(Circulation. 2000;101:1102.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Major Racial Differences in Coronary Constrictor Response Between Japanese and Caucasians With Recent Myocardial Infarction
From Università Cattolica del S Cuore, Rome, Italy (C.P., M.L.F., R.M., D.C., T.S., A.M.); Adelaide University, Adelaide, Australia (J.F.B.); and Kyoto University, Kyoto, Japan (R.H., M.F., S.S.).
Correspondence to Dr Christian Pristipino, Istituto di Cardiologia, Università Cattolica del S Cuore, L.go Agostino Gemelli 1, 00168 Rome, Italy. E-mail c.pristipino{at}eudoramail.com
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Abstract |
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Background—Enhanced coronary vasomotion may contribute to acute coronary occlusion during the acute phase of myocardial infarction (AMI). Japanese have a higher incidence of variant angina than Caucasian patients, but racial differences in vasomotor reactivity early after AMI are controversial.
Methods and Results—The same team studied 15 Japanese and 19 Caucasian patients within 14 days of AMI by acetylcholine injection into non–infarct-related (NIRA) and infarct-related (IRA) coronary arteries followed by nitroglycerin. Incidence of vasodilation, vasoconstriction, spasm, and basal tone were assessed in proximal, middle, and distal segments after each drug bolus by quantitative angiography. Japanese patients had much lower cholesterol levels than Caucasians (183±59 versus 247±53 mg/dL, P<0.006) but showed a lower incidence of vasodilation (2% versus 9% of coronary segments) and a greater incidence of spasm after acetylcholine (47% versus 15% of arteries, P<0.00001). Incidence of spasm was higher in IRAs than in NIRAs in both populations (67% versus 39% and 23% versus 11%, respectively). Multivessel spasm was more common (64% versus 17%, P<0.02) and vasoconstriction of nonspastic segments was greater in Japanese patients (-23.4±14.9% versus -20.1±15.7%, P<0.02) in the presence of similar average basal coronary tone with respect to post–nitroglycerin dilation and of nonsignificant differences of coronary atherosclerotic score.
Conclusions—Soon after AMI, Japanese patients exhibited a 3-fold-greater incidence of spasm and greater vasoconstriction of nonspastic segments after acetylcholine than Caucasians. The causes of such differences warrant further investigation because they may have relevant pathophysiological and therapeutic implications.
Key Words: vasoconstriction • vasospasm • vasodilation • myocardial infarction • acetylcholine
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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The acute coronary occlusion responsible for myocardial infarction is the result of thrombosis1 variably associated with local2 and distal3 coronary vasoconstriction. The role of vasoconstriction is less obvious than that of thrombosis, and one must specifically look for it. The greater incidence of induced coronary artery spasms in Oriental4 5 than in Western6 7 patients after myocardial infarction suggests important racial differences in the contribution of coronary vasoconstriction to the pathogenesis of acute myocardial infarction (AMI). This possibility would be compatible with the higher incidence of variant angina8 and with the lower lipid levels9 in Japanese than in Caucasians. However, in the studies reported so far,4 5 6 the differences in patient selection, vasoconstrictor tests, and evaluation of coronary reactivity are too large to allow firm conclusions. Therefore, we assessed epicardial coronary artery vasomotion in Japanese and Italian patients with recent myocardial infarction using the same provocative tests, applied by the same team of investigators, with centralized analysis of the angiograms.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Patients
Patients with their first documented AMI (ST elevation/depression
1 mm, creatine kinase [CK] rise >2-fold
from baseline values) were enrolled in the Catholic University in Rome
and in 6 Kyoto hospitals and scheduled for elective coronary
arteriography within 14 days from AMI (11±3 and 9±2 days,
respectively; P=NS). Patients with any of the following
criteria were excluded: age >80 years, documented history of variant
angina, symptomatic heart failure, postinfarction angina,
left main coronary stenosis, or severe left
ventricular dysfunction. During AMI, Italian patients
received intravenous thrombolysis, and
Japanese patients underwent immediate coronary angiography and
intracoronary thrombolysis. Nineteen Caucasian
patients (15 men; age, 54.8±10.5 years) were found eligible for the
study. Twenty-three Japanese patients met the inclusion criteria, but 8
were excluded (5 had a residual TIMI grade <2 flow in the
infarct-related artery [IRA] after intracoronary
thrombolysis and underwent an immediate rescue
angioplasty, and 3 refused intracoronary
thrombolysis and requested emergency PTCA); the other
15 Japanese patients did not undergo PTCA before the
provocative study and were thus enrolled (14 men; age,
68.8±7.2 years). All vasoactive drugs were suspended 48 hours before
the study with the consent of the physician. The study was approved by
the ethics committees of the hospitals involved, and all patients
signed an informed consent.
Provocative Protocol
The provocative protocol was conducted by the same 2
senior investigators (J.B. and M.L.F.) in Rome and Kyoto. Injections
into the non–infarct-related artery (NIRA) of 2 incremental
acetylcholine boluses (25 and 50 µg IC for the right coronary
artery; 50 and 100 µg IC for the left coronary artery) were
performed at 5-minute intervals, each over 20 seconds. The same
protocol was then repeated in the IRA. In the left coronary
artery, a safety 25-µg dose was administrated but not considered in
the analysis of results. At the completion of the protocol, a
250 µg bolus of nitroglycerin (NTG) was injected into
the IRA and NIRA. Coronary angiography was repeated immediately
after NTG boluses and 90 seconds after each acetylcholine bolus
injection.
Eighty-seven percent of IRAs and 82% of NIRAs were injected in Japanese and 82% and 90% in Caucasians, respectively (P=NS). The highest acetylcholine dose was not injected in the IRAs of 2 Japanese and 3 Caucasians and in the NIRAs of 8 Japanese and 4 Caucasians because of a severe vasospasm with the lower dose.
Angiography Analysis
Quantitative Coronary Angiography Analysis
All angiograms were analyzed in Rome by an independent
observer (C.P.) unaware of the sequence of infusions using the
previously validated7 computerized
Cardiovascular Measurement System, version 2.3 (MEDical
Imaging System). Each coronary artery was divided into 3
segments—proximal, middle, and distal—and each was analyzed
in its optimal view at baseline and after each intervention. Diameters
were measured on end-diastolic frames, and percent changes
from baseline luminal diameter were calculated after each intervention.
Visualization of IRA and NIRA segments was adequate for
analysis in 92% and 99% of Japanese and 97% and 94% of
Italian patients, respectively (Table 2
).
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For each coronary segment, we assessed the following: basal tone, which is percent constriction at baseline with respect to maximal dilation after NTG [100x(basal diameter-NTG diameter/NTG diameter)]; vasodilator response to acetylcholine, or number of segments dilated after acetylcholine; and spasm, in terms of occlusive or subocclusive (>90%) constriction (subocclusive segmental spasm, which involves >70% of the segment length with visible contrast, and focal spasm, defined as total occlusion without distal filling or focal subocclusion involving <70% of the segment length with normal or near-normal distal caliber). To avoid overestimation, the quantitative evaluation in the segments distal to a spasm occurring in more proximal segments was performed only in the presence of TIMI grade 3 flow and optimal filling with contrast medium. We also assessed vasoconstrictor response, the percent diameter reduction below baseline in nonspastic segments [100x(acetylcholine- baseline/baseline)]. Multivessel spasm was defined as spasm occurring simultaneously in >1 vessel at the same acetylcholine dose.
Assessment of Angiographically Detectable Atherosclerosis
For each artery, we assessed the severity and extent scores of
atherosclerosis in the basal angiograms. The
analysis was performed by 2 independent observers (C.P. and
T.S.) with a slightly modified version of the method of Bogaty et
al.10
The severity of atherosclerosis was assessed by the
number of vessels significantly diseased (with 70% diameter
reduction), coronary stenoses (50% obstruction), and
occluded vessels. An atherosclerotic extent score (ranging from 0 to 3)
was assigned to each coronary segment defined according to the
American Heart Association recommendations.11 Each segment
was scored 0 if it appeared angiographically normal, 1 if 
10% of its
length appeared abnormal (narrowed and/or irregular), 2 if >10% to
50% of its length was abnormal or if it was occluded or suboccluded
with poor distal flow, and 3 if >50% of its length was abnormal or
totally occluded with no distal flow. The global extent index was
calculated as the average score of all coronary segments
adequately visualized. The extent index of each main coronary
artery was the average score of its visualized segments. Thus,
the extent index ranged from 0 to 3.
Statistical Analysis
All values are expressed as mean±SD. Clinical characteristics
were compared by use of 2-tailed Student’s t test for
unpaired data, the Mann-Whitney U test, or Fisher’s exact
test as appropriate. The incidence of different vasomotor response and
angiographic findings were compared by use of Yates’ corrected
2 test or Fisher’s exact test as appropriate.
Absolute coronary luminal diameters were compared with
Student’s t test for unpaired data. Quantitative vasomotor
responses were compared by use of the Mann-Whitney U test or
Student’s t test for unpaired data as appropriate. A value
of P<0.05 was considered statistically significant.
Correlation between variables was assessed by use of
Spearman’s rank-order correlation test.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Japanese were significantly older (69±7 versus 55±10 years, P<0.002), whereas Caucasians had a significantly higher body mass index (26.5±3.21 versus 22.1±2.7 kg/m2, P<0.0002), cholesterol level (247±53 versus 183±59 mg/dL, P<0.006), and triglyceride level (209±116 versus 87±55 mg/dL, P=0.0006) on admission. Other risk factors and clinical findings were not significantly different between Japanese and Caucasians (Table 1
).
Japanese were treated with intracoronary prourokinase 6000
U and Caucasians with intravenous streptokinase or
recombinant tissue plasminogen activator.
Additional treatment was predominantly with calcium
antagonists, warfarin, and potassium channel openers in
Japanese and with ß-blockers and heparin in Caucasians (Table 1). Japanese had significantly higher peak CK values (2738±1609
versus 1493±1028 IU/L) but similar ejection fractions (Table 1).
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Angiographic Findings
Japanese showed a statistically nonsignificant trend toward more
severe coronary atherosclerosis than Caucasians
with a higher prevalence of 2- and 3-vessel disease, a higher number of
stenoses, and greater extension of angiographically detectable
atherosclerosis (Table 2
).
The IRA was the left anterior descending coronary artery in 8 Japanese and 11 Caucasian, the right coronary artery in 7 Japanese and 5 Caucasian, and the circumflex artery in 3 Caucasian patients.
Absolute diameters of proximal and middle segments were significantly
smaller in Japanese than Caucasian patients both at baseline (2.5±0.7
versus 2.9±0.7 mm, P<0.02, and 2.0±0.4 versus
2.4±0.7 mm, P=0.01, respectively) and after NTG
(2.7±0.7 versus 3.3±0.7 mm, P=0.0006, and 2.4±0.7
versus 2.8±0.7 mm, P=0.01, respectively), but distal
segments had similar diameters (Table 2).
Vasomotor Response
After intracoronary acetylcholine, a dilator effect
was observed in 9% of the visualized segments of Caucasian patients
(26 of 279 segments; 4 patients) and in 2% of segments of
Japanese (4 of 232 segments; 2 patients) (P=0.0005;
Table 2).
Incidence of Coronary Artery Spasm
Focal or segmental spasm was much more common in Japanese
than in Caucasians. It was observed in 80% (12 of 15) compared with
37% (7 of 19) of patients (P=0.01), in 47% (38 of 80)
compared with 15% (14 of 94) of arteries (P<0.00001)
(Table 2 and Figure 1 [bottom])
and in 27% (63 of 232) compared with 9% (24 of 279) of segments
(P<0.00001) (Figure 1 [top]). This occurred for
both IRAs and NIRAs (Figure 1 [top]) and was observed in
response to the lowest acetylcholine dose in 11 of 12 Japanese and in 3
of 7 Caucasian patients. A vasospastic response was significantly more
common in IRAs than in NIRAs in Japanese patients, and a similar but
statistically nonsignificant trend was observed in Caucasians (Figure 1 [bottom]). Spasm was more common in distal than in proximal
segments and more often segmental in both Japanese and Caucasians (73%
and 79%, respectively; P=NS) (Figures 1 [top] and
2).
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Considering the patients in whom the same dose of acetylcholine was
injected in 2 major coronary arteries, multivessel spasm was
observed in 9 of 14 Japanese and 3 of 18 Caucasians
(P<0.02; Figure 3).
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Vasoconstrictor Response of Nonspastic Segments
In segments that did not exhibit spasm or dilation after
acetylcholine, those from Japanese patients showed a significantly
greater vasoconstriction than those from Caucasians (-23.4±14.9%
versus -20.1±15.7%, P<0.02; Figure 4 [top]).
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Basal Tone and Vasomotor Response
Despite the striking difference in constrictor response, average
basal vasomotor tone was similar in both populations (-13.4±12.1%
versus -14.8±10.7%, P=NS; Table 2 and Figure 4 [bottom]). Segments with a spastic response had a greater
basal tone than the others in both groups (-17.7±11.7% versus
-11±10.1%, P=0.02, in Japanese and -20.2±12.8% versus
-14±10.3%, P=0.04, in Caucasians; Figure 4
[bottom]).
Atherosclerosis Score and Vasomotor
Response
The atherosclerosis extent index was similar in
spastic and nonspastic arteries (0.66±0.38 and 0.69±0.47,
respectively, of the possible maximum of 3), and no correlation was
found between extent index and severity of vasoconstrictor response
(R=0.06, P=NS) or between extent index and basal
tone. Only 10 of 63 occlusive or subocclusive spasms in Japanese and 2
of 24 in Caucasians (P=NS) occurred at the site of an
angiographically detectable stenosis, and 6 of 12 Japanese
patients who developed spasm after acetylcholine showed spasm at (or
also at) the site of "culprit" stenosis compared with 1 of
7 Caucasians (P=NS; Table 2).
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Discussion |
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The results of our study show that in the early post-MI phase, Japanese patients exhibit a 3-fold-greater incidence of vasospastic response to intracoronary acetylcholine in NIRAs and IRAs than Caucasians, a significantly higher incidence of multivessel spasm, a lower number of coronary segments that exhibited dilation, and a greater constriction in the segments that did not show a spastic or dilator response to acetylcholine. Such differences were observed despite a lower acetylcholine dose and a trend toward a higher atherosclerotic extent index and in the presence of a higher mean age, much lower cholesterol levels, and similar basal tone in Japanese.
Collectively, our findings are consistent with a review of the literature on the subject. In Caucasian patients with recent MI, Bertrand et al6 and Mongiardo et al7 reported a 20% and 11% incidence of spasm using methylergonovine and serotonin, respectively. In Oriental patients with recent MI, Okumura et al5 found a much higher incidence of coronary artery spasm after intracoronary acetylcholine (69%).
In patients >6 weeks after MI, Bertrand et al6 found a 6% incidence of spasm compared with a 21% incidence of spasm after ergonovine in patients with old MI reported by Nosaka et al.4
Possible Mechanisms
The strikingly greater vasospastic response observed in Japanese,
usually in response to lower acetylcholine doses, cannot be explained
by the levels of coronary risk factors because Japanese had
much lower cholesterol and triglyceride levels
and had similar prevalence of male sex, hypertension, family history of
coronary artery disease, and smoking history. However, they
were on average >10 years older and had a trend toward greater
severity and extent of angiographically detectable
atherosclerosis. The similar atherosclerotic extent
index of spastic and nonspastic arteries, the uncommon occurrence of
spasms at the site of stenoses, and the lack of correlation
between extent index and magnitude of vasoconstriction and between
extent index and basal coronary tone suggest that
angiographically detectable atherosclerosis was not a
major determinant of the observed differences in coronary
vasoconstrictor response.
A greater severity of endothelial dysfunction could be postulated because acetylcholine was used as a provocative agent.12 Unfortunately, interpretation of in vivo vasomotor response to acetylcholine is made difficult by the coexisting major direct constrictor action on the smooth muscle, which is responsible for a marked biphasic response in individuals with angiographically normal arteries, particularly in distal segments less likely to be affected by atherosclerosis.5 13 In fact, atherosclerotic coronary segments that constrict in response to acetylcholine were shown to dilate in response to substance P, a pure endothelium-dependent vasodilator.14 Thus, smooth muscle hyperresponsiveness to constrictive stimuli may also participate in the greater constrictor response observed in Japanese patients after acetylcholine. This possibility is supported by the greater incidence of variant angina among Japanese than among Caucasians.8
Study Limitations
In our study, the adoption of the same inclusion criteria, the
same provocative protocol, and a central analysis
of the data rules out methodology as a possible cause of the observed
differences. Patients had important differences in treatment during the
acute phase and the following days after MI but were in pharmacological
washout at the time of study. The use of different drug regimens is
thus unlikely to be a confounding factor in our results. Moreover, in
the presence of a similar degree of ventricular function
impairment and similar patency rates of IRAs (14 of 15 open IRAs in
Japanese versus 14 of 19 in Caucasians), the differences in
thrombolytic drug administration and earlier
reperfusion rate are unlikely to account for the large differences in
vasomotor response although they may explain the higher CK values in
Japanese patients (Table 1).
A higher prevalence of variant angina among Japanese patients is
unlikely to be a selection bias because this was an exclusion criterion
and because the prevalence of history of chest pain at rest was similar
in Caucasian and Japanese patients (Table 1). In Japanese
patients, the exclusion of those individuals who underwent rescue PTCA
(5 of 23, or 22%) also seems unlikely to explain the much greater
incidence of spastic response. Finally, a possible bias related to the
smaller body surface area and coronary diameter of Japanese
patients (Tables 1 and 2) cannot account for the observed
differences because the spastic response occurred at the lower
acetylcholine dose in 92% of Japanese patients and because the
incidence of vasospastic response also was greater in distal segments,
which had similar diameters of those of Caucasian patients (Figure 2).
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The adoption of acetylcholine as a provocative stimulus does not allow us to draw conclusions regarding the role of endothelial dysfunction in the observed higher constrictive response of Japanese patients. Specific investigations with pure endothelium-dependent vasoactive substances, such as substance P, are required to test this possibility.
Pathophysiological and Therapeutic
Implications
The constriction of pliable sections of the vascular wall with
preserved muscular media in response to vasoconstrictor agents locally
released by primary thrombosis can contribute to acute coronary
occlusion. Alternatively, a primary occlusive spasm may become
persistent when associated with the development of an even minor mural
platelet thrombus.15 An enhanced local smooth muscle
constrictor response may become a multiplier in this positive feedback
loop.
In Caucasians, the contributory role of vasoconstriction, whatever its causes (endothelial dysfunction and/or smooth muscle hyperresponsiveness), is suggested by the dilator response to intracoronary nitrates of infarct-related stenosis at the end of thrombolysis2 and by the observation that postmortem studies after acute coronary syndromes reveal platelet-rich thrombi that do not completely occlude the lumen.16 The strikingly enhanced vasoconstrictor response of Japanese soon after AMI, particularly in IRAs, suggests an even greater contributory role of coronary vasoconstriction in the pathogenesis of MI than that observed in Caucasians.1 2 In the presence of acute thrombosis, the dose of nitrates and calcium antagonists required to oppose the vasoconstrictor effects of thromboxane, serotonin, and thrombin continuously produced and released locally may be so large as to cause hypotension and reflex increase of neurogenic coronary tone. Indeed, the dilator response of infarct-related stenoses to intracoronary administration of nitrates observed in Caucasians occurred despite the previous administration of repeated, large intravenous doses of the drug.2 Therefore, prompt coronary recanalization during AMI may require specific inhibition of thromboxane and serotonin in association with thrombolytic drugs.17
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Acknowledgments |
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This study was supported by educational grants from Institut de Recherches Internationales Servier, by a research fund from Japan Heart Foundation, and by Associazione Ricerche Coronariche-Fondazione "per il Cuore."
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Appendix 1 |
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The following centers and investigators participated in the study in Kyoto, Japan: Ijinkai Takeda Hospital: Tetsuo Hashimoto, MD; Kyoto Mitsubishi Hospital: Akira Yoshida, MD; Otowa Hospital: Mitsugu Kida, MD; Rakuyu Hospital: Mamoru Takahashi, MD; and Takeda Hospital: Shunichi Tamaki, MD.
Received July 21, 1999; revision received August 9, 1999; accepted October 6, 1999.
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