Racial Differences in Coronary Vasomotor Response or Selection Bias?
To the Editor:
Pristipino et al1 found that, compared with white patients in Italy, Japanese patients with myocardial infarction had a 3-fold-greater incidence of coronary spasm and a vasoconstrictive response to acetylcholine. The authors conclude that these “major racial differences in the coronary constrictor response...warrant further investigations because they may have relevant pathophysiological and therapeutic implications.” In my opinion, interpreting these differences as “racial” can be problematic, particularly in view of the possibility of selection bias stemming from the different risk profile of the study groups. Japanese patients in this study were much older than the white patients (mean age, 68.8 versus 54.8 years) and had much lower mean serum cholesterol levels (183 versus 247 mg/dL), serum triglyceride levels (87 versus 209 mg/dL), and body mass indexes (22.1 versus 26.5 kg/m2). These dramatic differences cast serious doubts on the comparability of the underlying disease process in the 2 groups. Atherosclerotic disease is an extremely complex multifactorial process in which many metabolic and physical factors come into play. Furthermore, the old Virchowian hypothesis of the role of inflammation in this process has been recently resurrected.2
Compared with Western countries, coronary heart disease (CHD) is very uncommon in Japan. According to 1998 World Health Organization data,3 CHD mortality rates among men 35–74 years old are 5.7% in Japan, 15% in Italy, and 21.4% in the United States. This low CHD risk is consistent with the low cholesterol and low body weight of the Japanese population, and the Japanese patients in Pristipino et al’s study1 fit this general profile. Why then did these patients have a myocardial infarction? Why do they have angiographic features similar to their white counterparts despite their much lower lipid levels? Could it be that, among all the constellation of risk factors involved, the predominant factors that caused the underlying atherosclerosis disease in these Japanese patients are different than those in the white patients? For example, hyperlipidemia may play a secondary role, and inflammation, endothelial dysfunction, or other factors (eg, infection?)4 may be the predominant players. In other words, these 2 groups of patients may suffer from a different form of atherosclerosis, even if it looks similar in the angiogram.
Before concluding that the observed differences are racial, patients who have similar profiles with regard to the major CHD risk factors will need to be compared. For example, how will the vasomotor response of Japanese patients compare with that among lean whites with low cholesterol levels who experience a myocardial infarction?
- Copyright © 2001 by American Heart Association
Pristipino C, Beltrame JF, Finocchiaro ML, et al. Major racial differences in coronary constrictor response between Japanese and Caucasians with recent myocardial infarction. Circulation. 2000;101:1102–1108.
American Heart Association. 2000 Heart and Stroke Statistical Up-date. Dallas, Tex: American Heart Association, 1999. Available at: http://www.americanheart.org/statistics/index.html. Accessed December 6, 2000.
Nieto FJ. Infections and atherosclerosis: new clues from an old hypothesis? Am J Epidemiol. 1998;148:937–948.
We appreciate the stimulating points raised by Dr Nieto. Because our study was performed by the same team using the same protocol, it provides conclusive evidence of a much higher incidence of coronary vasospastic response in Japanese patients than in white patients after a myocardial infarction (MI). The differences we found between Japanese and white patients are consistent with previous separate reports in white and Oriental patients with MI and with the higher incidence of variant angina in Orientals. Collectively, these studies suggest that the hyper-reactivity of coronary arteries to constrictor stimuli has a more prevalent role in the pathogenesis of MI in Japanese patients.R1
Whether this greater racial prevalence of coronary spasm among Orientals is related to genetic or environmental factors remains to be investigated. The different risk profile found in our 2 groups reflects the different prevalence of risk factors among Japanese and white subjects and indicates a different prevalence of the underlying pathogenetic mechanisms of MI in these 2 populations. Despite their lower cholesterol levels, Japanese patients had more severe coronary atherosclerosis, although the difference did not reach statistical significance. Coronary spasm may be more likely to cause plaque fissure in severely atherosclerotic arteries, initiating a vicious circle of thrombosis and vasoconstriction.R2 The development of spasm, however, is largely unrelated to the severity of coronary atherosclerosis.R3 In addition, in our study, only 16% of spasm in Japanese patients and 8% in white patients occurred at the site of an angiographically detectable stenosis. Thus, the different prevalence of spasm in MI among Japanese and white patients may be related to environmental risk factors, as suggested by Dr Nieto; however, the response to potentially atherogenic and to constrictor stimuli may be genetically different. Indeed, known environmental risk factors for spasm are different from those for atherosclerosis in both ethnic groups.R1 R4
The concept that the predisposing and precipitating factors of MI are basically the same in all patients and the effort to find common mechanisms for all infarctions may delay progress. Indeed, an acute MI develops whenever blood flow through a major coronary artery is suddenly and persistently interrupted, regardless of the actual cause of the interruption (which, besides thrombosis, may include occlusive spasm, massive small vessel constriction, and their variable combinations). Each of these final triggers of sudden, persistent coronary flow interruption and their underlying environmental, genetic, predisposing, and precipitating factors might not have the same prevalence in different ethnic, geographical, age, and sex groups.R5
Beltrame JF, Sasayama S, Maseri A. Racial heterogeneity in coronary artery vasomotor reactivity: differences between Japanese and Caucasian patients. J Am Coll Cardiol. 1999;33:1442–1452.
Maseri A, Davies G, Hackett D, et al. Coronary artery spasm and vasoconstriction. The case for a distinction. Circulation. 1990;81:1983–1991.