© 1995 American Heart Association, Inc.
Articles |
Dose-Response Relationships of Serum Lipid Measurements With the Extent of Coronary Stenosis
Strong, Independent, and Comprehensive
From the Medical Statistics Unit, London School of Hygiene and Tropical Medicine, London, UK (I.B., S.G.T.), the Institut für Klinische Chemie und Laboratoriumsmedizin, Zentrallaboratorium, Westfälische Wilhelms-Universität Münster, Münster, Germany (A. von E., M.S., G.A.), and the Institut für Arterioskleroseforschung an der Universität, Münster, Germany (G.A.).
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Abstract |
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Abstract Serum lipids, lipoproteins, and more recently apolipoproteins and lipoprotein(a) [Lp(a)] have been shown to be independent risk factors for coronary vessel disease and its prognosis. However, the relationships between serum lipid levels and the extent of coronary artery disease (CAD) have not been consistently shown. Twenty-five hundred male and female patients with suspected angina pectoris were recruited from 18 European medical centers. The independent relations of total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, apo A-I and B, and Lp(a) with the presence and extent of CAD, as assessed by coronary angiography, were investigated. All of the lipid measures showed strong relations (P<.0001) with the presence of CAD, defined by the existence of at least one
50%
coronary vessel stenosis. Total
cholesterol, LDL cholesterol, apo B,
triglycerides, and Lp(a) were substantially higher and HDL
cholesterol and apo A-I lower in patients with CAD. The
odds ratio of CAD, in the high-risk tertile of each lipid's
distribution compared with the low-risk tertile, was in the range 1.5
to 2.3. Each of total cholesterol (or LDL
cholesterol or apo B), HDL cholesterol (or apo
A), and Lp(a) had an independent effect in predicting the presence of
CAD. In addition, all lipids showed a strong association
(P=.0006 for triglycerides, P<.0001
otherwise) with the extent of CAD as defined by the number of stenosed
coronary vessels. These relations, which conform to a
"dose-response" effect, remained after adjusting for other
coronary risk factors. This study provides direct evidence of
the role of serum lipid levels in determining not only the presence but
also the extent of atherosclerotic disease in coronary
arteries.
Key Words: triglycerides • total cholesterol and subfractions • apolipoproteins • coronary artery disease • lipoprotein(a)
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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Arteriosclerotic diseases, including CHD, are multifactorial in origin. Prospective epidemiological studies have identified several independent coronary risk factors, including smoking, dyslipidemia, hypertension, and diabetes mellitus.1 In these studies the risk of myocardial infarction was found directly related to the concentration of CH and LDL cholesterol and inversely related to HDL cholesterol.2 3 4 In more recent studies coronary risk was found to be positively associated with the serum concentration of apo B, which is the exclusive protein component of LDL, and negatively with the serum concentration of apo A-I, which is the major protein component of HDL.5 6 In a number of studies performed in various ethnic groups, Lp(a) has been shown to be a risk factor for coronary, cerebral, and peripheral vessel diseases, which is independent from other risk factors, including LDL and HDL cholesterol.7 8 9 10 Lp(a) is a unique cholesteryl ester–rich and apo B–containing lipoprotein to which a glycoprotein termed apo(a) is covalently attached. The plasma concentration of Lp(a) is largely determined by variation in the apo(a) gene. In its primary structure apo(a) closely resembles plasminogen. Therefore, the atherogenicity of Lp(a) has been related by many authors to its potential interference with fibrinolysis.11 12 13
Despite clarification of the role of lipids in CHD that such research provides, it has not been clearly shown how serum lipid profiles are related to the extent of CAD. To address this question, we analyzed plasma concentrations of CH, TG, HDL cholesterol, LDL cholesterol, apo A-I and B, and Lp(a) in 2587 coronary disease patients who underwent coronary angiography in the course of the ECAT AP study.14 We assessed the association of lipid levels with the presence and extent of atherosclerotic changes in coronary vessels independently of other CHD risk factors and of other lipid concentrations.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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Between 1984 and 1987, the ECAT AP study14 recruited 3043 male and female patients of any age undergoing coronary angiography because of clinically suspected CAD from 18 European medical centers (see "Appendix 1"). Those who had suffered acute myocardial infarction within the previous 2 months, had severe right heart failure, or had noncardiac diseases likely to cause death were excluded from the study. Patients from two centers for whom samples for lipid analysis were not available were also omitted. Thus, the present cross-sectional study was based on the 2587 patients with available data on medical examination, laboratory tests, and coronary angiogram.
Blood samples were drawn into tubes containing citrate, and plasma was frozen and sent to the Institute of Clinical Chemistry at the University of Münster (Germany), which performed all lipid measurements. Plasma concentrations of TG and CH were quantified with an autoanalyzer (Hitachi/Boehringer). HDL cholesterol concentrations were measured after precipitation with phosphotungstic acid/MgCl2 (Boehringer). Measurements of CH, TG, and HDL cholesterol were controlled externally by the Lipid Standardization Program of the Centers for Disease Control and Prevention, Atlanta, Ga. LDL cholesterol was calculated using the formula of DeLong et al15 with LDL=CH-HDL-(0.16xTG). Concentrations of apo A-I and apo B were determined with a modified commercially available turbidimetric assay (Boehringer).16 Lp(a) was quantified by electroimmunodiffusion using an anti-Lp(a) antiserum from Behringwerke and standards and controls from Immuno.8 Correction factors, derived from a separate experimental study, were applied to correct plasma concentrations into serum concentrations.
Coronary angiograms were performed generally using the method of Judkins and occasionally that of Sones.17 Four coronary arteries were considered: left main coronary, left anterior descending, circumflex, and right coronary. CAD was defined when any of these coronary vessels had a diameter stenosis of at least 50% (or a total occlusion); results of coronary angiograms were summarized through a score based on the number of diseased vessels. Patients' scores therefore ranged from 0 (no vessel with 50% stenosis) to 4 (all four vessels with at least 50% stenosis). In a substudy restricted to three centers (Giessen, Münster, and Vienna) patients scoring 0 were reclassified as 0% (ie, apparently clear coronary arteries) or 1% to 49% stenosis according to the most severe stenosis observed in any coronary artery branch.18
Multiple regression was employed to investigate the independent
association of the presence and extent of CAD, with each lipid measure
considered as the dependent variable. Adjustments were used for any
significant (P
.01) effect of center differences, age, sex,
daily drug use, and other coronary risk factors (history of
acute myocardial infarction, history of diabetes, history of
hypertension, smoking habit, body mass index, and systolic blood
pressure). Results are presented as lipid mean values and
standard deviations (SD) in milligrams per deciliter (see "Appendix
2" for conversion to SI units) or as odds ratios (approximate
relative risks) of CAD according to tertiles of lipid distributions.
Since the distributions of TG and Lp(a) were skewed to the right, we
applied logarithmic transformation in the statistical analysis
to improve their normality; for these lipids, geometric means and
approximate SDs are presented. Finally, the combined effect of
lipids in predicting CAD was studied with logistic regression, and
results were expressed as odds ratios according to tertiles of each
lipid's distribution.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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Of the 2587 patients, 85% were male and 15% female with mean ages at the time of coronary angiogram of 55 and 58 years, respectively (Table 1
). Some coronary risk factors
were more prevalent in patients with CAD (eg, history of myocardial
infarction), but others were not (eg, history of hypertension). Similar
numbers of patients had each of 0, 1, 2, and 3 coronary vessels
with at least 50% stenosis. Of the 657 patients in the
three-center substudy, 179 (27%) had <50% stenosis; of the
latter, 161 (90%) had no detectable stenosis and 18 (10%) had
detectable stenosis of <50%.
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Table 2 shows mean values of lipid measurements and also
the correlations between them. HDL and apo A-I were on average lower
among patients with CAD, whereas all other lipid measurements were
higher (all P<.0001). These mean lipid differences
according to the presence of CAD were similar in both sexes except for
TG and HDL cholesterol, whose differences were greater in
women (P=.003 and P=.006, respectively). There
were two groups of highly correlated lipid measurements: one group
formed by HDL and apo A-I and another group formed by CH, LDL, and apo
B. TG had moderate positive correlations with the CH group and negative
correlations with the HDL group. Lp(a) did not correlate strongly with
any other lipid. In general, these correlations of lipid levels were
similar for men and women, except that between TG and HDL, being
slightly stronger in women (P=.004); correlations were also
similar for patients with and without CAD, except that between TG and
apo A-I, being somewhat stronger in the absence of CAD
(P=.008).
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The relationship between each lipid and the presence of CAD is
summarized in Table 3 as the odds ratio of CAD according
to tertiles of each lipid distribution. The odds ratios, comparing
highest- to lowest-risk tertiles, were over twofold for CH, LDL, and
apo B and in the range 1.5 to 1.7 for the remaining lipid
measurements.
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The association between lipid concentrations and the extent of CAD,
based on the number of vessels with 50% diameter reduction, is shown
in Fig 1. For all lipids the association with the extent
of CAD was highly significant (always P<.0001 except for TG
where P=.0006). CH, LDL, and apo B showed a near-linear
increase with the number of stenosed coronary vessels. HDL
cholesterol and apo A-I had an inverse association, with a
decrease in their concentrations as the number of stenosed vessels
increased, whereas TG concentrations increased with the number of
stenosed vessels. For TG, the most substantial difference was between
patients who had no coronary vessel with 50%
stenosis and those who had one or more. Mean values of Lp(a)
increased as more stenosed vessels were present. The apparent
decrease from 3 to 4 coronary stenoses might be due to
the relatively small number of patients in the last category (n=89).
The confounding effect of other coronary risk factors on these
relations was negligible (Fig 1).
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Sex differences of the relationships between lipid concentrations and
extent of CAD are shown in Fig 2 with the categories
of 3 and 4 stenosed vessels combined because of the small number of
women with 4 stenosed vessels (n=8). In general, mean serum lipid
concentrations were higher in women than in men at each grade of CAD,
except for TG, which were lower in women than men. The relationships
between lipids and extent of CAD were similar in men and women for CH,
LDL, apo B, and Lp(a). However, mean TG levels had a slightly greater
increase with the number of stenosed vessels in women than men
(P=.008). Mean apo A-I and HDL cholesterol
levels presented a somewhat greater decrease with the number of
stenosed vessels in women than men (P=.008 and
P=.0005, respectively).
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The study of the joint effect of different lipid measures in
determining the presence of CAD is limited by the strong correlations
existing between them (Table 2
). For example, it is not realistic to
attempt to distinguish the effects of CH from LDL, or of HDL
cholesterol from apo A-I, in these data. Odds ratios were
therefore calculated for CH, TG, HDL, and Lp(a) for each lipid
considered separately and then successively adding each lipid one at a
time (Table 4). Each lipid considered alone showed a
strong and significant association with CAD, but the effect of TG
became less strong after adjusting for CH and was no longer
statistically significant after also adjusting for HDL. In contrast,
the odds ratios for CH, HDL, and Lp(a) were similar whether or not
adjustment was made for the other lipids. Hence, each of CH, HDL, and
Lp(a) (but not TG) remained strongly associated with the risk of CAD
even after adjusting for the effects of each other. Patients with serum
levels of these three lipids in the high-risk tertile had an odds ratio
of CAD of 3.84 (obtained by multiplying together their adjusted odds
ratios in Table 4) compared with those patients with serum levels in
the other two tertiles. Similar results to these were obtained when
either LDL or apo B was considered instead of CH or when apo A-I was
considered instead of HDL.
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Similarly, the relations of serum lipids with the extent of CAD were still highly significant when other lipid variables were adjusted for, the only exception being TG, for which the relation disappeared after adjusting for CH, HDL, or apo B.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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Many clinical and epidemiological studies have established the association between coronary risk and high serum levels of CH and LDL cholesterol, apo B, and Lp(a), as well as of low concentrations of HDL cholesterol and apo A-I.1 2 3 4 5 6 7 8 9 10 Furthermore, secondary intervention studies have demonstrated that decreasing LDL cholesterol or apo B and increasing HDL cholesterol in dyslipidemic patients with angiographically assessed CAD are accompanied by less progression and more regression of atherosclerotic lesions.19 20 This raises the question of whether or not the degree of dyslipidemia is related to the extent of CAD. We addressed this question in the ECAT AP study, which analyzed the coronary angiograms of 2500 patients with angina pectoris from 18 European centers.
The analysis revealed strong relations of CH, TG, LDL, HDL, apo
A-I, apo B, and Lp(a) with the presence of CAD as defined by the
observation of at least one 50% vessel stenosis. Moreover,
all lipid parameters exhibited highly significant relations
to the number of stenosed coronary vessels. These relations
were similar for both sexes, except for TG, apo A-I, and HDL, where
women showed stronger relations than men. Also, these relations, with
the exception of TG, were independent from one another as well as from
nonlipid risk factors. These observations conform to strong and
independent dose-response relations of all the studied serum lipid
parameters on the extent of CAD, which to our knowledge has
not been reported in this uniformity before.
CAD, defined as 50% diameter reduction in any coronary
vessel, was used to construct an angiographic score summarizing the
extent of coronary stenosis. Accordingly, some patients
classified as not having CAD might have intermediate stenoses,
perhaps, of 10% to 50%. As a result, this might have underestimated
the dose-response relations of serum lipid measurements with the extent
of coronary stenosis. However, from the three-center
substudy, the proportion of patients with such intermediate
stenoses was small, and the extent of underestimation would be
expected to be correspondingly slight. Although an angiographic score
based on the number of stenosed coronary vessels does not
completely determine the prognosis of CAD,21 it is a
powerful predictor of subsequent clinical events, for example, in the
patients with angina pectoris in the ECAT AP study.22
Hence, this study directly documents the role that the extent of CAD
plays in the link between blood lipid concentrations and clinical
events.
Although studies of lipids and the degree of coronary atherosclerosis began in the late 1960s, uncertainty remained up to now over which lipid measurement discriminates the degree of CAD. Discussions over which is the "most influential" lipid parameter have been particularly unrewarding.23 Recent examples of conflicting results are some studies comparing the prediction of CAD by apolipoproteins or subfractions of HDL cholesterol in relation to total lipids and lipoproteins5 24 25 ; none of the lipid, lipoprotein, or apolipoprotein variables was a significant predictor of the severity of CAD. Classic lipid measurements, though more uniformly shown to correlate with the degree of CAD, have yielded some negative findings either in patients undergoing coronary angiography26 or in young survivors of myocardial infarction.27 28 Negative findings increase when a number of lipid variables are considered together to explore their independent effects.29 30 Some authors have used lipid ratios to demonstrate significant associations.31 32 Finally, less evidence exists on the relationship between Lp(a) and the severity of CAD.33 34 35
Several reasons have been proposed to explain this confused situation24 30 36 : there are methodological and technical differences, and each patient group studied has specific characteristics. However, many of the problems of negative results stem from the generally small number of subjects included in previous studies. In addition, there is a complex metabolic interrelation between lipoprotein particles in human plasma such that the discriminant power of a single lipid measurement should be interpreted cautiously.23 37 38 For example, hypertrygliceridemia may involve increased levels of several lipoproteins with varying degrees of atherogenicity.36 Similarly, some authors explain that apolipoproteins are better discriminators of CAD in part due to the inaccuracy of the determination of LDL and HDL, whose compositions are highly variable in plasma.36 38 However, quantification of apo A-I and B was not standardized until 1989, so that comparisons and extrapolations of results obtained in different laboratories were not possible.39 Moreover, standardization of Lp(a) has as yet not been achieved and will remain a major problem due to the extensive heterogeneity of this lipoprotein with regard to the size of apo(a) and the density of Lp(a).40 In the ECAT AP study we tried to minimize these difficulties by following strict protocols on blood sampling41 and performing all lipid measurements centrally. Additionally, we assessed a large sample of coronary disease patients under wide eligibility criteria in a number of clinical centers.
Cross-sectional analysis of other coronary risk
parameters in the ECAT AP study, including hemostatic
variables, revealed that these are associated only with the
presence of CAD but without any relation to the number of
stenoses.14 The present results therefore
indicate an important role of hyperlipidemia in
particular for the atheromatous manifestation of CAD.
The relative effect of each lipid parameter on the
development of coronary stenosis can be described by
the odds ratio of CAD, comparing its highest- to lowest-risk tertiles
(Table 3). The odds ratios of CAD according to tertiles of LDL and apo
B (or HDL and apo A) were not different. Therefore, quantification of
apolipoproteins did not prove advantageous for the characterization of
CAD. Similar conclusions have been drawn from the outcome of a large
prospective study that compared the predictive values of
apolipoproteins and HDL subclasses for myocardial
infarction.6
In the ECAT AP study, TG were significantly associated with CAD only in
univariate analysis. Consideration of CH and HDL
cholesterol removes this association in many prospective
studies1 2 3 4 5 35 as well as in the present study (Table 4). However, we did not perform any subgroup analysis according
to age and sex groups or CH/HDL cholesterol ratio tertiles,
where other authors have reported an independent effect of TG on the
risk of CAD.3 42 43
Both CH and HDL cholesterol, when considered together,
remained strongly related to the presence and extent of CAD. This
denotes the importance of CH and HDL cholesterol as
predictors of CAD. A similar phenomenon occurred for Lp(a), which was
still significantly related to the presence and extent of CAD after
adjustment for CH, TG, and HDL cholesterol. Although Lp(a)
may also add to the risk of CAD by means of the thrombotic
pathway,11 12 13 nevertheless Lp(a) did not prove as strongly
associated with CAD as the classic lipid parameters CH and
LDL cholesterol (Table 3). A broad variety of case-control
studies have been published, in which Lp(a) emerged as a powerful
discriminator between patients with various atherosclerotic diseases
and control subjects.7 8 9 10 However, only little information
is available from prospective studies on the predictive value of Lp(a).
In the ARIC Study, Lp(a) was identified as a risk predictor of stroke
in both blacks and whites, and in a small Swedish study, as a risk
predictor for myocardial infarction.44 45 By contrast,
three recently published nested studies did not report any significant
difference in the Lp(a) concentrations of probands who later on
suffered from myocardial infarction and of control
subjects.46 47 48 A future longitudinal evaluation will have
to demonstrate whether or not elevated Lp(a) levels predict myocardial
infarction in the ECAT AP study.
In conclusion, the present multicenter cross-sectional study revealed that various well-known coronary risk factors of lipid metabolism are powerful discriminators of both the presence and extent of CAD. This finding appears to be generalizable because the patients studied were recruited from a large number of centers across Europe. A future longitudinal evaluation is needed to establish the relative prognostic value of the angiographic results and the extent of the various dyslipidemias.
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Selected Abbreviations and Acronyms |
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Footnotes |
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Reprint requests to S.G. Thompson, Medical Statistics Unit, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
Participants of the ECAT Angina Pectoris Study Group are listed in "Appendix 1."
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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This work was carried out within the framework of the European Action on Thrombosis and Disabilities (ECAT) of the Commission of the European Communities.
Executive Committee: F. Duckert, Basel (Switzerland); F. Haverkate, Leiden (Netherlands); J. van de Loo, Münster (Germany); S.G. Thompson, London (UK).
Study Coordinator: J. van de Loo, Münster (Germany).
ECAT Project Leader: F. Haverkate, Leiden (Netherlands).
Participating Centers (in order of number of patients recruited; numbers in brackets): Bordeaux (France): Hôpital Cardiologique, Clinique Medicale Cardiologique and Laboratoire d'Hémobiologie (341). Lyon (France): Hôpital Cardiovasculaire et Pneumologique Louis Pradel and Faculté de Médicine Alexis Carrel, Laboratoire d'Hémobiologique (325). Münster (Germany): University Departments of Cardiology and Haematology (319). Bad-Rothenfelde (Germany): Schüchtermann-Klinik, Department of Cardiology (288). Basel (Switzerland): Kantonsspital, University Department of Cardiology and Haemostasis Laboratory (235). Vienna (Austria): I. University Department of Medicine (208). Athens (Greece): NIMTS Hospital, Department of Cardiology, Alexandra Hospital, Department of Clinical Therapeutics and Laikon General Hospital, Blood Tranfusion Centre (162). Frankfurt (Germany): University Centre for Internal Medicine, Departments of Cardiology and Angiology (156). Giessen (Germany): University Department of Internal Medicine (144). Paris (France): Hôpital Broussais, Clinique Cardiologique, and Hotel-Dieu, Laboratoire Centrale d'Hématologie (132). Bern (Switzerland): Inselspital, University Department of Medicine (128). Pisa (Italy): C.N.R. Institute of Clinical Physiology (118). Brussels (Belgium): Clinique Universitaire St Luc, Department of Cardiology, and University of Leuven, Laboratory for Haemostasis and Thrombosis Research (114). Leeds (U.K.): General Infirmary, Departments of Cardiology and Medicine (84). Nauheim (Germany): Kerckhoff-Clinic and MPG Research Group for Blood Coagulation and Thrombosis (82). Mannheim (Germany): I. University Department of Medicine (80). Marseille (France): C.H.U. Timone, Department of Cardiology and Laboratoire d'Hématologie (67). Eindhoven (Netherlands): Catharina Hospital, Departments of Cardiology and Haematology (60).
Responsible Investigators: Athens: C.D. Michalopoulos and S.D. Moulopoulos (Cardiologists=C), T. Mandalaki (Haematologist=H). Bad-Rothenfelde: R. Buchwalsky (C), J. Kienast (H; Münster). Basel: F. Burkart (C), F. Duckert (H). Bern: H.P. Gurtner (C), P.W. Straub (H). Bordeaux: H. Bricaud and J. Bonnet (C), M.R. Boisseau (H). Brussels: F. Lavenne (C), R. Masure (H). Eindhoven: H.R. Michels and J.J.R.M. Bonnier (C), J.J.M.L. Hoffman (H). Frankfurt: W.D. Bussmann (C), K. Breddin and C.M. Kirchmaier (H). Giessen: B. Wüsten (C), F.R. Matthias (H). Nauheim: M. Schlepper (C), G. Müller-Berghaus (H). Leeds: D.R. Smith (C), C.R.M. Prentice (H). Lyon: J.P. Delahaye (C), M. Dechavanne (H). Mannheim: B. Stegaru (C), W. Kirschstein (H). Marseille: A. Serradimigni (C), I. Juhan-Vague (H). Münster: U.S. Müller (C), U. Schmitz-Hübner (H). Paris: L. Guize (C), M.M. Samama (H). Pisa: A. L'Abbate (C), R. de Caterina (H). Vienna: G. Kronik (C), H. Niessner (H).
Statistical Center: Medical Statistics Unit, London School of Hygiene and Tropical Medicine: S.G. Thompson, London.
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Appendix 2 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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Table
for conversion of lipid measurements from mg/dL to SI
units: Total cholesterol, HDL, and LDL:
mg/dL÷38.66=mmol/L Triglycerides:
mg/dL÷86.96=mmol/L Apolipoprotein A-I: mg/dL÷2.81=µmol/L
Apolipoprotein B: mg/dL÷55.0=µmol/L Lp(a) cannot be converted into molar concentrations because of the size heterogeneity of apo(a).
Received September 21, 1994; accepted May 5, 1995.
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