Correspondence
Angiotensin-Converting–Enzyme Genotype and Ischemic Heart Disease
N Engl J Med 1995; 333:458-460August 17, 1995
- Article
To the Editor:
Lindpaintner et al. (March 16 issue)1 conclude that the presence of the angiotensin-converting–enzyme (ACE) genotype does not alter the risk of myocardial infarction or coronary artery disease. We think that the results of their study may have been influenced by the use of ACE inhibitors, which reduce the level of ACE in the blood.2 During the period from 1982 to 1992, when ACE inhibitors were widely used to treat hypertension, 28.1 percent of the case patients and 16.7 percent of the controls had hypertension.
The use of ACE inhibitors would tend to obscure the effect of the DD genotype if ACE inhibition either was used more frequently in patients with the DD allele or was more effective in reducing the risk of myocardial infarction in this population.
2 ReferencesB. Robert Meyer, M.D.
Anshu Vashishtha, M.D., Ph.D.
Bronx Municipal Hospital Center, Bronx, NY 104611
Lindpaintner K ,Pfeffer MA ,Kreutz R , et al. A prospective evaluation of an angiotensin-converting-enzyme gene polymorphism and the risk of ischemic heart disease. N Engl J Med 1995;332:706-711
Full Text | Web of Science | Medline2
Kawamura M ,Imanashi M ,Matsushima Y ,Ito K ,Hiramori K . Circulating angiotensin II levels under repeated administration of lisinopril in normal subjects. Clin Exp Pharmacol Physiol 1992;19:547-553
CrossRef | Web of Science | Medline
To the Editor:
Although the results reported by Lindpaintner et al. are disappointing, particularly in view of the potential for therapeutic intervention, they are predictable. It is well recognized that the ACE DI polymorphism is unlikely to influence plasma ACE levels directly. Instead, it is thought to represent a marker in linkage disequilibrium with the culprit locus. Therefore, as the authors point out, the DI polymorphism is likely to be of limited predictive value in the heterogeneous North American population. Furthermore, the study cohort was a relatively atypical sample of this population. In addition, other possible genetic risk factors for coronary artery disease have recently been identified.1 Similarly, there are the putative effects of cytokine growth factors and lipoprotein subfractions,2 which are also under genetic control. The population studied may have had a particularly low incidence of other genes that influence the development of atheroma or a high prevalence of cardioprotective loci. It is also possible that the presence of the ACE DD genotype has a relatively minor effect on the development of atheroma but results in a variant of the repair mechanisms that follow a vascular injury, leading to unfavorable outcomes, such as left ventricular dilatation after myocardial infarction.
The results of the study by Lindpaintner et al. cast doubt on the relevance of the ACE genotype in cardiovascular disease. Their findings should not, however, discourage further study of the genetic basis of cardiac diseases. Conclusions should be based on large population studies and on a recognition of the multiple environmental and genetic influences involved.
2 ReferencesGraham Hillis, M.B., B.S.
Abdallah Al-Mohammad, M.D.
Kevin Jennings, M.D.
Aberdeen Royal Infirmary, Aberdeen AB9 2ZB, Scotland1
Ishigami T ,Umemura S ,Iwamoto T , et al. Molecular variant of angiotensinogen gene is associated with coronary atherosclerosis. Circulation 1995;91:951-954
Web of Science | Medline2
Hayden MR ,Reidy M . Many roads lead to atheroma. Nat Med 1995;1:22-23
CrossRef | Web of Science | Medline
To the Editor:
The prospective study by Lindpaintner et al. underestimates the risk of myocardial infarction associated with the presence of the D allele of the ACE gene. Myocardial infarction is a multifactorial disease for which hypertension, hypercholesterolemia, and diabetes mellitus are important risk factors. However, the patients with myocardial infarction enrolled in the study by Lindpaintner et al. had a higher incidence of these risk factors than the controls. Furthermore, the mean age of the subjects was five to seven years older than that of subjects in earlier studies by us1 and by Cambien et al.,2 which reported an increased risk of myocardial infarction associated with the DD genotype. These differences in age may seriously affect the incidence of myocardial infarction, despite the discussion to the contrary by Lindpaintner et al., because older subjects have more nongenetic risk factors for myocardial infarction than younger subjects. Therefore, we think the sample in the study by Lindpaintner et al. was not appropriate for an evaluation of the genetic risk of myocardial infarction.
On the other hand, we agree that there is an association between the ACE genotype and ischemic heart disease without myocardial infarction. In our recent study,1 the frequencies of the ACE genotypes among the patients with angiographic evidence of effort-induced angina were 0.17, 0.46, and 0.37 for the DD, DI, and II genotypes, respectively (P = 0.66 for the comparison with the controls). The different causes of myocardial infarction and effort-induced angina may explain the difference in the impact of the genetic risk of the ACE genotype in the two diseases.
2 ReferencesMitsuru Ohishi, M.D.
Hiromi Rakugi, M.D.
Jitsuo Higaki, M.D.
Tetsuro Miki, M.D.
Toshio Ogihara, M.D.
Osaka University Medical School, Osaka 565, Japan1
Zhao Y ,Higashimori K ,Higaki J , et al. Significance of the deletion polymorphism of the angiotensin converting enzyme gene as a risk factor for myocardial infarction in Japanese. Hypertens Res 1994;17:55-57
CrossRef2
Cambien F ,Poirier O ,Lecerf L , et al. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 1992;359:641-644
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We appreciate the comments of Drs. Meyer and Vashishtha regarding the possible confounding effect of ACE-inhibitor therapy on the results of our study. Although specific information about the use of ACE inhibitors among case patients and controls is not yet available, it is unlikely that ACE-inhibitor therapy would have influenced our results, for several reasons. First, there is no reason to suspect that persons with the DD genotype would have been preferentially treated with this class of drug. Second, a differential effect of ACE-inhibitor therapy among the subjects with the DD genotype and those with the DI or II genotype is extremely unlikely to account for our negative findings. If one assumes that all cases of hypertension were treated with ACE inhibitors and that ACE inhibition may reduce the incidence of myocardial infarction by 25 percent,1 it can be shown that a therapy-related reduction in morbidity would have had to occur exclusively among persons with the DD genotype, preventing two of every three myocardial infarctions in this group, in order to reconcile our findings with those of Cambien et al.2 With a smaller proportion of treated cases, an even greater selective advantage of ACE inhibition among the subjects with the DD genotype would have had to be present. It should be noted that the effects of aCE inhibitors on the plasma renin–angiotensin system are complex and poorly correlated with their clinical effects. Although long-term treatment lowers plasma ACE activity, it has no effect on circulating angiotensin II levels.3,4
We agree with Dr. Hillis and colleagues that our findings, as we state in our article, do not rule out the existence of disease-relevant alleles of the ACE gene; however, the D–I polymorphism does not represent a useful marker for ischemic heart disease in a population consisting predominantly of white U.S. men. The study sample is representative of a large, outbred population, and there is no reason to suspect the presence of a genetic bias. It is clear that physicians represent a population at low risk for ischemic heart disease, presumably because of a number of lifestyle variables, especially cigarette smoking.5 Since a more pronounced risk associated with the DD genotype has been reported among persons with a low overall risk,2 our study might have been expected to demonstrate a larger, rather than smaller, effect of the DD genotype on the relative risk of ischemic heart disease.
Dr. Ohishi and colleagues point out that the prevalence of the usual risk factors was higher among the case patients than among the controls. Except for matching variables, this difference is to be expected in any observational study, and we accounted for it with analyses adjusted for covariates. The mean age of our case patients differed by five years from the mean age in the earlier study — a difference we consider relatively minor, particularly in view of the otherwise lower incidence of the usual risk factors in our sample.
5 ReferencesKlaus Lindpaintner, M.D.
Charles H. Hennekens, M.D., Dr.P.H.
Brigham and Women's Hospital, Boston, MA 021151
Pfeffer MA ,Braunwald E ,Moye LA , et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction -- results of the Survival and Ventricular Enlargement Trial. N Engl J Med 1992;327:669-677
Full Text | Web of Science | Medline2
Cambien F ,Poirier O ,Lecerf L , et al. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 1992;359:641-644
CrossRef | Web of Science | Medline3
Bernasconi M ,Marone C ,Beretta-Piccoli C ,Lepori G ,Shaw S ,Weidmann P . Cardiovascular pressor reactivity after chronic converting enzyme inhibition. Am J Hypertens 1991;4:348-355
Web of Science | Medline4
Kawamura M ,Imanashi M ,Matsushima Y ,Ito K ,Hiramori K . Circulating angiotensin II levels under repeated administration of lisinopril in normal subjects. Clin Exp Pharmacol Physiol 1992;19:547-553
CrossRef | Web of Science | Medline5
Robbins AS ,Manson JE ,Lee IM ,Satterfield S ,Hennekens CH . Cigarette smoking and stroke in a cohort of U.S. male physicians. Ann Intern Med 1994;120:458-462
Web of Science | Medline
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Ahmed Khalil, Tari Tarik, David T. Porembka. (2007) Aortic pathology: Aortic trauma, debris, dissection, and aneurysm. Critical Care Medicine 35:Suppl, S392-S400
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Andreas Gardemann, Monika Fink, Jürgen Stricker, Quoc D Nguyen, Jörg Humme, Norbert Katz, Harald Tillmanns, Friedrich Wilhelm Hehrlein, Matthias Rau, Werner Haberbosch. (1998) ACE I/D gene polymorphism: presence of the ACE D allele increases the risk of coronary artery disease in younger individuals. Atherosclerosis 139:1, 153-159
CrossRef3
O. Costerousse, S. Danilov, F. Alhenc-Gelas. (1997) Genetics of Angiotensin I-Converting Enzyme. Clinical and Experimental Hypertension 19:5-6, 659-669
CrossRef4
Kassirer, Jerome P., Angell, Marcia, . (1995) Redundant Publication: A Reminder. New England Journal of Medicine 333:7, 449-450
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