoronary acetylcholine. Am J Cardiol 1988:61:77-82.
Acetycholine
versus ergonovine
in coronary spasm
47
15. Sakanishi M, Yonemura K. On the mode of action of ergometrine in the isolated dog coronary artery. Eur J Pharmocol 1980;64:157-60. 16. Henry PD, Yokoyama M. Supersensitivity of atherosclerotic rabbit aorta to ergonovine: mediation by a serotonergic mechanism. J Clin Invest 1980;66:306-13. 17. Kaski JC, Crea F, Meran D, Rodriguez L, Araujo L, Chierchia S, Davies G, Maseri A. Local coronary supersensitivity to diverse vasoconstrictive stimuli in patients with variant angina. Circulation 1986;74:1255-65. 18. Shibata N, Mizobe H, Miyazaki Y, Miura M, Miyazawa Y. Komatsu Y. The comparison of acetylcholine and ergonovine in the provocations of coronary vasospasm [Abstract]. J Am Co11 Cardiol 1989;13:132A. 19. Okumura K, Yasue H, Matsuyama K, Goto K, Miyagi H, Ogawa H, Matsuyama K. Sensitivity and specificity of intracoronary injection of acetylcholine for the induction of coronary artery spasm. J Am Co11 Cardiol 1988;12:883-8. 20. Ludmer PL, Selwyn AP, Shook TL, Wayne RR, Mudge GH, Alexander RW, Ganz P. Paradoxic vasoconstrictions induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med 1986;315:1046-51. 21. Bossaller C, Habib GB, Yamamoto H, Williams C, Wells S. Henry PD. Impaired muscarinic endothelium-dependent relaxation and cyclic guanosine 5’.monophosphate formation in atherosclerotic human coronary artery and rabbit aorta. J Clin Invest 1987;79:170-4.
with
To investigate the mechanism of coronary spasm, we compared the action of acetylcholine with that of ergonovine in 11 patients with vasospastic angina (group 1) and in 15 patients with chest pain (group 2). Coronary arteriography was performed immediately after the patients received intracoronary injections of titrated increments of each agent. In the patients in group 1 occlusive or near-occlusive (99% luminal narrowing) coronary spasm associated with angina and ischemic electrocardiographic ST changes was noted in nine of 11 patients receiving acetylcholine and in all 11 patients receiving ergonovine. The region and the degree of the most severe coronary spasm on coronary arteriograms evoked by the two agents were the same in nine of the 11 patients in group 1. In the other two patients in group 1, spontaneous focal coronary spastic stenosis in the baseline coronary arteriogram was relieved by the intracoronary injection of acetylcholine, and a focal coronary occlusive spasm in the same region was induced repeatedly by the subsequent intracoronary injection of ergonovine (paradoxic phenomenon). In contrast, occlusive or near-occlusive coronary spasm was not induced by either agent in any patient in group 2. These results suggest that the two provocative tests for coronary spasm that involve acetylcholine and ergonovine are clinically useful in the diagnosis of vasospastic angina, but testing with intracoronary ergonovine is needed when a spontaneous focal coronary spasm is relieved by the intracoronary injection of acetylcholine. The results also indicate that in many patients with vasospastic angina, nonspecific hypersensitivity to acetylcholine or ergonovine in a definite region of the coronary arteries generally plays an important role in the induction of coronary spasm. This theory alone, however, is not sufficient to explain the paradoxic phenomenon observed in a few patients with vasospastic angina. (AM HEART J 1992;124:39.)
Yukisono Suzuki, MD, Shingo Tokunaga, MD, Shigeru Ikeguchi, MD, Shinji Miki, MD,” Tomoyuki Iwase, MD,” Tetsuya Tomita, MD,” Tomoyuki
Murakami, MD,” and Chuichi Kawai, MD.” Kyoto, Japan
Coronary artery spasm is widely recognized as the cause of variant angina.l However, the true mechanism of coronary artery spasm remains unclear. Various agents and stimuli can provoke coronary artery spasm.2-7 Ergonovine is most commonly used to induce coronary spasm in vivo by intravenous or intracoronary injection.” Recently Yasue et a1.greported that intracoronary injection of acetylcholine was useful in the induction of coronary artery spasm. Some in vitro experiments have elucidated and compared the vasoactive properties of various agents.l@r” In the clinical setting, however, no such comparison
has been reported. The aim of this study is to compare the action of acetylcholine with that of ergonovine in provoking coronary artery spasm in vivo and to clarify the mechanism of coronary artery spasm.
From the Cardim ascular Department, Third Division of Internal Medicine.
10 men and one woman with a mean age of 54 years, ranging from 43 to 76 years (Table I). Eight patients had fixed coronary stenosis with 25 % to 90 % luminal narrowing, and three had no fixed coronary stenosis. The patients in group 1 were divided into active-disease and inactive-disease groups. The active-disease group con-
Received Reprint Kyotn Japan. -1/l/37350
for publication -quests. Universit>
Chuichi Hospital,
Aug.
Ijinkai aKyoto
:X1, 1990;
Takeda General Hospital University Hospital.
accepted
Kawai. MD, Third Division 5-l Kawaracho, Shogoin.
Dec.
and
12, 1991.
of Internal Sakyo-ku,
Medicine, Kynto 606,
METHODS Patients.
We studied 26 patients. Eleven had a history of typical vasospasticangina (chestpain at rest early in the morning). Transient ST segmentelevation or depression occurring spontaneously at rest was documented with standard 1%lead electrocardiogramsor Holter electrocardiograms in six patients before cardiac catheterization (cases1, 2, 3, 8, 9, and 11). This group (group 1) included
39
40
Suzuki
et al.
American
Table I. Clinical findings and results of intracoronary vasospastic angina (group 1) Coronary
Disease Case
artcry -
inject,ion
Sex
Sitfxl dose CF.&
c
and ergonovine Ach
strnosis
Age Csrll
UCtiL~it)
of acetylcholine
pain
Chest
in patients
Heart
with
test
KG: ST segment change (mV, leadi
-
STl.Of V,-VC; STl.l* II, III, aVF
(‘A(; --~ __.~S6: 99’,
1 2
A A
52/M
S6: 75’,
7.5’ /
44/M
Normal
Normal
Li2,5 R/s
20/10
:3
I
47/M
s13: 50’,
I,/50
“oil0
4
A
56/M
s7: 25’, s13: 50’, s1,2,3: SO’,
s1,2: ‘Ii’ UC <
R/25
7ilU
I
63/M
Normal
Normal
L/50
6ilO
I I
43/F 52/M
Sll: 75(, S6: 5O’c
Normal S6: 50 I’,
L/100 L/25
0 5ilO
8
A
.56/M
x/10
ST0.41 II, III, aVp
A
76/M
s2: SO’, S6: 50’, S6: 50°C
R/25
9
s2: 25’1 S6: 75”c S6: 50’~
Lb5
ill0
STO.l, V;-VI-;
Sll: 75°C
57/M
Sll: 75’, s13: 90’, s1,2: 25’,
S6,ll: s13:
R/50
lO/lO
STO.lt II, III, aVk
Sl:
SO’,
s2:
loo’,
I
10
A
11
44/M
r,/lO
July 1992 Journal
STO.4, I. II, III, aVl aVF, Vd-Vtj ST0.21 II, III, aVF ST0.2t I. aVI,, VS-VI; No change ST0.41 VI-V;, STO.lj aV1
Sl: 75”, s2: loo”,
si: loo’, s1:i: loo’, Sl: 75’1 <
S’), -. 100’ / 57: 75f, S8,Y: 100 I( Sll: 501, S6,7.8: 75’< s9: 99’c
(I))
Sl: 75’, s”:
loo’, 75’ lOO’((
s13: 90’1
s1.2: 25’,
R/50
S2: 7si,
0
No change
s2: 50”,
JPI,: 75 ( / Ach.
Acetylcholine;
EM.
artery: ST!, ST segment Wry;
ST!,
ST segment
ergonovine;
C, control; coronary I, inactive
elevation; S. depression:
NTC. artery disease;
nitroglycerin: ECG. electrocardiogram; segment according to the reporting II. diffuse luminol narrowing.
sisted of six patients in whom angina had occurred during the 4 days before the provocation test, and the inactivedisease group consisted of five patients in whom angina had not occurred for at least 7 days before the provocation test. Fifteen patients in the control group (group 2) were examined because they were experiencing chest pain. This group included nine men and six women with a mean age of 54 years, ranging from 39 to 69 years (Table II). Group 2 was subdivided into groups 2A and 2B on the basis of the type of chest pain. The nine patients in group 2A had atypical chest pain and a history that was not suggestive of vasospastic angina. The six patients in group 2B had chest pain resembling angina. Twelve patients in group 2 had normal coronary arteriograms, and three had fixed coronary stenosis of 25 % to 50% luminal narrowing. Fully informed consent was obtained in writing from each patient. Procedures. All medications were discontinued for at least 24 hours before the procedures were begun, but the patients were allowed to use sublingual nitroglycerin. No patient took nitroglycerin during the 2 hours before a procedure. One patient in group 1 (case 6) had mistakenly taken 30 mg diltiazem and 5 mg nicorandil the previous evening. Cardiac catheterization was performed in the morning with the femoral puncture method. First, simultaneous biplane left ventricular cineangiography was performed. Second, control coronary arteriograms of the left
CAG. coronary arteriogram; system of the .4merican Heart
A, active disease: L, left coronary Association; R. right cormar~ nr-
coronary artery and the right coronary artery in the right anterior oblique projection and in the left anterior oblique projection were obtained with a biplaned cineangioiystem. A temporary pacemaker was inserted into the right ventricle, and the pacing rate was set at 50 beats/min. Selection of the right or left coronary artery for provocative tests. In six patients in group 1, whose angina attacks were documented by electrocardiograms, the coronary artery was chosen for testing on the basis of previous regional electlvcardiographic localization of myocardial ischemia during an angina attack. In the other five patients in group 1, whose angina attacks were not documented by electrocardiograms, the process of selection of the right or left coronary artery for provocative testing was as follows. First, the patients were asked to describe the details of their angina attacks. When near-syncope was recognized during an attack, the right coronary artery was chosen. Next, t,he left ventriculogram that was recorded before baseline coronary arteriography was examined carefully. When anterior wall motion of the left ventricle was judged to be slightly hypokinetic, the vasospastic angina-related coronary artery was believed to be the left coronary artery. When inferior wall motion of the left ventricle was judged to be slightly hypokinetic, the vasospastic angina-related coronary artery was believed t,o be the right coronary artery. This method was useful in the determination of’
Volume Number
124 1
Acetycholine
EM
nnsl-
(pg)
(‘host
pain
5/10
test
ECG: ST segment change f m V, lead)
lo/lo
ST0.6’ ST0.4f
v,-vs II, III,
“/lO
ST0.2+
VI-V6
9/10
STO.3:
II, III,
10
5110
STO.l,
Vty
10
8/10 4/10
ST0.3f STO.l/
I, v2-vI; aVL
10
5/10
ST0.3,
I, VI-VI;
.5
7/10
ST0.2;
Vs-VG
IO
2OilO
STO.21
II, III,
10
6/10
STO.15f
:10 5
II, III.
aVF
aVF
aVF aVF
CAG S6: 9gc,, Sl: 25’, s2: lOO@, s7: 50’; s13: loo’; Sl: 25? s2: loot;’ s7,8: 5O’c s9: loo’, S7,ll: 1OO’r SG: 75’; S7.8: 305 s9: loo”;’ Sl: 50’; s2: 99°F s3: 50”,, S6,ll: 75”~’ s13: 99’c Sl: 75’,’ s2: loo’; Sl: 5O’c s2: 99’; 4PL: 75’,;8
which coronary artery was responsible for vasospastic angina. We also examined the baseline coronary arteriogram carefully to determine whether focal stenosis or diffuse coronary segmental constriction caused by coronary spasm was present. When this angiographic finding was recognized in the right or left coronary arteriogram, either the right or left coronary artery was judged to be spastic, and this spastic coronary artery was chosen for testing. The above-mentioned three methods were used for the selection of the left or right coronary artery for the provocation test. The left coronary artery was judged to be the cause of vasospastic angina in two patients (cases 5 and 7) on the basis of slight hypokinesis of the anterior wall of the left. ventricle and in one patient (case 6) on the basis of spastic coronary artery. The right coronary artery was implicated in one patient by both a history of near-syncope during an atI ack and the spastic right coronary artery (case 4) and in another patient by only the spastic right coronary artery (case 10). As a result six left coronary arteries and five right coronary arteries were selected for provocative tests in group 1. These three points were also considered in the selection of the left or the right coronary artery for provocative tests in all 15 patients in group 2. One patient (case 15) had an episode of near-syncope during an attack, but there were no abnormal findings in the others. The left coronary artery was selected for provocative testing in 12 of the 15 patients in group 2. In bhe ot,her three patients, including case 15, t.he right coronary artery was selected for provocation test,ing.
versus ergorbne
in coronary spasm
41
Provocative tests. First, acetylcholine was injected in incremental doses of 50 and 100 pg in 5 ml 0.9 CCsaline solution into the left coronary artery (25 pg acetylcholine was injected first if the patient was suspected of definitely having vasospastic angina), and doses of 25 fig and 50 pg acetylcholine were injected into the right coronary artery. Patients were asked to report any chest pain and to grade it from 1 to 20 points. Ten points was considered to be equal to the intensity of the usual angina1 pain. A standard 12. lead electrocardiogram was recorded every minute. One minute after each injection coronary arteriograms were obtained, and subsequent injection of acetylcholine was done. The time interval between each injection was 2 minutes. The administration of acetylcholine was stopped when angina or ischemic ST changes appeared on the electrocardiogram, and coronary arteriography was performed immediately. When coronary artery spasm induced by acetylcholine did not disappear spontaneously within 3 minutes, 0.1 mg nitroglycerin was injected into the coronary artery, coronary arteriography was performed, and the Judkins catheter was removed. The sheath was left in the femoral artery, and the patient was moved to the observation room near the catheterization laboratory. For 2 hours the patient was carefully observed, the blood pressure was monitored, and a standard 12-lead electrocardiogram was recorded. The patient then returned to the catheterization laboratory, and the test of coronary artery spasm induced by ergonovine was started. When coronary artery spasm was not induced by acetylcholine or disappeared spontaneously, the intracoronary injection of nitroglycerin was not done, and intracoronary ergonovine injection was started 3 minutes after the last coronary arteriogram was t,aken. Baseline coronary arteriography was first performed in the same plane as in the acetylcholine provocat,ion test. Ergonovine in 0.9”; saline solution was slowly injected into the same coronary artery into which acetylcholine had been injected in titrated, l-minute increments of 1,5,10, and 30 pg that were diluted in volumes of 10 ml 0.9”, saline solution, as reported by Hackett et al.” At least 3 minutes were allowed to elapse between increments. Patients were asked to report any chest pain and to grade it from 1 to 20 points. A grading of 10 points was considered to be equal to the intensity of the usual angina1 pain. A standard 12-lead electrocardiogram was recorded every minute. If any chest pain or ischemic ST changes on the electrocardiogram occurred, coronary arteriography was performed. It was also performed after each increment of ergonovine was administered. The administration of ergonovine was stopped when angina or ischemic ST changes appeared on the electrocardiogram, and coronary arteriography was performed again. After the ergonovine provocation test was performed, an intracoronary injection of 0.1 mg nitroglycerin was given, and a final coronary arteriogram was performed. In seven of the 11 patients in group 1, the ergonovine provocation test was performed 2 hours after the intracoronary injection of nitroglycerin in the acetylcholine provocation test. In three patients (cases 5, 6, and 11) the ergonovine provocation test was performed 3 minutes after
42
Suzuki
et al.
Amencan
Hean
July 1992 Journal
Fig. 1. Left coronary arteriogram of patient 1 in group 1. Baseline arteriogram shows 75(, stenosis of proximal portion of left anterior descending art,ery (A). Injection of 25 pg acetylcholine into left coronary artery induced 99 ‘:; stenosis at this site (B). Coronary spasm was relieved by an intracoronary injection of nitroglycerin. Two hours later, injection of ergonovine (cumulative dose 6 Fg) into left coronary artery induced 99 “I stenosis at same site of left anterior descending artery (C). After intracoronary inject ion ot‘ nitroglycerin, spasm disappeared, but 75 “; stenosis remained in proximal portion of left anterior descending artery (D).
the acetylcholine provocation test, because the coronary artery spasm induced by acetylcholine disappeared spontaneously in one patient (case 5), and coronary artery spasm had not been induced by acetylcholine in the other patients (cases 6 and 11). In one patient (case 3) the ergonovine provocation test was performed 7 days after the acetylcholine provocation test. In all patients in group 2 the ergonovine provocation test was performed 3 minutes after the acetylcholine provocation test without any intracoronary injection of nitroglycerin. The diameter of the coronary arteries was measured with calipers at end diastole from 35 mm cineangiograms that were projected on a 28 x 20 cm screen. The measurement was performed in the same projection of coronary arteriography at each stage in the acetylcholine or ergonovine provocation test. The percentage of luminal narrowing of the coronary arteries was classified according to the reporting system of the American Heart Association.l” Diffuse luminal narrowing of the coronary arteries was recorded as “D.”
RESULTS
The results are summarized in Tables I and II. Group 1. Acetylcholine-induced coronary spasm occurred in nine of the 11 patients. Complete occlusion was demonstrated in seven patients, and 99 ‘, luminal narrowing of the coronary artery was demonstrated in two patients. Coronary spasm involved coronary segments with fixed stenosis in six of the seven patients. The cumulative dose of acetylcholine required for provocation of spasm was 26 to 75 pg. Acetylcholine-induced coronary spasm was associated with chest pain in all nine cases(grade 3 to 20); seven patients had ST elevation and two patient,s had ST depression. Ergonovine-induced coronary spasm occurred in all 11 patients. Complete occlusion was demonstrated in seven patients, and 99 c( luminal narrowing of the coronary artery was demonstrated in four
Volume Number
124 1
Acet~~cholinc
versus ergonovine
in coronar
spa:sm
43
Fig. 2. Left coronary arteriogram of patient 6 in group 1. Baseline arteriogram shows75% stenosisof proximal portion of left circumflex artery and no stenosisof left anterior descendingartery (A). Injection
ofacerylchofine (cumulative dose150pg) into left coronary artery did not induce spasm,and improvement of luminal narrowing in proximal portion of left circumflex artery (50[;. stenosis)is seen(8). Injection of 10pg ergonovineinto left coronary artery wasthen performed, and complet,eocclusionsare shownat proximal portions of left circumfiex artery and left anterior descendingartery (C). After an intracoronary in.jection of nitroglycerin, spasmsdisappeared,left coronary artery wasgenerally dilated, and there wasno stenosisin left circumflex artery or in left anterior descendingartery (0).
patients. The cumulative dose of ergonovine required for the provocation of’ spasm was 6 to 46 /lg. Ergonovine-induced coronary spasm was associated with chest. pain (grade 2 to 20) and with ST elevation in six patients and ST depression in five patients. In all except two paGents in group 1, the regions of occlusive (100 “C obstruction) or near-occlusive (99 5’0
luminal narrowing) spasm induced by acetylcholine were the same as those induced by ergonovine. That is, complete agreement (loo’> vs loo”, or 99‘1 vs 99 c,t) was obtained in six of nine patients, and nearly complete agreement (lOO”( vs 99(‘( 1 was obtained in
three patients, but electrocardiographic
changes dur-
ing attacks induced by acetylcholine were essentially the same as those induced by ergonovine in only seven of nine patients in group 1.
In three of six patients
in the acbive-disease group,
complete agreement of coronary spasm and electro-
cardiographic change between two provocation tests was obtained (cases 1,2, and 4). In contrast, complete agreemtint of coronary spasm and electrocardiographic change between two provocation tests was obtained in only one of five patients in the inactivedisease group (case 10). A typical case (case 1) is shown in Fig. 1. Near-occlusive spasm (99 % luminal narrowing) in the proximal portion of the left anterior descending coronary artery was induced by the intracoronary injection of acetylcholine, and focal coronary spasm in the same portion was repeatedly induced by the intracoronary injection of ergonovine. In two patients in group 1 (cases 6 and 11) the coronary artery response to the intracoronary injection of acetylcholine was quite different from the response to the intracoronary injection of ergonovine. One patient belonged to the inactive-disease group (case 6) and the other to the active-disease group (case 11). In
44
Suzuki
et al.
Table II. Clinical pain (group 2)
Group 2A 1 43/M ‘2 65/M
American
findings
Normal Normal
and results
Normal Normal
L/100 L/l00
of intracoronary
0 0
injection
No change No change
3 4
68/F
SG: 50’;
S6: 50°C
52/F
Normal
Normal
L/100 R/50
5
45/F
Normal
Normal
L/l00
6
39/M 64/M
Normal Normal
Normal Normal
L/100 L/l00
8 69/M 59/F 9 Group 2B 10 51/M
s1:3: 25rct Normal
s13: 25(‘. Normal ’
L/l00 L/l00
Normal
Normal
L/100
11
60/M
Normal
Normal
L/100
Discomfort 0
12 13 14
44/F 54/M 52/F
Normal Normal Normal
Normal s2: 25’r Normal
L/100 R/50 L/100
0 11 0
Biphasic T vr-v:j No change No change No change
15
51/M
Normal
Normal
R/50
5/10
No change
7
Ikxvnfort.
Chest discomfort.
Ot.her abbreviations
0 0 Discomfort 0 Discomfort 0 7/1O
No change
of acetylcholine
S6: 50’, s7: SO’,
and ergonovine
30 30
No change
S6: 50’, Sl,2,3,4:
30 30
No change
75”r (D) Normal
:10
No change No change No change No change No change
-
Normal S6,8: 5O’r 511,13: 50’, 513: 25’, Normal
30 30 30 :30
S6: 50’, s1.3: 751, S6: Sh’,
30
Normal s1,2,3: SO’< L-33,7: 50’, S8: ‘is’, 7, 50’ , h.3:
0 0 0 0 Discom fort 0 I) 0 0
in patients
No change No change
July 1992 Journal
with chest
S6:
50’,
S6:
“5’ -,
,
No change No change
s7: 50’ / SC? W’, 51,2: X’,
iLo change
Normal
No change No change
Normal S6.8: 2h”, s11.13: 25’ s1:3: SO’, Normal
No change No change No change
:30
Discom fort 0
30 30 30
0 0 0
No change No change No change
9/10
No change
30
Heart
No change
as in Table I.
case 6 focal spastic 75”O luminal narrowing of segment 13 in the left circumflex artery on the baseline coronary arteriogram decreased to 50 “;# luminal narrowing after the intracoronary injection of acetylcholine. Three minutes later the intracoronary injection of ergonovine induced occlusive spasm of the proximal portions of both the left circumflex artery and the left anterior descending artery (Fig. 2). The attack was associated with chest pain and ST elevation on the electrocardiogram. This paradoxic phenomenon was also demonstrated in case 11. Focal spastic 75’, luminal narrowing of segment 2 in the right coronary artery on the baseline coronary arteriogram decreased to 50’, luminal narrowing after the intracoronary injection of acetylcholine. Angina and ischemic electrocardiographic ST changes were not recognized. Three minutes later the intracoronary injection of ergonovine induced near-occlusive spasm of the same region of segment 2 in the right coronary artery. The attack was associated with chest pain and ST elevation on the elect.rocardiogram. Group 2. In all 15 patients chest pain associated with ischemic ST changes on the electrocardiogram
was not. induced by the intracoronary injection 01’ acetylcholine or ergonovine, but chest pain or chest discomfort was reported by five patients. Luminal narrowing of the coronary arteries of 90”;) or more was not induced. The cumulative dose of acetylcholine was 75 to 150 ~g and that of ergonovine was 46 P%. In group 2A acetylcholine induced 75’( luminal narrowing of a coronary art,ery in one patient and 25’l, to 50“;’ in three patients. In the remaining five patients there was no change. Ergonovine induced 25’C’ to 50’ ( luminal narrowing of a coronary arteq in five patients. In the remaining four patients there was no change. In group 2B acet,ylcholine induced 75”; luminal narrowing of a coronary artery in three patients and 25”, to 50 “(’ in two patients. In the remaining patient there was no change. Ergonovine induced 75’; luminal narrowing of a coronary artery in one patient and 25’, to 50’( in four patients. In the remaining patient there was no change. In all patients in group 2, except in the five patients who showed no response on coronary arteriograms to the intracoronary injection of the two agents, CONnary vasoconst.riction tended to occur in the same
Volume Number
124 1
regions after either provocation. However, the grade of coronary vasoconstriction differed, and both the region and the grade after acetylcholine injection were the same as that after ergonovine injection in only one patient (case 1). DISCUSSION Comparison of various pharmacologic agents for induction of coronary spasm. Several pharmacologic
agents have been used to induce coronary spasm, but there have been no detailed descriptions of coronary arteriography during coronary artery spasms induced by these agents except for a few incomplete studies that compared histamine with ergonovine (Kaski et a1.r7) and dopamine with ergonovine (Crea et, al.“). Acetylcholine has recently been introduced for the induction of coronary artery spasm.g Shibat,a et a1.18compared the acetylcholine and ergonovine provocation tests and found false-negative result,s with the ergonovine test, but they used intravenous and not intracoronary injections of ergonovine, and they did not state whether the coronary spasms induced by acetylcholine and by ergonovine were in the same segment. In our present study occlusive or near-occlusive (2-99’ ( luminal narrowing) coronary spasm was not induced by intracoronary injection of acetylcholine or ergonovine in the patients in group 2, but occlusive or near-occlusive coronary spasm with angina was induced in the same regions of the coronary arteries in all but two patients (cases6 and 11) in group 1. In these nine patients ergonovine-induced electrocardiographic changes occurred basically in the same leads in which acetylcholine-induced attacks were documented, except in one patient (case 8). In this patient bilateral coronary artery spasm was suspected, although a left coronary arteriogram was not obtained. The int.racoronary injection of ergonovine may have affected not only the directly injected right coronary artery but also the opposite left coronary artery through the coronary vein. In the cLinica setting the intracoronary injection of acetylchoine or ergonovine is considered to be useful for the induction of coronary art,ery spasm, but a subsequent intracoronary injection of ergonovine is needed when a spontaneous focal coronary spasm is relieved by the intracoronary injection of acetylcholine. The paradoxic phenomenon may be due to the fl,llowing: (1) an agent factor (that is, either a difference between acetylcholine and ergonovine in their ability to induce coronary spasm or the occurrence of endothelium-dependent relaxation induced by acetylcholine) or (2) a coronary arterial wall factor (that is. either the response of a local vascular smooth
Acetycholirw
L’ersus ergonoL:ine in coronary
spasm
45
muscle to the vasoconstrictive agents or the production, release, and diffusion of an endothelium-dependent relaxation factor in the local vascular endothelium). It can easily be predicted that coronary spasm will be induced by the intracoronary injection of either acetylcholine or ergonovine in patients with extremely active vasospastic angina. However, the paradoxic phenomenon cannot be explained by disease activity alone, because only one patient (case No. 6) had inact,ive disease and the other (case No. 11) had active disease. The exact mechanism of this phenomenon remains unknown. Of considerable interest is the observation that the focal spastic coronary segment in which ergonovine-induced coronary spasm is subsequently demonstrated can exhibit vasodilation in responseto the endothelium-dependent relaxation factor induced by the intracoronary injection of acetylcholine. Mechanism of coronary artery spasm. The mechanism of the induction of coronary artery spasm by the intracoronary injection of acetylcholine remains unclear. Ludmer et al.“O performed intracoronary injections of acetylcholine in patients with coronary atherosclerosis and frequently noted vasoconstriction. They reported that vasoconstriction induced by acetylcholine occurred both early and late in the course of coronary atherosclerosis, and they suggested that the abnormal vascular response to acetylcholine represented a defect in endothelial vasodilator function, which was important in the pat.hogenesis of coronary spasm. Yasue et al.” proposed that a direct cholinergic muscarinic effect of acetylcholine caused the coronary spasm in patient,s with variant angina and suggested that the coronary arteries involved in spasm might have atherosclerosis with dysfunctional endothelium. Miwa et al. l4 also postulated that the coronary arteries in patients with variant, angina were supersensitive to acetylcholine and suggested that they had a malfunctioning endothelium that could not produce sutlicient protective factors against spasm, such as prostaglandin 12 or other endothelium-derived relaxing factors. These reports indicate that coronary spasm may result, from dysfunctional endothelium that, cannot release endothelium-dependent relaxing factor. In their experiment,al study, however, Bossaller et al.“’ reported that impaired cholinergic responses in atherosclerotic arteries reflected a muscarinic defect and not an inability of the endothelium to release endothelial factor or of smooth muscle to respond to it. In two of our patients in group 1 the paradoxic phenomenon was observed, and this phenomenon was considered to be related to the endothelium-dependent, relaxing factor induced
46
Suzuki
et al.
by acetylcholine. Thus the mechanism of coronary artery spasmcaused by the intracoronary injection of acetylcholine is not explained simply by impaired endothelium-dependent relaxation induced by coronary atherosclerosis. The mechanism of the induction of coronary artery spasm by ergonovine also remains unclear, although ergonovine has been the most commonly used agent, to provoke coronary spasm in vivo. Some experimental studies have indicated that ergonovine acts mainly through serotogenic receptors and that there is some relationship between the hypercontraction of smooth muscle induced by ergonovine and the atherosclerotic change in coronary arteries.‘l, I53l6 Kawachi et al.‘l reported that endothelial denudation and a long-term high-cholesterol diet in dogs resulted in a regional atherosclerotic change and that smooth muscle in atherosclerotic arteries becan& hypersensitive to ergonovine. They suggested that coronary spasm induced by ergonovine in humans was related to the presence of atherosclerotic changes in coronary arteries. In vivo studies, however, have not confirmed these results. Hackett et. a1.8reported that the intracoronary injection of ergonovine induced localized coronary spasm and postulated that local arterial hyperactivity was the cause of spasm in patients with variant angina. In our study both acetylcholine and ergonovine induced coronary artery spasm in the same region of the coronary arteries in all patients except two in group 1. Although seven patients in group 1 had received intracoronary injections of nitroglycerin 2 hours earlier, coronary artery spasm was repeatedly documented after the intracoronary injection of ergonovine in all seven patients. In contrast, mild (Zc’;’ to 50’0 luminal narrowing) or moderate (75”~ luminal narrowing) coronary vasoconstriction was frequently induced by intracoronary acetylcholine or ergonovine in patients in group 2, but the grade of coronary vasoconstriction induced by the two agents differed in many patients in group 2. Our results indicate that nonspecific hypersensitivity to various agents (i.e., acetylcholine and ergonovine) located in definite regions of the coronary arteries in many patients with vasospastic angina generally plays an important role in the induction of coronary artery spasm, but this theory alone is not sufficient to explain the paradoxic phenomenon. Limitations of this study. This study has two limitations. One is the study population. Vasospastic angina was definitely diagnosed in only six patients in group 1. In the remaining five patients angina attacks were first demonstrated in the catheterization laboratory, although the patients had a history of typical
American
Heart
July 1992 Journal
vasospastic angina. In all five patients, however. the character of the attack in t,he cathet,erizat,ion laboratory was the same as that of usual at.tacks, and the ergonovine provocation test (the standard method for the diagnosis of vasospastic angina) documented coronary spasm in these five patients. Group 2 COG sisted of patient,s with chest pain, and the results of acetylcholine and ergonovine provocation tests were generally reasonable. In some patients, however (cases4, 10, Il. 13, and 14). 75 ‘; luminal narrowing of the coronary arteries without an angina attack or ischemic ST changes in the elect.rocardiogram wa:, induced by the intracoronary inject,ion of acetylcholine or ergonovine. This moderate coronary vasoct )ilstriction was more common in group 2B than in group 2A. An int.ermediat,e stage between normal and typ ical vasospastic angina is possibly present. Some pa tients in group 2B may have t,he intermediate stage. Further follow-up study is needed tc~ romfirm 1hi:, hypothesis. The second limitation is the methodology of the angina provocation test. Intracoronary injection 01’ ergonovine was performed after that of acetylcholinr on the same day in all but, one patient. Therefore thud response of the coronary artery to intracoronary ?I gonovine was affected by endotheliun-derived relax ing factor induced by acetylcholine and by intracol.~ onary nitroglycerin injected for the relief of coronar>’ artery spasm that did not disappear spontaneous11 To reduce the effect of t,hese fact.ors we did the ergonovine provocation test 2 hours after the acetJ.1 choline provocation test. Actually, the baseline ctii’ onary arteriograms taken immediately before the C”I gonovine provocation test were nearly the same ah those taken before the acetylcholine provocation ?esi REFERENCES
A, Severi S, De Nes M, 1,‘Abbate A. Marzilli M, Baii estra A. Parodi 0, Biagini A, Distante A. “Variant angina”: one aspect of a continuous spectrum of vasospastic mpocardial i-chemia. Am .I Cardiol 1978;42:1019-36. Schroeder .JS. Bolen JL. Quint RA. Provocation of coronar> spasm with ergonovine maleate: new test with results in 57 patients undergoing coronary arteriography. .4m .J (‘artlioi 1977;40:4R7-91. Heulper FA. Proudfit WI,, Razavi M. Shirey El<, Greentitreet K, Sheldon WC. Ergonovine maleate provocative test for car onary artery spasm. Am J Cardiol 1978;41:6:1 l-40. Ginsburg R, Bristow MR, liantrowitz N, Haim 1)s. Harrison LX. Histamine provocation of clinical corcrnar?; artery spasm: implications concerning pathogenesis of’ variant angina p”~’ toris. AM HEAK’I‘ J 1981;102:819-38. Crea F, C’hierchia S, Eiaski JC. Davies GJ. Margonato A. Mi ran DO. Rlaseri A. I’rovtrcat ion of’ cnronarv hpasm hy dopam ine in patients with active variant angina pectoris. Circulation I I)Hfi:74:“lil’-‘I. Yasue H, Nagao M, Omote S, Takizawa A, Miwa li. Tanaka S. Coronary arterial spasm and Prinzmetal’s variant form 1)f’ angina induced by hyperventilation and Trii-buffer infusirjn I’irrulatitrn 1978:.58:.X-62.
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4
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124
Number
1
7. Waters DD, Szlachcic d, Bonan R, Miller DD, Dauwe F, Theroux P. Comparative sensitivity of exercise, cold pressor, and ergonovine testing in provoking attacks of variant angina in patients with active disease. Circulation 1983;67:310-5. 8. Hackett D, Larkin S. Chierchia S, Davies G, Kaski JC, Maseri A. Induction of coronary artery spasm by a direct local action cut’ ergonovine. Circulation 1987;75:577-82. 9. Yasue H, Horio Y. Nakamura N. Fujii H, Imoto N, Sonoda R, Kuzivama K. Obata K. Morikami Y. Kimura T. Induction of coronarv artery spasm by acetylcholine in patients with variant angina: possible role of the parasympathetic nervous system in the pathogenesis of coronary artery spasm. Circulation 19Rti:i?:~%i6-63. lti. ‘l‘oda N. Isolated human coronary arteries in response to vasoconstrictor substances. Am J Physiol 1983;245:H937-41. 11. Kawach: Y, Tomoike H, Maruoka Y, Kikuchi Y, Araki H, Ishii Y.,‘l’anaka K, Nakamura M. Selective hypercontraction caused hy ergonovine in the canine coronary artery under conditions of induced atherosclerosis. Circulation 1984;69:441-50. 12. Kalsnee S. Richards R. Coronary arteries of cardiac patients are hyperactive and contain stores of amines: a mechanism for CI )ronary spasm. Science 1984;223:1435-7. 13 American Heart Association committee report.. A reporting s;;stem on patients evaluated for coronary artery disease. Circulatinn 1976;51:5-40. 14. Miwa K. Goto M, Lee .JD, Matsuyama F, Schimizu H, Kato T, H ara A, Uakamura T. Supersensitivity of coronary arteries in variant angina to spasm induced by intracoronary acetylcholine. Am J Cardiol 1988:61:77-82.
Acetycholine
versus ergonovine
in coronary spasm
47
15. Sakanishi M, Yonemura K. On the mode of action of ergometrine in the isolated dog coronary artery. Eur J Pharmocol 1980;64:157-60. 16. Henry PD, Yokoyama M. Supersensitivity of atherosclerotic rabbit aorta to ergonovine: mediation by a serotonergic mechanism. J Clin Invest 1980;66:306-13. 17. Kaski JC, Crea F, Meran D, Rodriguez L, Araujo L, Chierchia S, Davies G, Maseri A. Local coronary supersensitivity to diverse vasoconstrictive stimuli in patients with variant angina. Circulation 1986;74:1255-65. 18. Shibata N, Mizobe H, Miyazaki Y, Miura M, Miyazawa Y. Komatsu Y. The comparison of acetylcholine and ergonovine in the provocations of coronary vasospasm [Abstract]. J Am Co11 Cardiol 1989;13:132A. 19. Okumura K, Yasue H, Matsuyama K, Goto K, Miyagi H, Ogawa H, Matsuyama K. Sensitivity and specificity of intracoronary injection of acetylcholine for the induction of coronary artery spasm. J Am Co11 Cardiol 1988;12:883-8. 20. Ludmer PL, Selwyn AP, Shook TL, Wayne RR, Mudge GH, Alexander RW, Ganz P. Paradoxic vasoconstrictions induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med 1986;315:1046-51. 21. Bossaller C, Habib GB, Yamamoto H, Williams C, Wells S. Henry PD. Impaired muscarinic endothelium-dependent relaxation and cyclic guanosine 5’.monophosphate formation in atherosclerotic human coronary artery and rabbit aorta. J Clin Invest 1987;79:170-4.