(Circulation. 1995;91:1888-1890.)
© 1995 American Heart Association, Inc.
Articles |
Angiotensin-Converting Enzyme and Lipoprotein(a) as Risk Factors for Myocardial Infarction
From the Center for the Prevention of Cardiovascular Disease, Harvard School of Public Health and Harvard Medical School, Boston, Mass.
Correspondence to Edgar Haber, MD, Harvard School of Public Health, 677 Huntington Ave, Boston, MA 02115.
Key Words: angiotensin • enzymes • myocardial infarction • lipoproteins
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Introduction |
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 Top Introduction References |
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In this issue Badenhop et al1 present a study of genetic markers in schoolchildren and death from coronary artery disease or myocardial infarction or a history of coronary artery bypass surgery or angioplasty in their grandparents. The study shows a correlation between these end points and both an angiotensin-converting enzyme (ACE) genotype and the plasma concentration of lipoprotein(a) [Lp(a)]. These observations remind us that we do not fully understand the risk factors governing coronary artery disease. Over many years, a wealth of studies have identified smoking, hypertension, sex, increased low-density lipoprotein (LDL) cholesterol, diabetes mellitus, and a sedentary lifestyle as having a significant impact on the incidence of arteriosclerosis and myocardial infarction or stroke. Yet data from the Framingham Study show that the probability of developing one of the manifestations of coronary artery disease within 10 years is 6% for a 50-year-old man without any of the known risk factors; for a 60-year-old man in the same condition, the probability is 9%.2 It is not surprising, then, that the identification of other risk factors for arteriosclerosis and its consequences —especially those factors for which a positive linkage exists between a genetic locus and disease—remains the focus of considerable research activity. Of particular interest in the context of the report by Badenhop et al1 are the plasma concentrations of angiotensin II and Lp(a).
Angiotensin II is a potent vasoconstrictor, cardiac inotropic agent, and smooth muscle cell growth factor. Elevated levels of angiotensin II have been recognized for some time to correlate with hypertension, and they appear to be associated with an increased risk of myocardial infarction.3 The plasma and tissue concentrations of angiotensin II are determined by the renin-angiotensin system. The enzyme renin cleaves its substrate angiotensinogen to release an inactive peptide, angiotensin I. A second enzyme, ACE, then removes a dipeptide from the carboxyl terminus of angiotensin I to produce angiotensin II. Because the genes coding for each protein in the renin-angiotensin system have been identified and cloned, we can now examine possible relations between polymorphisms in these genes and manifestations of hypertension or other forms of cardiovascular disease. Cleavage of angiotensinogen by renin, for example, is clearly a rate-limiting step in the series of reactions leading to the release of angiotensin II. A correlation between renin gene polymorphism and hypertension would therefore seem plausible. However, a careful analysis of a large pedigree in Utah with a high prevalence of coronary artery disease and hypertension failed to show a significant association between blood pressure and restriction fragment length polymorphisms in the renin gene.4 Two more studies, of a hypertensive population in France5 and of a set of hypertensive sib pairs,6 also failed to show that the renin gene was a genetic determinant of hypertension.
The plasma concentration of the substrate for renin, angiotensinogen, is another clear determinant of plasma angiotensin II levels, and increased levels of angiotensinogen, such as occur in oral contraceptive–induced hypertension7 or Cushing's syndrome,8 have long been associated with hypertension. In a study of 574 subjects published in 1979, a strong association between plasma angiotensinogen and blood pressure was demonstrated.9 It is not surprising, therefore, that a large study of hypertensive siblings in both Utah and France has provided evidence of genetic linkage between the angiotensinogen gene and hypertension.10 Among 15 observed variants in the angiotensinogen gene, a mutation coding for a change of methionine at position 235 to threonine (M235T) was found to be associated with increased angiotensinogen levels, and the mutation was more frequently present in severely hypertensive subjects. This linkage between the M235T variant and hypertension was then confirmed in a second cohort of patients who were not selected for a family history of hypertension.11 A subsequent study of a different group of subjects, however, failed to show an association between hypertension and the M235T variant, even though it did confirm a strong linkage between essential hypertension and the angiotensinogen gene locus.12 The M235T variant of the angiotensinogen gene has also been associated with the hypertension of pregnancy.13 Yet there has been no report of an association between the M235T genotype and the occurrence of either coronary artery disease or primary cardiac hypertrophy. This lack of association is noteworthy in light of reports that the renin-angiotensin system appears to play a role in both smooth muscle cell proliferation,14 a necessary accompaniment of chronic arteriosclerosis, and cardiac remodeling after myocardial infarction.15
ACE is not a limiting factor in the production of angiotensin II, and indeed, no correlation has been demonstrated between plasma levels of ACE and hypertension. There does, however, appear to be a linkage between plasma ACE levels and the insertion (I) or deletion (D) of a 287–base pair DNA fragment of the ACE gene.16 The presence of the D allele is associated with high ACE levels: tissue and plasma ACE levels are both highest in DD homozygotes, intermediate in DI heterozygotes, and lowest in II homozygotes. Although all studies but one17 have failed to show an association or linkage between hypertension and the ACE gene locus,18 19 20 21 two studies have shown that ACE polymorphism at the I/D locus is a risk factor for coronary disease: the DD genotype increases the risk for myocardial infarction by 2.6-fold.22 23 The ACE DD genotype also seems to be associated with an increased incidence of coronary artery stenosis after angioplasty,24 idiopathic dilated cardiomyopathy,25 familial hypertrophic cardiomyopathy,26 and left ventricular hypertrophy in middle-aged men.27 Nevertheless, a pathophysiological association between genotype and these vascular and cardiac diseases is not yet apparent. Although the DD genotype is associated with increased plasma levels of ACE, it does not necessarily follow that plasma levels of angiotensin II are likely to increase, since, as I mentioned earlier, there is no association between the ACE genotype and hypertension. The angiotensinogen gene mutation discussed in the preceding paragraph does indeed correlate with hypertension. Although this mutation probably produces an increase in plasma angiotensin II concentration, the angiotensinogen gene mutation does not appear to be associated with cardiac hypertrophy or arteriosclerosis.
The association between the D allele of the ACE gene and coronary artery disease shown by Badenhop et al1 does not prove causality. ACE is not necessarily implicated in pathogenesis; it is possible that the D allele may only be a marker for another closely linked gene—yet to be identified—that may not even be related to the renin-angiotensin system.
Lp(a) is a cholesterol-ester, LDL-like particle containing apolipoprotein (apo) B-100 (the apolipoprotein of common LDL) linked by a disulfide bridge to apo(a).28 Apo(a) is a glycoprotein coded by a single gene locus on the long arm of chromosome 6 that has a great deal of homology with plasminogen. There are many tandem repeats in apo(a) that resemble the fourth kringle domain of plasminogen, as well as a single homologue of the fifth kringle domain of plasminogen and one homologue of the protease domain. There are also several alleles of the apo(a) gene, which account for considerable size polymorphism (300 to 800 kD). Interestingly, a direct relation exists between the size of the apo(a) protein and the plasma levels of Lp(a). Because of the many alleles of the apo(a) gene, plasma levels of Lp(a) vary considerably. Unfortunately, elevated plasma Lp(a) levels are refractory to the drug and dietary manipulations that are useful for modifying plasma LDL levels.
In vitro, Lp(a) can compete with plasminogen by inhibiting fibrinolysis. Because of an epidemiological linkage between inhibition of fibrinolysis and the recurrence of myocardial infarction,29 high plasma concentrations of Lp(a) have been proposed as a risk factor for arteriosclerotic disease. In support of this hypothesis, Lawn et al30 have shown that transgenic mice expressing human apo(a) manifest arteriosclerotic lesions and that apo(a) colocalizes with lipid deposition in artery walls. Clinical and epidemiological studies in humans, however, have not been decisive with respect to assigning a role to Lp(a) as a risk factor for myocardial infarction.
In a recent nested, case-control study of prospectively collected plasma samples, 14 916 male physicians in the United States aged 40 to 84 years with no prior history of myocardial infarction were followed for an average of 5 years.31 Samples from 296 physicians who subsequently developed myocardial infarction were analyzed for Lp(a) levels, together with samples from paired controls matched for smoking status and age. The distribution of Lp(a) levels among myocardial infarction patients was virtually identical to that among controls, and there was no significant difference between the groups in median Lp(a) level. The authors concluded that in predominantly middle-aged white men, there was no evidence of an association between Lp(a) level and risk of future myocardial infarction. In another study (from Finland) of 7424 men and women aged 40 to 64 years and followed over 9 years, there was also no association between Lp(a) blood levels and myocardial infarction.32 In contrast, in a study (from Germany) of 6002 men aged 40 to 59.9 years and followed over 5 years, Lp(a) was found to be an important risk factor for myocardial infarction, ranking fifth behind LDL cholesterol, family history of myocardial infarction, plasma fibrinogen, and HDL cholesterol.33 The Prospective Cardiovascular Munster (PROCAM) study (also from Germany) of survivors of myocardial infarction less than 46 years old also showed that an increased concentration of Lp(a) constituted an independent risk factor for early myocardial infarction.34 And in a cohort of women from the Framingham Heart Study, an indirect measure of Lp(a) was a strong, independent predictor of myocardial infarction, intermittent claudication, and cerebrovascular disease.35 Finally, in a study that resembles the report by Badenhop et al1 in this issue, Marquez et al36 showed that children from kindreds with premature parental myocardial infarction were distinguished from children from control kindreds by high Lp(a) levels (as well as high apo B and triglyceride levels but low apo A-1 levels). Thus, it appears that carefully performed epidemiological studies are in conflict with respect to the importance of Lp(a) as a risk factor for myocardial infarction.
Badenhop et al1 add to the weight of evidence for the importance of the D allele of the ACE gene and contribute to the uncertainty about the importance of Lp(a) as a risk factor for myocardial infarction. Their comment on an association between the D allele of the ACE gene and Lp(a) should be discounted because of the demonstrated weakness of the correlation.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
Received January 30, 1995; accepted January 30, 1995.
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References |
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