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J Am Coll Cardiol, 1999; 33:1442-1452
© 1999 by the American College of Cardiology Foundation
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REVIEW ARTICLES

Racial heterogeneity in coronary artery vasomotor reactivity: differences between Japanese and caucasian patients

John F. Beltrame, BMBS, FRACP*, Shigetake Sasayama, MD, FACC{dagger} and Attilio Maseri, MD, FACC{ddagger}

* Cardiology Unit, The North Western Adelaide Health Service, University of Adelaide, Adelaide, Australia
{dagger} Department of Cardiovascular Medicine, Kyoto University Hospital, Kyoto University Graduate School of Medicine, Kyoto, Japan
{ddagger} Cardiology Institute, Agostino Gemelli Hospital, The Catholic University of the Sacred Heart, Rome, Italy

Manuscript received June 29, 1998; revised manuscript received December 14, 1998, accepted January 21, 1999.

Reprint requests and correspondence: Dr. J.F. Beltrame, Cardiology Unit, The North Western Adelaide Health Service, The Queen Elizabeth Hospital Campus, 28 Woodville Rd, Woodville South, SA 5011, Australia


   Abstract
Top
 Abstract
Important factors in coronary...
 Racial vasomotor heterogeneity...
 Acute myocardial infarction: do...
 Clinical differences
 Pathophysiologic differences
 Conclusions
 References
 
Japanese investigators have provided a substantial contribution in the understanding of coronary vasomotor reactivity. On occasions, their findings have been at variance with those undertaken on caucasian patients, raising speculation that vasomotor differences between races may exist. In a comparative review of the published literature, we evaluated the vasoreactive differences among Japanese and caucasian patients with variant angina or myocardial infarction. In variant angina, Japanese patients appear to have diffusely hyperreactive coronary arteries compared with caucasian people, manifested by their segmental rather than focal spasm, hyperreactive nonspastic vessels and multivessel spasm. These differences may reflect the increased basal tone among Japanese variant angina patients and may relate to controversial differences in endothelial nitric oxide production or autonomic nervous system activity. Provocative vasomotor studies of Japanese patients with a recent myocardial infarction report a higher incidence of inducible spasm than caucasian studies, an observation recently supported by a controlled study. Furthermore, the hyperreactivity was diffuse, occurring in both non–infarct- and infarct-related vessels. These observations support the existence of racial coronary vasomotor reactivity differences but require confirmation in further prospectively conducted studies.

Japanese investigators have made significant contributions in cardiovascular research, particularly in the field of coronary vasomotor reactivity. On occasions discrepancies have arisen between the findings of such investigators and those of their Western colleagues. Some researchers (1–4) have speculated that the discrepancies are due to ethnic differences in coronary vasomotor reactivity; however, except for a study that we have conducted in patients with recent myocardial infarction (5), prospective studies comparing coronary vasomotor reactivity between different ethnic groups are limited. The aim of this review is to examine the evidence for possible differences in coronary vasomotor reactivity between Japanese and caucasian patients by reviewing comparable published studies from the Medline database (1966–1998) which differ in the racial group assessed. Where appropriate, the findings of both caucasian and Japanese studies were pooled and comparisons between these racial groups made using chi-squared analysis.


   Important factors in coronary vasomotor reactivity
Top
 Abstract
 Important factors in coronary...
Racial vasomotor heterogeneity...
 Acute myocardial infarction: do...
 Clinical differences
 Pathophysiologic differences
 Conclusions
 References
 
Before embarking upon comparisons between vasomotor studies, it is important to distinguish between coronary "spasm" and "vasoconstriction" (6). These two entities differ with regard to the extent of luminal reduction, induction of myocardial ischemia, associated predisposing risk factors and possibly the pathophysiologic mechanisms.

For the purposes of this review, coronary "spasm" is defined as a total or subtotal (≥90%) reduction of luminal diameter which would invoke myocardial ischemia. Other researchers have used less conservative reductions in coronary luminal diameter such as 75% and even 50%, which would not be expected to reduce resting blood flow (7). Although in such patients a stronger constrictor stimulus might have resulted in occlusion, we adopted a stricter definition to maximize the specificity of the diagnosis.

At the other end of the vasomotor spectrum, provocative testing with vasoconstrictor agents may produce a mild reduction in luminal diameter (i.e., <30%), which will be referred to as "vasoconstriction" in this review. This vasomotor response would not invoke myocardial ischemia per- se and may or may not be pathologic depending upon the vasoconstrictor agent and dosage utilized. For example, a 10% constrictor response to high dose ergonovine would be considered an appropriate response, whereas a similar response to low dose acetylcholine or serotonin may be regarded as abnormal.

Between these two extremes are patients with intermediate/severe vasoconstriction, where luminal reduction is less than subocclusive and therefore may result in ischemia only in the presence of additional factors such as increased oxygen demand and associated distal vessel constriction.

Clinical risk factors predisposing to coronary "spasm" and "vasoconstriction" also differ. Cigarette smoking is the only predisposing factor associated with coronary spasm (8–11), whereas age ≥30 years (3), male gender (12), hypertension (13–15), hypercholesterolemia (12), family history of coronary disease and atherosclerosis (16) have all been associated with an exaggerated constrictor response to intracoronary acetylcholine. Whether Japanese ethnicity is also a predisposing factor to coronary spasm or vasoconstriction requires further evaluation (3).

Different clinical syndromes may also respond differently to vasoactive agents. For example, ergonovine (17) and acetylcholine (18) produce coronary spasm in patients with variant angina but only a mild constrictor response in chronic stable angina patients. In the following sections, Japanese- and caucasian-based studies of patients with variant angina or recent myocardial infarction will be compared to determine if there are racial differences in coronary vasomotor reactivity in these clinical syndromes.

Variant angina: is there a "Japanese variant"?.   Variant angina is the conventional clinical manifestation of large vessel coronary spasm, and Japanese researchers have made major contributions in the understanding of this disorder. A review of the Medline database over the past 30 years has identified over 600 original studies of variant angina, with 30% of these being performed on Japanaese variant angina patients. The apparent ease with which the Japanese researchers have accumulated these patients (compared with the studies by caucasian researchers) has prompted the belief that this disorder is more prevalent in Japan (19,20). However, there are no systematic studies comparing the incidence of variant angina between countries.

In evaluating racial differences in variant angina, the definition of this syndrome must be clarified. Variant angina is clinically characterized by recurrent episodes of rest pain associated with reversible ST elevation and preserved exercise tolerance (21). Angiography during an ischemic episode typically demonstrates a subtotal/total occlusive spasm of a major epicardial coronary artery. In their original report, Prinzmetal et al. (22) postulated an increase of "tonus" at the site of a subcritical stenosis, but over a decade later a "variant of the variant" with angiographically normal coronary arteries was reported (23).

Vasospastic angina is a disorder of large vessel vasomotor reactivity which has particularly featured in Japanese research articles. The definition of vasospastic angina focuses more upon the angiographic demonstration of coronary spasm in patients with rest pain irrespective of the electrocardiogram showing ST elevation or depression (24,25).

For the purpose of this review, patients will only be considered as "variant angina" if they fulfill the following criteria: 1) rest pain, 2) spontaneous or induced reversible ST elevation and 3) no evidence of myocardial infarction on serial cardiac enzymes. "Vasospastic angina" will be used for patients with 1) rest pain, 2) reversible ST elevation or depression and 3) spontaneous or induced coronary spasm on angiography. This distinction between "variant" and "vasospastic" angina is rather artificial, but is used in this review largely to categorize the characteristics of the populations being compared with regard to the reported studies. Overall, it may well be that the two groups should be combined and designated "vasomotor angina."

Comparison of vasomotor angina studies undertaken on Japanese or caucasian patients reveal both clinical and pathophysiologic differences between these groups and are outlined below.

Clinical differences.   Table 1, and Figures 1 and 2, summarize the results of seven large clinical studies (26–32) which have endeavored to determine the prognosis of variant angina; however, they also serve to provide information on clinical characteristics of such patients. Table 1 shows a similar mean age and male preponderance among the variant angina patients, although the condition appears to be slightly more common in caucasian than Japanese women (i.e., 22% vs. 13% respectively, p < 0.0001).


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  		Table 1 Major Variant Angina Prognostic Studies

 


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  		Figure 1 Survival in variant angina patients. Major prognostic studies in variant angina patients showing up to 5-year survival figures for Japanese-based studies (26–28) (filled shapes) as compared with caucasian studies (29–32) (open shapes). Filled squares = Nakamura et al. (26); filled triangles = Yasue et al. (27); filled circles = Shimokawa et al. (28); open squares = Severi et al. (29); open triangles = Waters et al. (30); open squares = Mark et al. (31); open diamonds = Walling et al. (32).

 


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  		Figure 2 Survival without myocardial infarction in patients with variant angina. Five-year survival without myocardial infarction in Japanese (26–28) (filled shapes) and caucasian (29–32) (open shapes) variant angina patients. Symbols as in Figure 1.

 
Pooled analysis of the data from Table 1 reveals significant differences between Japanese and caucasian variant angina patients with respect to: 1) prior myocardial infarct (7% vs. 24% respectively, p < 0.0001), 2) the presence of obstructive coronary artery disease (41% vs. 66%, p < 0.0001), 3) survival at three-year follow-up (97% vs. 89%, p < 0.0001), and 4) myocardial infarct-free survival at three-year follow-up (91% vs. 75%, p < 0.0001).

Analysis of Table 1 confirms that caucasian variant angina patients not only have a higher incidence of atherosclerotic disease than Japanese, but also have more extensive disease (i.e., multivessel disease in Japanese = 24% vs. caucasian = 44%, p < 0.0001), which has also been reported in the respective general populations (28,33). Multivariate analysis of predictors of infarction in variant angina patients has shown that the extent of atherosclerosis is an important determinant (27); thus the more extensive atherosclerotic disease in caucasian variant angina patients accounts for the higher incidence of myocardial infarction observed in this group (Table 1) (26–30).

Caucasian variant angina patients have a worse overall survival than their Japanese counterparts (Table 1, Fig. 1 and 2), which may relate to their more extensive atherosclerotic coronary disease, higher incidence of myocardial infarction and more frequent left ventricular dysfunction (Table 1). Yet, 52% of the Japanese patients with cardiac fatalities have normal or near-normal coronary arteries compared with only 16% of the caucasian patients (chi-square = 11.8, p = 0.0006). Hence, the Japanese patients more often succumb with sudden cardiac death (presumably arrhythmic) rather than fatal myocardial infarction (26,34).

The overrepresentation of normal or nonobstructive coronary disease in the Japanese variant angina cardiac fatalities may be due to several factors. Animal experiments have demonstrated that ventricular fibrillation after reperfusion of an occluded coronary artery is more common if the affected vessel is "normal" than if it had a preexisting obstructive lesion (35). Hence occlusive spasm of a normal coronary artery may be more likely to produce sudden death than if it occurred in a significantly obstructed vessel. Alternatively, the autonomic nervous system response to ischemia may differ.

Multivessel spasm (i.e., spasm involving more than one epicardial vessel) has also been shown to be an important predictor of cardiac mortality in patients with variant angina (36). Although early reports of multivessel spasm were in caucasian (37), this disorder appears to be much more common among Japanese (i.e., Table 1; up to 11% of Japanese patients have both anterior and inferior ST elevation, whereas none of the caucasian patients are affected) and may account for some of the cardiac fatalities in patients with normal coronary angiograms. Review of the literature shows that multivessel spasm is well described in Japanese patients, with reports characterizing the clinical features (38,39) of the phenomenon and over 20 studies reporting on its incidence. In contrast, description of the disorder in caucasian variant angina patients has largely been limited to case reports (37,40,41) suggesting that the phenomenon is uncommon in this population. Some of the Japanese studies have suggested that as many as 76% of their variant angina patients (42) have multivessel spasm. This variability in the reported incidence of multivessel spasm (i.e., 9% to 76% in Japanese variant angina patients) reflects differences in the definitions of coronary spasm.

Pathophysiologic differences.   The exact subcellular mechanism(s) responsible for spasm remain to be elucidated, although interesting data have been obtained from a pig model (43). Furthermore, why patients with variant or vasospastic angina are predisposed to coronary artery spasm is unclear. Studies examining the pathophysiology of coronary vasospastic disorders have occasionally found conflicting results, and some of these paradoxes may be due to differences between Japanese and caucasian patients as outlined below.

Focal versus segmental spasm
Studies in Europe and North America have noted that coronary artery spasm in variant angina was usually focal and localized to a coronary plaque. This observation stimulated diverse theories, such as focal coronary spasm initiating atherosclerotic lesion development (44) and the geometric theory of coronary spasm, which proposed that spasm is an amplification of normal vasoconstriction at atheromatous plaques (45). Such theories have since been discredited (46,47) but illustrate the thought processes based upon clinical observation of caucasian variant angina patients. Currently, Western researchers propose that coronary spasm involves postreceptoral smooth muscle hyperreactivity of a coronary segment because it can be caused by several pharmacologic stimuli acting on different receptors (6,48).

In contrast, studies of Japanese patients with variant angina have generally observed segmental or diffuse coronary artery spasm, typically involving normal coronary artery segments. Accordingly, Japanese researchers have explored mechanisms involving generalized coronary hyperreactivity, such as autonomic nervous system imbalances (49) and endothelial dysfunction (50).

Hyperreactive nonspastic coronary artery segments
Several studies (50–53) of Japanese patients with vasomotor angina have demonstrated that not only the spastic segments are hyperreactive to provocative agents but also remote nonspastic segments. Table 2 summarizes the response to vasoconstrictor agents in nonspastic coronary artery segments from caucasian and Japanese patients with either atypical chest pain and no inducible spasm (control patients) or vasomotor angina. All the Japanese studies demonstrate an increased constrictor response in vasomotor angina patients as compared with control subjects, an observation confirmed in an in vitro study (54). This diffuse coronary hyperreactivity in the Japanese patients is consistent with the above-mentioned diffuse segmental spasm and the high frequency of multivessel spasm. However, it contrasts with studies performed in caucasian people (46,55,56), where there were no differences in coronary reactivity between control subjects and variant angina patients (Table 2). This finding can be explained by a greater prevalence of multiple hyperreactive sites in Japanese patients.


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  		Table 2 Vasoconstrictor Responses of Nonspastic Segments

 
Increased basal tone
The response to nitrates has been utilized as an index of basal tone (57), where a greater dilator response suggests a higher resting tone. Table 3 demonstrates that the nitrate response is similar between caucasian (55,56,58) and Japanese (50–53,59) control patients (i.e., atypical chest pain and no inducible spasm). Also, the caucasian patients with variant angina have a vasodilator response in nonspastic and spastic segments similar to that of control subjects. However, Japanese patients with variant angina show a marked dilator response at both spastic and nonspastic sites. This has been consistently shown in all but one (59) of six studies and suggests that Japanese patients with vasomotor angina have a higher basal tone in both spastic and nonspastic segments (50–53). Furthermore, the tone is higher in spastic as compared with nonspastic segments, thus suggesting that basal tone may be related to hyperreactivity in Japanese patients (51,52).


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  		Table 3 Basal Tone at Nonspastic and Spastic Segments

 
The role of endothelial nitric oxide in Japanese vasospastic angina patients
There are two schools of thought in Japan concerning the role of endothelium-derived nitric oxide in vasospastic angina patients. Unfortunately, there are no comparable studies in caucasian patients to date.

One group of investigators has proposed that a localized deficiency of coronary nitric oxide production is responsible for coronary spasm in vasospastic angina patients. This is supported by the following findings in vasospastic angina patients relative to control subjects: 1) an exaggerated vasodilator response to nitrates but not diltiazem (50), 2) impaired flow-dependent (nitric oxide mediated) epicardial coronary artery dilation (60), 3) a reduced constrictor response to intracoronary NG-monomethyl-L-arginine (an inhibitor of nitric oxide synthase) (50) and 4) an increased prevalence of a point mutation in the endothelial cell constitutive nitric oxide synthase gene (61). Accordingly, the deficient endothelial nitric oxide production may predispose to a higher basal tone and coronary spasm with acetylcholine provocation testing because of unopposed constrictor effects.

Paradoxically, other Japanese investigators have reported that endothelial nitric oxide production is intact in vasospastic angina patients (62). These researchers have demonstrated the following in vasospastic angina patients: 1) intact endothelium-dependent vasodilation by low dose acetylcholine (62), substance P (62,63) and bradykinin (64); and 2) an increased constrictor response to NG-monomethyl-L-arginine at spastic sites compared with nonspastic sites (59). The explanation for these disparate findings as regards vascular reactivity requires further evaluation but appears to relate to methodological differences between the studies (65,66). The status of caucasian vasospastic angina patients with regard to endothelial nitric oxide production requires investigation. Acetylcholine does not appear a suitable agent because it does not allow the separation of the role of endothelial dysfunction from that of smooth muscle hyperreactivity.

The role of parasympathetic activity in coronary spasm
Although the stimuli responsible for triggering coronary spasm in patients with variant angina remain unknown, the autonomic nervous system has been implicated from studies utilizing heart rate variability. Yoshio et al. (67) assessed heart rate variability 30 min before an episode of spontaneous ST elevation in seven Japanese variant angina patients with nonobstructive coronary artery disease. They observed an increase in high frequency activity 10 min before the onset of an episode of ST elevation, suggesting an increase in parasympathetic activity before an episode of coronary spasm. Low frequency (sympathetic) activity also increased 5 min before the onset of spasm.

Lanza et al. (68) also assessed heart rate variability 30 min before an episode of spontaneous ST elevation in 23 Italian variant angina patients with nonobstructive or single vessel (56% of patients) coronary artery disease. Unlike the Japanese study they observed a fall in high frequency activity 5 min before spasm onset and concluded that there was a withdrawal of parasympathetic activity in their patients. Furthermore, subgroup analysis demonstrated that this occurred independent of the presence of significant coronary artery disease.

Although these differences may, in part, be due to methodological variations between the studies, they may also reflect racial differences in the pathogenesis of coronary spasm between Italian and Japanese variant patients and warrant further investigation. Also, the diurnal variability of coronary spasm, which may be influenced by the autonomic nervous system, should be investigated because previous studies have suggested differences between Japanese and caucasian variant angina patients (69). These earlier studies did not account for differences in coronary stenoses, which have since been shown to influence coronary spasm circadian variation (70).


   Racial vasomotor heterogeneity in vasomotor angina: a synthesis of the data
Top
 Abstract
 Important factors in coronary...
 Racial vasomotor heterogeneity...
Acute myocardial infarction: do...
 Clinical differences
 Pathophysiologic differences
 Conclusions
 References
 
In summary, reviewing the literature would suggest that Japanese and caucasian patients with vasomotor angina have clinical and pathophysiologic differences. These differences essentially relate to two fundamental features, namely 1) a reduced prevalence of "fixed" coronary artery stenoses and 2) diffuse coronary hyperreactivity in the Japanese patients. The reduced extent of coronary stenoses may result in a lower incidence of myocardial infarction and better prognosis; the diffuse vasomotor reactivity could relate to the increased basal tone, the increased incidence of multivessel spasm and greater representation of normal/nonobstructive coronary arteries in the cardiac fatalities. The role of the autonomic nervous system, endothelial nitric oxide synthesis and specific smooth muscle hyperresponsiveness to constrictor stimuli, in this apparent racial heterogeneity in variant angina, requires further evaluation.


   Acute myocardial infarction: do Japanese patients differ?
Top
 Abstract
 Important factors in coronary...
 Racial vasomotor heterogeneity...
 Acute myocardial infarction: do...
Clinical differences
 Pathophysiologic differences
 Conclusions
 References
 
Since the landmark "Seven Countries Study" (71), it has been appreciated that the Japanese have a substantially lower coronary artery disease mortality compared with most caucasian populations (e.g., in the U.S., men aged 25 to 74 years the coronary mortality is 156/100,000 population as compared with 27/100,000 among age-matched Japanese men [72]). This difference is primarily due to environmental factors, as shown by coronary artery disease mortality studies in men of Japanese ancestry which demonstrate an increasing mortality gradient from Japan to Hawaii to California, despite a common genetic origin (73,74). Furthermore, cholesterol levels have been implicated (71,75) because they follow the same gradient (76).


   Clinical differences
Top
 Abstract
 Important factors in coronary...
 Racial vasomotor heterogeneity...
 Acute myocardial infarction: do...
 Clinical differences
Pathophysiologic differences
 Conclusions
 References
 
Although the prevalence of myocardial infarction is lower in Japanese, the Japanese patient with a myocardial infarct appears to differ clinically from his or her caucasian counterpart. Both Saito et al. (77) and Nakamura et al. (78) reported differences in the posthospital course of Japanese and caucasian patients with acute myocardial infarction. Compared with caucasian patients, Japanese patients with a similar initial infarct size had a more favorable posthospital course with fewer coronary events. This difference was independent of coronary risk factors or medications utilized (78) and remains unexplained.


   Pathophysiologic differences
Top
 Abstract
 Important factors in coronary...
 Racial vasomotor heterogeneity...
 Acute myocardial infarction: do...
 Clinical differences
 Pathophysiologic differences
Conclusions
 References
 
These clinical differences raise the possibility of different pathophysiologic mechanisms in Japanese and caucasian patients with myocardial infarction. Coronary vasomotor studies examining the inducibility of coronary spasm in patients with a recent myocardial infarction support the existence of pathophysiologic racial differences.

Inducible coronary spasm in patients with myocardial infarction.   Bertrand et al. (79) performed provocative testing within six weeks of acute myocardial infarction and found that 21% of French infarct patients developed coronary spasm in response to intravenous methylergonovine. This was significantly more frequent than the 9% observed in control patients with coronary atherosclerosis but without infarction. Similarly Mongiardo et al. (80), utilizing intracoronary serotonin in Italian myocardial infarct patients 7 to 10 days postinfarction, observed an 11% incidence of inducible spasm.

In contrast, Okumura et al. (81) found a very high incidence of coronary spasm, with 69% of their Japanese myocardial infarct patients showing a spastic response to provocative agents as compared with 21% of stable angina patients without previous infarction (Table 4). This suggests that Japanese patients with a recent myocardial infarct have greater coronary vasoreactivity than their caucasian counterparts and so may imply that spasm is a more important factor in the pathogenesis of infarction in the Japanese patients. This racial difference in coronary vasomotor reactivity is also observed when patients undergo provocative testing remote from the time of infarction (82,83) (e.g., >6 weeks), as shown in Table 4. These observations are particularly impressive when it is considered that the largest caucasian study (79) utilized a broad definition of spasm (i.e., ≥75% reduction in lumen diameter in normal arteries) and therefore would have inflated frequencies compared with the other tabulated studies.


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  		Table 4 Inducible Coronary Spasm in Postmyocardial Infarct Patients

 
This marked difference in inducible spasm may be due to other potential confounding factors which may affect vasomotor responses including, 1) smoking (8–11), 2) associated atherosclerosis (27), 3) the provocative agents utilized (84,85), 4) the timing of testing after infarction between the studies (79), and 5) inadvertent enrollment of patients with variant angina. Thus the tentative conclusion at this stage would be that the incidence of postmyocardial infarct spasm is greater in Japanese than caucasian patients, and that in both cases the incidence reduces with the efflux of time postinfarct. No study to date has examined all of these factors prospectively.

In the first prospective comparative study of coronary spasm across racial groups, we compared the incidence of inducible spasm in Japanese and Italian patients 7 to 10 days after myocardial infarction. This study observed a marked difference in vasomotor reactivity between these two groups, with 80% of the Japanese and 37% of the caucasian patients showing inducible coronary artery spasm (5), despite a similar frequency of cigarette smoking between groups. The similarity of these findings to those previously published (Table 4) add further credence to the data and confirm that there is a difference between races in patients with a recent myocardial infarct. Furthermore, the hyperreactivity among the Japanese was observed in both the infarct-related and noninfarct-related arteries (5).

Multivessel spasm in myocardial infarction.   As observed in vasomotor angina, our study (5) found a higher incidence of acetylcholine-induced multivessel spasm in Japanese infarct patients as compared with caucasian patients (64% vs. 17%, p < 0.00001, respectively). Thus, in a study population with similar clinical characteristics, the Japanese again show coronary hyperreactivity compared with their caucasian counterparts.

Coronary occlusion in myocardial infarction.   Definitive data in caucasian patients on the temporal relationship between acute myocardial infarction and occlusion of the relevant coronary artery have been provided by DeWood et al. (86). This group demonstrated that 87% of patients with transmural infarction had total coronary occlusion when angiography was performed within 6 h of chest pain onset. The incidence of total occlusion decreased with the duration postinfarct so that by 24 h only 65% of patients had totally occluded vessels (86).

In contrast to the above findings, Akiyama et al. (87) observed total occlusions in only 59% of the 296 Japanese patients undergoing angiography within 6 h of infarction. Furthermore, 21% of the patients showed Thrombolysis in Myocardial Infarction grade 3 (TIMI-3) flow and thus were believed to have "spontaneously reperfused." These patients were also shown to have an increased resting coronary tone (reflected by a greater response to intracoronary nitrate) as compared with matched segments proximal to a total occlusion, therefore suggesting that coronary spasm may be an important contributor to infarction in the reperfusion patients.

Although this study is particularly relevant to the current review, comparable data on "spontaneous reperfusion" in caucasian patients are not available. Also, the data concerning total occlusions are not directly comparable with DeWood’s study, as Akiyama et al. included patients with non–Q-wave infarction; a condition less frequently associated with total occlusion (88). However, a number of studies have examined the frequency of total occlusion within 6 h of infarct onset (and before reperfusion therapy) in caucasian (86,89–97) and Japanese (98–100) patients presenting with ST elevation (Table 5). Pooled analysis of these data suggests that persistent total occlusion in the first 6 h of infarct onset is more common in caucasian patients (pooled data, 82% vs. 65%, respectively, p < 0.0001), a finding that would be consistent with Akiyama’s data, again raising the possibility that Japanese people and caucasian people differ in their pathogenetic components of myocardial infarction.


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  		Table 5 Total Coronary Occlusion in Acute Myocardial Infarct Patients

 
Myocardial infarction in patients with insignificant coronary artery disease.   Patients with acute myocardial infarction who have normal or near-normal coronary arteries on angiography form an interesting subset whose pathogenesis of infarction remains unclear. A number of small caucasian-based studies (79,101–105) have undertaken provocative ergot testing in these patients and reported an incidence of inducible spasm between 0 and 31%. In contrast, Fukai et al. (106) reported a 75% incidence of inducible spasm among Japanese patients with myocardial infarction and angiographically normal/near-normal coronary arteries. Thus, similar to patients with myocardial infarction associated with atherosclerotic coronary artery disease, the Japanese have shown a higher frequency of inducible spasm.


   Conclusions
Top
 Abstract
 Important factors in coronary...
 Racial vasomotor heterogeneity...
 Acute myocardial infarction: do...
 Clinical differences
 Pathophysiologic differences
 Conclusions
References
 
This review has examined clinical and pathophysiologic differences between Japanese and caucasian patients in two coronary ischemic syndromes and provided evidence for racial heterogeneity in coronary vasomotor reactivity. In particular, Japanese patients with variant angina or myocardial infarction have hyperreactive vessels compared with caucasian patients. Furthermore this hyperreactivity is diffuse, as nonspastic/noninfarct arteries also exhibited enhanced vasomotor reactivity, and there is a high incidence of multivessel spasm.

The implications of these observations effect both clinical and research practice. In particular, data derived from coronary vasomotor studies in one population can no longer be automatically extrapolated to another. Furthermore, the observations justify the tendency of Japanese physicians to frequently undertake provocative tests for coronary spasm in patients with unexplained chest pain and to routinely use calcium antagonists in preference to beta-adrenoceptor antagonists in acute coronary syndromes (5,78).

The mechanism responsible for the diffuse hyperreactivity among Japanese variant angina/myocardial infarct patients remains to be elucidated, but both genetic and environmental factors are likely to play a role. Genetic factors predisposing to coronary spasm have recently been implicated in Japanese patients (61,107,108), with particular interest focusing upon an amino acid substitution of the endothelial nitric oxide synthetase gene (thereby resulting in deficient nitric oxide production). Although no comparable data on caucasian patients are available, the missense gene mutation is more frequent in Japanese patients with either vasospastic angina (61) or myocardial infarction (108), as compared with control subjects. However, the frequency of the gene in these coronary syndromes is low (approximately 21% in each group), suggesting that other factors also contribute. Future studies of Japanese patients living in caucasian societies may further aid our understanding of environmental factors contributing to the phenomenon.

Study limitations.   The findings of this review should be interpreted with caution, because most of the data are derived from published reports, thus introducing publication bias. Furthermore, comparisons between the independent studies may be limited because of undisclosed confounding factors. For example, cigarette smoking is the only known risk factor predisposing to coronary spasm, yet many studies do not report the frequency of smokers in their study group.

These limitations indicate the need for more prospective comparative studies evaluating racial differences in vasomotor activity. The only such study to date examining differences between Japanese and caucasian patients has supported the findings in published reports, and we hope other studies will support the observations made in this review. Certainly, assessing racial heterogeneity in coronary vasomotor reactivity may have further important implications regarding both pathophysiology and also therapeutics of coronary disease.


   Footnotes
 
Dr. Beltrame was supported by grants from the National Health and Medical Research Council of Australia.


   References
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 Abstract
 Important factors in coronary...
 Racial vasomotor heterogeneity...
 Acute myocardial infarction: do...
 Clinical differences
 Pathophysiologic differences
 Conclusions
 References
 

  1. Maseri A, Kaski J. Pathogenetic mechanisms of coronary artery spasm. J Am Coll Cardiol. 1989;14:610–612
  2. Mashiba H, Hoshio A, Kotake H. Interaction between coronary artery tone and spasm. J Am Coll Cardiol. 1991;17:1063–1064[Medline]
  3. Yasue H, Matsuyama K, Matsuyama K, Okumura K, Morikami Y, Ogawa H. Responses of angiographically normal human coronary arteries to intracoronary injection of acetylcholine by age and segment. Possible role of early coronary atherosclerosis. Circulation. 1990;81:482–490[Abstract/Free Full Text]
  4. Opie LH. Calcium channel antagonists in the management of anginal syndromes: changing concepts in relation to the role of coronary vasospasm. Prog Cardiovasc Dis. 1996;38:291–314[CrossRef][Medline]
  5. Pristipino C, Finocchiaro M, Beltrame J, et al. Differences in coronary vasospastic response after recent myocardial infarction in Japanese and Caucasian patients. Circulation. 1997;96:I-534
  6. Maseri A, Davies G, Hackett D, Kaski JC. Coronary artery spasm and vasoconstriction. The case for a distinction. Circulation. 1990;81:1983–1991[Free Full Text]
  7. Gould K, Lipscomb K. Effect of coronary stenoses on coronary flow reserve and resistance. Am J Cardiol. 1974;34:48–55[CrossRef][Medline]
  8. Caralis DG, Deligonul U, Kern MJ, Cohen JD. Smoking is a risk factor for coronary spasm in young women. Circulation. 1992;85:905–909[Abstract/Free Full Text]
  9. Scholl JM, Benacerraf A, Ducimetiere P, et al. Comparison of risk factors in vasospastic angina without significant fixed coronary narrowing to significant fixed coronary narrowing and no vasospastic angina. Am J Cardiol. 1986;57:199–202[CrossRef][Medline]
  10. Sugiishi M, Takatsu F. Cigarette smoking is a major risk factor for coronary spasm. Circulation. 1993;87:76–79[Abstract/Free Full Text]
  11. Nobuyoshi M, Abe M, Nosaka H, et al. Statistical analysis of clinical risk factors for coronary artery spasm: identification of the most important determinant. Am Heart J. 1992;124:32–38[CrossRef][Medline]
  12. Vita JA, Treasure CB, Nabel EG, et al. Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation. 1990;81:491–497[Abstract/Free Full Text]
  13. Panza JA, Quyyumi AA, Brush JE Jr, Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med. 1990;323:22–27[Abstract]
  14. Brush JE Jr, Faxon DP, Salmon S, Jacobs AK, Ryan TJ. Abnormal endothelium-dependent coronary vasomotion in hypertensive patients. J Am Coll Cardiol. 1992;19:809–815[Abstract]
  15. Treasure CB, Manoukian SV, Klein JL, et al. Epicardial coronary artery responses to acetylcholine are impaired in hypertensive patients. Circ Res. 1992;71:776–781[Abstract/Free Full Text]
  16. Ludmer PL, Selwyn AP, Shook TL, et al. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med. 1986;315:1046–1051[Abstract]
  17. Crea F, Davies G, Romeo F, et al. Myocardial ischemia during ergonovine testing: different susceptibility to coronary vasoconstriction in patients with exertional and variant angina. Circulation. 1984;69:690–695[Abstract/Free Full Text]
  18. Okumura K, Yasue H, Matsuyama K, et al. Sensitivity and specificity of intracoronary injection of acetylcholine for the induction of coronary artery spasm. J Am Coll Cardiol. 1988;12:883–888[Abstract]
  19. Maseri A, Chierchia S. Coronary artery spasm: demonstration, definition, diagnosis, and consequences. Prog Cardiovasc Dis. 1982;25:169–192[CrossRef][Medline]
  20. Yasue H, Kugiyama K. Coronary artery spasm: Japanese view. Coron Artery Dis. 1990;1:668–673
  21. Maseri A. Variant angina. Ischemic Heart Disease: A Rational Basis for Clinical Practice and Clinical Research. New York: Churchill Livingstone; 1995. p. 559
  22. Prinzmetal M, Kennamer R, Merliss R, Wada T, Bor N. A variant form of angina pectoris: preliminary report. Am J Med. 1959;27:375–388[CrossRef][Medline]
  23. Cheng T, Bashour T, Kelser GJ, Weiss L, Bacos J. Variant angina of Prinzmetal with normal coronary arteriograms. A variant of the variant. Circulation. 1973;47:476–485[Abstract/Free Full Text]
  24. Yasue H, Omote S, Takizawa A, et al. Comparison of coronary arteriographic findings during angina pectoris associated with S-T elevation or depression. Am J Cardiol. 1981;47:539–546[CrossRef][Medline]
  25. Miwa K, Fujita M, Ejiri M, Sasayama S. Usefulness of intracoronary injection of acetylcholine as a provocative test for coronary artery spasm in patients with vasospastic angina. Heart Vessels. 1991;6:96–101[CrossRef][Medline]
  26. Nakamura M, Takeshita A, Nose Y. Clinical characteristics associated with myocardial infarction, arrhythmias, and sudden death in patients with vasospastic angina. Circulation. 1987;75:1110–1116[Abstract/Free Full Text]
  27. Yasue H, Takizawa A, Nagao M, et al. Long-term prognosis for patients with variant angina and influential factors. Circulation. 1988;78:1–9[Abstract/Free Full Text]
  28. Shimokawa H, Nagasawa K, Irie T, et al. Clinical characteristics and long-term prognosis of patients with variant angina. A comparative study between Western and Japanese populations. Int J Cardiol. 1988;18:331–349[CrossRef][Medline]
  29. Severi S, Davies G, Maseri A, Marzullo P, L’Abbate A. Long-term prognosis of "variant" angina with medical treatment. Am J Cardiol. 1980;46:226–232[CrossRef][Medline]
  30. Waters DD, Miller DD, Szlachcic J, et al. Factors influencing the long-term prognosis of treated patients with variant angina. Circulation. 1983;68:258–265[Abstract/Free Full Text]
  31. Mark DB, Califf RM, Morris KG, et al. Clinical characteristics and long-term survival of patients with variant angina. Circulation. 1984;69:880–888[Abstract/Free Full Text]
  32. Walling A, Waters DD, Miller DD, Roy D, Pelletier GB, Theroux P. Long-term prognosis of patients with variant angina. Circulation. 1987;76:990–997[Abstract/Free Full Text]
  33. Kimura E, Kishida H. Treatment of variant angina with drugs: a survey of 11 cardiology institutes in Japan. Circulation. 1981;63:844–848[Abstract/Free Full Text]
  34. Koyanagi S, Takeshita A, Nakamura M. Clinical characteristics of sudden cardiac death in patients with vasospastic angina. Jpn Circ J. 1989;53:1541–1545[Medline]
  35. Sheehan FH, Epstein SE. Determinants of arrhythmic death due to coronary spasm: effect of preexisting coronary artery stenosis on the incidence of reperfusion arrhythmia. Circulation. 1982;65:259–264[Abstract/Free Full Text]
  36. Yasue H, Okumura K. Clinical diagnosis of the pathogenesis of coronary spastic angina. Jpn J Med. 1990;29:665–666[Medline]
  37. Dunn RF, Kelly DT, Sadick N, Uren R. Multivessel coronary artery spasm. Circulation. 1979;60:451–455[Abstract/Free Full Text]
  38. Igarashi Y, Tamura Y, Tanabe Y, et al. Clinical and angiographic characteristics of patients with multivessel coronary spasm in variant angina. Significance of progressive course of angina and disease activity. Jpn Heart J. 1994;35:419–430[Medline]
  39. Onaka H, Hirota Y, Shimada S, et al. Clinical observation of spontaneous anginal attacks and multivessel spasm in variant angina pectoris with normal coronary arteries: evaluation by 24-hour 12-lead electrocardiography with computer analysis. J Am Coll Cardiol. 1996;27:38–44[Abstract]
  40. Bell MR, Lapeyre AC, Bove AA. Angiographic demonstration of spontaneous diffuse three vessel coronary artery spasm. J Am Coll Cardiol. 1989;14:523–527[Abstract]
  41. Crea F, Abela GS, Pepine CJ. Multivessel coronary spasm without electrocardiographic changes. Am Heart J. 1985;110:1064–1067[CrossRef][Medline]
  42. Okumura K, Yasue H, Horio Y, et al. Multivessel coronary spasm in patients with variant angina: a study with intracoronary injection of acetylcholine. Circulation. 1988;77:535–542[Abstract/Free Full Text]
  43. Kadokami T, Shimokawa H, Fukumoto Y, et al. Coronary artery spasm does not depend on the intracellular calcium store but is substantially mediated by the protein kinase C-mediated pathway in a swine model with interleukin-1 beta in vivo. Circulation. 1996;94:190–196[Abstract/Free Full Text]
  44. Marzilli M, Goldstein S, Trivella MG, Palumbo C, Maseri A. Some clinical considerations regarding the relation of coronary vasospasm to coronary atherosclerosis: a hypothetical pathogenesis. Am J Cardiol. 1980;45:882–886[CrossRef][Medline]
  45. MacAlpin RN. Contribution of dynamic vascular wall thickening to luminal narrowing during coronary arterial constriction. Circulation. 1980;61:296–301[Abstract/Free Full Text]
  46. Freedman B, Richmond DR, Kelly DT. Pathophysiology of coronary artery spasm. Circulation. 1982;66:705–709[Abstract/Free Full Text]
  47. Kaski JC, Tousoulis D, McFadden E, Crea F, Pereira WI, Maseri A. Variant angina pectoris. Role of coronary spasm in the development of fixed coronary obstructions. Circulation. 1992;85:619–626[Abstract/Free Full Text]
  48. Kaski J, Maseri A. Coronary artery spasm: European view. Coron Artery Dis. 1990;1:660–667
  49. Yasue H, Touyama M, Shimamoto M, Kato H, Tanaka S. Role of autonomic nervous system in the pathogenesis of Prinzmetal’s variant form of angina. Circulation. 1974;50:534–539[Abstract/Free Full Text]
  50. Kugiyama K, Yasue H, Okumura K, et al. Nitric oxide activity is deficient in spasm arteries of patients with coronary spastic angina. Circulation. 1996;94:266–272[Abstract/Free Full Text]
  51. Hoshio A, Kotake H, Mashiba H. Significance of coronary artery tone in patients with vasospastic angina. J Am Coll Cardiol. 1989;14:604–609[Abstract]
  52. Kuga T, Egashira K, Inou T, Takeshita A. Correlation of basal coronary artery tone with constrictive response to ergonovine in patients with variant angina. J Am Coll Cardiol. 1993;22:144–150[Abstract]
  53. Okumura K, Yasue H, Matsuyama K, et al. Diffuse disorder of coronary artery vasomotility in patients with coronary spastic angina. Hyperreactivity to the constrictor effects of acetylcholine and the dilator effects of nitroglycerin. J Am Coll Cardiol. 1996;27:45–52[Abstract]
  54. Yokoyama M, Akita H, Hirata K, et al. Supersensitivity of isolated coronary artery to ergonovine in a patient with variant angina. Am J Med. 1990;89:507–515[CrossRef][Medline]
  55. Hackett D, Larkin S, Chierchia S, Davies G, Kaski JC, Maseri A. Induction of coronary artery spasm by a direct local action of ergonovine. Circulation. 1987;75:577–582[Abstract/Free Full Text]
  56. Kaski JC, Tousoulis D, Gavrielides S, et al. Comparison of epicardial coronary artery tone and reactivity in Prinzmetal’s variant angina and chronic stable angina pectoris. J Am Coll Cardiol. 1991;17:1058–1062[Abstract]
  57. Feldman R, Pepine C, Curry R, Conti C. Coronary arterial responses to graded doses of nitroglycerine. Am J Cardiol. 1979;43:91–97[CrossRef][Medline]
  58. Hill JA, Feldman RL, Pepine CJ, Conti CR. Regional coronary artery dilation response in variant angina. Am Heart J. 1982;104:226–233[CrossRef][Medline]
  59. Egashira K, Katsuda Y, Mohri M, et al. Basal release of endothelium-derived nitric oxide at site of spasm in patients with variant angina. J Am Coll Cardiol. 1996;27:1444–1449[Abstract]
  60. Kugiyama K, Ohgushi M, Motoyama T, et al. Nitric oxide-mediated flow-dependent dilation is impaired in coronary arteries in patients with coronary spastic angina. J Am Coll Cardiol. 1997;30:920–926[Abstract]
  61. Yoshimura M, Yasue H, Nakayama M, et al. A missense Glu298Asp variant in the endothelial nitric oxide synthase gene is associated with coronary spasm in the Japanese. Hum Genet. 1998;103:65–69[CrossRef][Medline]
  62. Egashira K, Inou T, Yamada A, Hirooka Y, Takeshita A. Preserved endothelium-dependent vasodilation at the vasospastic site in patients with variant angina. J Clin Invest. 1992;89:1047–1052[Medline]
  63. Yamamoto H. Preserved endothelial function in the spastic segment of the human epicardial coronary artery in patients with variant angina—role of substance P in evaluating endothelial function. Eur Heart J. 1993;14:118–122
  64. Kuga T, Egashira K, Mohri M, et al. Bradykinin-induced vasodilation is impaired at the atherosclerotic site but is preserved at the spastic site of human coronary arteries in vivo. Circulation. 1995;92:183–189[Abstract/Free Full Text]
  65. Kugiyama K, Yasue H. Nitric oxide activity at the site of coronary spasm: deficient or preserved? Circulation. 1997;96:1048–1049
  66. Egashira K, Takeshita A. Nitric oxide activity at the site of coronary spasm: deficient or preserved? Circulation. 1997;96:1048
  67. Yoshio H, Shimizu M, Sugihara N, et al. Assessment of autonomic nervous activity by heart rate spectral analysis in patients with variant angina. Am Heart J. 1993;125:324–329[CrossRef][Medline]
  68. Lanza GA, Pedrotti P, Pasceri V, Lucente M, Crea F, Maseri A. Autonomic changes associated with spontaneous coronary spasm in patients with variant angina. J Am Coll Cardiol. 1996;28:1249–1256[Abstract]
  69. Waters DD, Miller DD, Bouchard A, Bosch X, Theroux P. Circadian variation in variant angina. Am J Cardiol. 1984;54:61–64[CrossRef][Medline]
  70. Lanza G, Patti G, Pasceri V, et al. Circadian variation of transient ischaemia in patients with variant angina with and without coronary stenoses. Circulation. 1997;96:I-761
  71. Keys AE. Coronary heart disease in seven countries: summary. Circulation. 1970;41:I-186–I-195
  72. Heart and Stroke Facts Report. Canberra: Australian National Heart Foundation; 1995.
  73. Gordon T. Mortality experience among the Japanese living in the United States, Hawaii and Japan. Public Health Rep. 1957;72:543–553[Medline]
  74. Marmot MG, Syme SL, Kagan A, Kato H, Cohen JB, Belsky J. Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: prevalence of coronary and hypertensive heart disease and associated risk factors. Am J Epidemiol. 1975;102:514–525[Abstract/Free Full Text]
  75. Simons LA. Interrelations of lipids and lipoproteins with coronary artery disease mortality in 19 countries. Am J Cardiol. 1986;57:5g–10g
  76. Worth R, Rhoads G, Kagan A, Kato H, Cohen J, Belsky J. Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: mortality. Am J Epidemiol. 1975;102:481–490[Abstract/Free Full Text]
  77. Saito M, Fukami K, Hiramori K, et al. Long-term prognosis of patients with acute myocardial infarction: is mortality and morbidity as low as the incidence of ischemic heart disease in Japan. Am Heart J. 1987;113:891–897[CrossRef][Medline]
  78. Nakamura Y, Kawai C, Moss AJ, et al. Comparison between Japan and North America in the posthospital course after recovery from an acute coronary event. Int J Cardiol. 1996;55:245–254[CrossRef][Medline]
  79. Bertrand ME, Lablanche JM, Tilmant PY, Thieuleux FA, Delforge MG, Chahine RA. The provocation of coronary arterial spasm in patients with recent transmural myocardial infarction. Eur Heart J. 1983;4:532–535[Abstract/Free Full Text]
  80. Mongiardo R, Finocchiaro ML, Beltrame J, et al. Low incidence of serotonin-induced occlusive coronary artery spasm in patients with recent myocardial infarction. Am J Cardiol. 1996;78:84–87[CrossRef][Medline]
  81. Okumura K, Yasue H, Matsuyama K, et al. Effect of acetylcholine on the highly stenotic coronary artery: difference between the constrictor response of the infarct-related coronary artery and that of the noninfarct-related artery. J Am Coll Cardiol. 1992;19:752–758[Abstract]
  82. Bertrand ME, LaBlanche JM, Tilmant PY, et al. Frequency of provoked coronary arterial spasm in 1089 consecutive patients undergoing coronary arteriography. Circulation. 1982;65:1299–1306[Abstract/Free Full Text]
  83. Nosaka H, Nobuyoshi M. Coronary arterial spasm and symptomatology in ischemic and nonischemic heart diseases: study of the ergonovine maleate provocative test in 3,000 consecutive patients. J Cardiogr Suppl. 1987;12:35–47[Medline]
  84. Kanazawa K, Suematsu M, Ishida T, et al. Disparity between serotonin- and acetylcholine-provoked coronary artery spasm. Clin Cardiol. 1997;20:146–152[Medline]
  85. Suzuki Y, Tokunaga S, Ikeguchi S, et al. Induction of coronary artery spasm by intracoronary acetylcholine: comparison with intracoronary ergonovine. Am Heart J. 1992;124:39–47[CrossRef][Medline]
  86. DeWood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med. 1980;303:897–902[Abstract]
  87. Akiyama H, Ishikawa K, Kanamasa K, et al. Increased coronary vasomotor tone in acute myocardial infarction patients with spontaneous coronary recanalization. Jpn Circ J. 1997;61:503–509[CrossRef][Medline]
  88. DeWood MA, Stifter WF, Simpson CS, et al. Coronary arteriographic findings soon after non-Q-wave myocardial infarction. N Engl J Med. 1986;315:417–423[Abstract]
  89. Ganz W, Buchbinder N, Marcus H, et al. Intracoronary thrombolysis in evolving myocardial infarction. Am Heart J. 1981;101:4–13[CrossRef][Medline]
  90. Timmis GC, Gangadharan V, Hauser AM, Ramos RG, Westveer DC, Gordon S. Intracoronary streptokinase in clinical practice. Am Heart J. 1982;104:925–938[CrossRef][Medline]
  91. Anderson JL, Marshall HW, Bray BE, et al. A randomized trial of intracoronary streptokinase in the treatment of acute myocardial infarction. N Engl J Med. 1983;308:1312–1318[Abstract]
  92. Leiboff RH, Katz RJ, Wasserman AG, et al. A randomized, angiographically controlled trial of intracoronary streptokinase in acute myocardial infarction. Am J Cardiol. 1984;53:404–407[CrossRef][Medline]
  93. Simoons ML, Serruys PW, v. d. Brand M, et al. Improved survival after early thrombolysis in acute myocardial infarction. A randomized trial by the Interuniversity Cardiology Institute in The Netherlands. Lancet. 1985;2:578–582
  94. Valentine RP, Pitts DE, Brooks Brunn JA, Williams JG, Van Hove E, Schmidt PE. Intravenous versus intracoronary streptokinase in acute myocardial infarction. Am J Cardiol. 1985;55:309–312[CrossRef][Medline]
  95. von Essen R, Uebis R, Schmidt W, et al. Intracoronary streptokinase in acute myocardial infarct. Experience with 461 patients. Dtsch Med Wochenschr. 1985;110:570–575[Medline]
  96. Messmer BJ, von Essen R, Minale C, et al. Intracoronary thrombolysis and early bypass surgery for acute myocardial infarct: five years’ experience. Thorac Cardiovasc Surg. 1986;34:1–4[Medline]
  97. Steg PG, Himbert D, Benamer H, et al. Conservative management of patients with acute myocardial infarction and spontaneous acute patency of the infarct-related artery. Am Heart J. 1997;134:248–252[CrossRef][Medline]
  98. Nakagawa S, Hanada Y, Koiwaya Y, Tanaka K. Angiographic features in the infarct-related artery after intracoronary urokinase followed by prolonged anticoagulation. Role of ruptured atheromatous plaque and adherent thrombus in acute myocardial infarction in vivo. Circulation. 1988;78:1335–1344[Abstract/Free Full Text]
  99. Yasue H, Ogawa H, Okumura K. Coronary artery spasm in the genesis of myocardial ischemia. Am J Cardiol. 1989;63:29e–32e
  100. Dote K, Sato H, Tateishi H, Uchida T, Ishihara M, Sasaki K. Clinical features of patients with spontaneous recanalization of the infarct-related artery during evolving acute myocardial infarction. J Cardiol. 1989;19:729–739[Medline]
  101. Betriu A, Pare JC, Sanz GA, et al. Myocardial infarction with normal coronary arteries: a prospective clinical-angiographic study. Am J Cardiol. 1981;48:28–32[CrossRef][Medline]
  102. Legrand V, Deliege M, Henrard L, Boland J, Kulbertus H. Patients with myocardial infarction and normal coronary arteriogram. Chest. 1982;82:678–685[Abstract/Free Full Text]
  103. Lindsay J Jr, Pichard AD. Acute myocardial infarction with normal coronary arteries (editorial). Am J Cardiol. 1984;54:902–904[CrossRef][Medline]
  104. Salem B, Haikal M, Zambrano A, Bollis A, Gowda S. Acute myocardial infarction with "normal" coronary arteries: clinical and angiographic profiles, with ergonovine testing. Tex Heart Inst J. 1985;12:1–7[Medline]
  105. Raymond R, Lynch J, Underwood D, Leatherman J, Razavi M. Myocardial infarction and normal coronary arteriography: a 10 year clinical and risk analysis of 74 patients. J Am Coll Cardiol. 1988;11:471–477[Abstract]
  106. Fukai T, Koyanagi S, Takeshita A. Role of coronary vasospasm in the pathogenesis of myocardial infarction: study in patients with no significant coronary stenosis. Am Heart J. 1993;126:1305–1311[CrossRef][Medline]
  107. Horimoto M, Wakisaka A, Takenaka T, et al. Familial evidence of vasospastic angina and possible involvement of HLA-DR2 in susceptibility to coronary spasm. Jpn Circ J. 1998;62:284–288[CrossRef][Medline]
  108. Shimasaki Y, Yasue H, Yoshimura M, et al. Association of the missense Glu298Asp variant of the endothelial nitric oxide synthase gene with myocardial infarction. J Am Coll Cardiol. 1998;31:1506–1510[Abstract/Free Full Text]



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