© 1997 American Heart Association, Inc.
Articles |
The Severity of Coronary Atherosclerosis in Type 2 Diabetes Mellitus Is Related to the Number of Circulating Triglyceride-Rich Lipoprotein Particles
From Department of Medicine, WHO Collaborating Center for Study of Atherosclerosis in Diabetes (I.T., K.U., G.S.); Department of Medicine, Division of Cardiology (B..P.K.); Department of Medicine, Division of Endocrinology (G.L.); The Toronto Hospital, University of Toronto.
Correspondence to Dr. George Steiner, Department of Medicine, WHO Collaborating Center for Study of Atherosclerosis in Diabetes, Room NUW 9–112, The Toronto Hospital - General Division, 200 Elizabeth Street, Toronto, Ontario, M5G 2C4 Canada.
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Abstract |
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Abstract The presence or absence of coronary artery disease (CAD) in diabetic patients has been related to the level of circulating plasma lipoproteins. This study examines whether there is a relationship between the actual severity of CAD and the plasma concentration of major classes of plasma lipoproteins (HDL, LDL, triglyceride-rich lipoproteins (TRL), and their Sf 12 to 60 and Sf 60 to 400 subfractions), particularly the numbers of lipoprotein particles, in men and women with type 2 diabetes. 174 diabetic patients (136 men, 38 women) who underwent angiography were studied. Nine specific coronary segments were scored. The population was divided into tertiles according to the angiographic severity of their coronary disease: mild CAD: coronary score 1 to 10; moderate CAD: coronary score 11 to 13; or severe CAD: coronary score 14 to 22. The main findings were that the numbers of particles (as reflected by the apoB levels) of the TRL were greater in those with moderate and severe disease than in those with mild disease (P=.001). There was a significant correlation between the coronary score and the apoB in TRL (P=.006). There were parallel but nonsignificant changes in triglyceride levels. ApoA-I was lower in patients with moderate and severe disease (P=.01). These differences were more striking in women than they were in men. There were no differences in plasma, LDL, or HDL cholesterol or in LDL apoB or Lp(a). Multiple linear regression analysis, when adjusted for sex, age, and BMI, showed that three lipid variables (TRL apoB, LDL cholesterol, and plasma apoA-I) significantly and independently predicted the coronary score. This study demonstrates that in type 2 diabetes, the severity of angiographically evaluated CAD is positively related to the numbers of TRL particles in the plasma. This relationship is stronger in women than in men, and it is independent of HDL and LDL.
Key Words: triglycerides • diabetes • coronary artery disease
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Introduction |
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The most frequently observed complication of diabetes is coronary artery disease.1 It is a particular problem in people who have type 2 (noninsulin-dependent) diabetes. This is partly because type 2 diabetes is the most common form of diabetes and partly because the prevalence of both type 2 diabetes and coronary artery disease (CAD) increases with age. The commonest form of dyslipoproteinemia in type 2 diabetes is hypertriglyceridemia.2 Triglyceride-rich lipoprotein particles (TRL) are in the ultracentrifugal fraction with a Svedberg flotation of Sf 12 to 400. In people with diabetes,2 as in those without,3 the vast majority of TRL particles is in the Sf 12 to 60 population, a fraction that has been referred to as small VLDL and as IDL. Furthermore, most of the increase in triglyceride levels in hypertriglyceridemia can be accounted for by an increase in the numbers, rather than the size, of these particles.3 A previous study by Steiner et al4 reported that higher levels of lipoproteins in the Sf 12 to 60 fraction were associated with angiographically proven CAD in nondiabetic men and this was independent of LDL cholesterol and HDL cholesterol. This is of particular interest as hypertriglyceridemia has been found to be a risk factor for CAD in diabetes.5 6
Most studies, such as those cited above, have related lipoprotein levels only to the presence or absence of CAD but not to its angiographic severity. Clinical manifestations of CAD such as angina or myocardial infarction may not reflect the same components of the atherosclerotic process as those assessed by angiographic measures of disease severity. This may be particularly so in the case of diabetes, because ischemic heart disease is often silent.7 In populations without diabetes or in mixed populations, (ie, populations with and without diabetes), the severity of CAD has been found to be positively related to cholesterol in the plasma or the apoB-containing lipoproteins,8 9 10 plasma apoB,9 11 and plasma Lp(a)12 13 and negatively related to HDL cholesterol10 11 14 or plasma apoA1.15 16
The relationship between CAD severity and TRLs is more controversial, however. Some investigators have reported that the angiographic severity of CAD in nondiabetic populations is greater in those with higher plasma triglyceride levels,9 17 in men with higher triglyceride content of total LDL8 or dense LDL,11 and in women with higher IDL triglyceride levels.17 The Monitored Atherosclerosis Regression Study (MARS) showed that progression of coronary atherosclerosis in a population without diabetes was related to triglyceride-rich lipoprotein levels.18 Two of the above-mentioned studies measured the apoB content in the TRL subfractions, and these studies showed gender-related differences.11 17 In neither study was a relationship between CAD severity and IDL or VLDL apoB observed in males, but Reardon et al17 found a relationship between coronary score and IDL apoB in females. Although it was reported that angiographic severity of CAD was higher in diabetic that in nondiabetic subjects,12 only one study has examined the relationship between the severity of CAD and lipoproteins specifically in those with diabetes mellitus, but it examined only 36 patients and did not measure TRL.19 Lp(a) was the only lipoprotein that it reported to be related to CAD severity. Because of the limitation of that study and because clinical disease and angiographic severity may differ, we examined the relationship between the severity of angiographically evaluated CAD and the levels of major classes of lipoproteins in 174 individuals with type 2 diabetes, paying particular attention to the numbers of lipoprotein particles.
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Methods |
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One hundred seventy-four consecutive eligible patients (136 males, 38 females), aged 37 to 72 years, with type 2 diabetes mellitus who were undergoing coronary angiography because of clinical or ECG symptoms of CAD were studied. Diabetes was considered to be present if a person had been diagnosed as having diabetes according to the WHO criteria.20 It was judged to be type 2 diabetes if adequate glycemic control was achieved by diet alone (n=26) or by diet plus oral antidiabetic drugs (n=95). Participants who were treated with insulin (n=53) were felt to have type 2 diabetes if its onset was after the age of 35 and there was no history of ketoacidosis. While this last criterion might have allowed some individuals with late-onset type 1 diabetes to be studied, this is considered to be minimal.21 Patients were excluded if they had clinical or laboratory evidence of a systemic illness (other than diabetes) or of any other illness that could alter lipoprotein levels (eg, untreated hypothyroidism), if they had not fully recovered from a surgical procedure or major systemic illness or if either had occurred in the past two months, or if they were using drugs (other than hypoglycemic agents or postmenopausal hormone replacement) that are known to alter plasma lipids.
Selective coronary angiograms were performed in all subjects by
using standard multiangulated angiographic techniques, as previously
described.22 All studies were performed via the
femoral artery, under local (2% Lidocaine) anesthesia, and
used nonionic contrast media (Iohexol 350). Each angiographic series
was visually assessed by an experienced angiographer (B.P.K.), who had
no knowledge of individuals' lipoprotein values. In nine discrete
segments, representing the proximal and mid portions of the
coronary arteries (left main stem: one segment, left anterior
descending artery: two segments, circumflex artery: three segments, and
right coronary artery: three segments), lesion severity was
evaluated according to the following grading scale: <10%
stenosis: 0 points, 10% to 49%: 1 point, 50% to 74%: 2
points, 75% to 90%: 3 points, 
90%: 4 points. The total
coronary score was calculated by adding the number of points
assigned to each of the nine segments. The higher scores indicated more
severe coronary atherosclerosis. Every patient
who was studied had at least one minor coronary lesion. In an
examination of random repeated evaluations of angiograms on 25
individuals, the intraobserver variability was very low. The standard
deviation of the percent diameter stenosis was ±5.9%, and
that for the overall scoring of nine segments was ±4.3%. In a
preliminary analysis, the patients were ranked according to
their coronary scores, and the population was divided into
tertiles. Those in the tertile with the mildest disease had
coronary scores ranging from 1 to 10; those with more moderate
disease had scores from 11 to 13; and those with the severest disease
had scores from 14 to 22.
Fasting (12-hour) blood samples were drawn into Na2 EDTA (1 mg/mL) and chilled to 4°C. The plasma was separated within 2 hours, and the Sf 60 to 400 (larger VLDL) and Sf 12 to 60 (small VLDL and IDL) fractions were separated by ultracentrifugal procedures identical to those reported previously.23 Examination of the Sf 12 to 60 fraction was based on kinetic studies23 24 and has been used in several previous studies of coronary disease.4 17 HDL was separated after manganese/heparin precipitation of plasma apoB–containing lipoproteins.25 ApoB was quantified in whole plasma and in the Sf 60 to 400 and Sf 12 to 60 fractions by an electroimmunoassay procedure that had been developed to permit the measurement of apoB in TRLs26 and calculated in TRL as a sum of the Sf 60 to 400 and Sf 12 to 60 fractions. The CV of this assay ranged from 1.25% to 3.62% within a run and from 3.93% to 4.70% between runs. The LDL apoB was calculated by subtracting the TRL apoB from the total plasma apoB. ApoA-I was measured in whole plasma by a rocket electroimmunoassay (Sebia). Peak LDL density was determined by density gradient ultracentrifugation.27 Cholesterol and triglycerides were measured enzymatically in plasma, Sf 60 to 400, Sf 12 to 60, and HDL fractions (Boehringer Mannheim GmbH, cholesterol kit No. 236 691, triglyceride kit No. 450 032) and calculated in TRL (Sf 60 to 400 + Sf 12 to 60) and in LDL (plasma-TRL-HDL). Lp(a) was determined by ELISA (TintElize® Biopool, kit No 610221). ApoE phenotypes were determined by isoelectric focusing.28 Fasting blood glucose and creatinine were determined by routine enzymatic methods. Lipid determinations were standardized against the Canadian Reference Laboratory.
The data are expressed as mean±SEM. The normality of the distribution
in the subgroups of patients was tested by the Kolmogorov-Smirnov test.
For comparison of three groups (Tables 1
and 2), one-way and two-way ANOVA was
used. The Newman-Keul's or Dunn's multiple comparison procedure was
then used to isolate the group or groups that differed from the others.
For the comparison of two groups (Table 3) with normal distribution, the
two-tailed Student's t test for unpaired data was used;
otherwise, the Mann-Whitney rank-sum test was used. Because there were
several comparisons of two groups, we used Bonferroni's
approach29 to set a level of statistical
significance for these tests at P<.01. For the comparison
of rates, chi-square test was used. Spearman rank correlations were
calculated between coronary score and the lipid variables.
Multiple linear regression analysis was used to investigate the
independent association of various lipoproteins and of age, sex, and
BMI to the severity of CAD. Coronary score was the dependent
variable, and variables expressing the composition of
lipoproteins fractions (TRL apoB, LDL apoB, LDL
cholesterol, LDL triglycerides, apoA-I, HDL
cholesterol), were included as independent variables.
Among lipoprotein variables those with skewed distribution (LDL
triglycerides and TRL apoB) were first logarithmically
transformed before being entered into multiple linear regression
models. Because of multicollinearity with TRL apoB, both TRL
triglycerides and TRL cholesterol were not
entered in the multivariate analysis. These
statistical approaches have been reviewed,29 and
the calculations were conducted with the software package Sigmastat
1.0 (Jandel Corporation).
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Results |
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The clinical characteristics of the tertiles of the study population divided into tertiles by coronary score are shown in Table 1
. The lipoprotein levels in the three groups of patients are
displayed in Table 2. Because of sex-related differences in some lipid
variable levels, in the primary analysis of lipoprotein
variables, two-way ANOVA with sex as the second factor was used.
The three groups significantly differed in levels of apoB in the Sf 12
to 60 fraction and TRL, as well as in plasma apoA-I levels. A
borderline difference was observed for apoB levels in the Sf 60 to 400
fraction. No significant difference was observed for plasma apoB, LDL
apoB, LDL density, or triglyceride or
cholesterol concentration in the plasma or in any of its
lipoprotein subfractions. TRL apoB and apoB in the Sf 12 to 60 fraction
both in those with the severest and moderate disease were significantly
different from the values in those with the mildest disease. The
differences in plasma apoA-I were significant only between the groups
with mild versus moderate disease. No significant difference was
observed for any of lipoprotein variables between those with more
moderate and those with the severest CAD. That allowed us to merge the
patients with moderate and severe CAD into one group. The patients with
mildest disease (coronary score 1 to 10) are compared with
those with moderate and severe disease (coronary score 11 to
22) in Table 3. Those with the more moderate and the severest CAD had
significantly higher levels of apoB in the plasma and in the TRL
fraction (and both its Sf 60 to 400 and Sf 12 to 60 subfractions) than
did those with the mildest CAD. The differences observed in the plasma
apoB reflected the TRLs as there was no difference in LDL apoB. As
every particle of TRL or LDL contains one molecule of
apoB,30 the levels of apoB reflect the numbers of
particles in these fractions. Although the content of apoA-I is not as
constant in each HDL particle and a small amount is found in the TRLs,
plasma apoA-I still does provide an indirect reflection of HDL particle
number. It was lower in those with moderate and severe disease than in
those with mild CAD. The triglyceride content of the
plasma, of the TRL and its Sf 12 to 60 and Sf 60 to 400 subfractions,
and of the LDL tended also to be higher in the individuals with
moderate and severe CAD than they were in those with mild CAD, but
these differences were not significant and therefore are not shown.
Cholesterol in plasma, TRL, LDL, and HDL and Lp (a) did not
differ significantly between the groups.
Comparisons similar to those for the entire population were conducted
separately for men and for women (Table 3). They were subdivided by
using the same coronary score ranges as those used for the
whole population. Interestingly, 53% of women had scores that put them
in the group with mildest coronary disease. This was a
significantly higher proportion (P<.04) than the 32% of
men who were in the same category. Women with moderate or severe CAD
had more circulating TRL particles. This was due to an increased amount
of both the Sf 60 to 400 and Sf 12 to 60 particles. Women with moderate
or severe CAD also had lower levels of HDL cholesterol
(1.06±0.04 mmol/L) than did those with mild CAD (1.29±0.05
mmol/L, P=.003). Men with moderate or severe CAD, when
compared to men with mild CAD, showed patterns of apoB changes that
were qualitatively similar to those seen in women and in the entire
population. However, except for a higher plasma apoB level in men with
more severe disease, they were of no statistical significance.
Spearman correlations between lipoproteins and coronary score
were examined in the entire group of patients and in women and men
separately. Significant correlations between coronary score and
both TRL apoB (r=.21, P=.006) and apoB in the Sf
12 to 60 fraction (r=.20, P=.007) were observed
in the whole group of patients and in women (r=.42,
P=.009 for both TRL and Sf 12 to 60 lipoproteins). Women
also showed a significant inverse correlation between coronary
score and HDL cholesterol (r=-.42,
P=.009). Multiple linear regression analysis was
conducted with coronary score as the dependent variable and
sex, age, BMI, and lipoproteins (plasma apoA-I, HDL
cholesterol, LDL apoB, LDL cholesterol, LDL
triglyceride, and TRL apoB) as the independent
variables. Since some of the lipoprotein data were missing for 14
patients, this analysis was conducted on data from 160
patients. Three lipoprotein variables (TRL apoB, LDL
cholesterol, and plasma apoA-I) and male gender made
independent and significant contributions to the model and explained
15% of the coronary score (Table 4).
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The only lipid variable that was significantly influenced by the apoE phenotype was the LDL cholesterol (P<.01, ANOVA). Significantly lower levels of LDL cholesterol were observed in the group of individuals with either E2/E2 or E3/2 (2.53±0.18 mmol/L) when compared to both E3/E3 (3.18±0.09 mmol/L, P<.05) and E4/E3 (3.28±0.15 mmol/L, P<.05) groups. However, the coronary scores were not related to the apoE phenotypes.
Smoking had no relation to the severity of coronary disease in this population whether nonsmokers (mean CAD score±SEM, 10.9±0.5) were compared to those who had ever smoked (11.7±0.4) or to those who currently smoked (11.4±0.7). Current smoking in type 2 diabetic patients also had no significant effect on the level of any lipid variables (data not shown).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present study, performed on 174 patients with type 2 diabetes mellitus, examined the relationship between the severity of CAD and a variety of lipoprotein parameters. The people who were selected for the present study had a very high probability of having existing CAD, as only those who had undergone angiography were studied. The principal finding of this work is that the severity of CAD is related to the number of circulating fasting triglyceride-rich lipoprotein particles. The number of these particles in each fraction is reflected by its content of apoB. The present study also found that those with more severe CAD tended to have higher levels of triglyceride in the plasma, in TRL, and in LDL. However, the trends in the case of triglyceride levels were not significant, whereas the increases in TRL apoB were highly significant. This suggested that in individuals with type 2 diabetes who were not on lipid-lowering therapy, the severity of CAD may be more strongly associated with TRL particle number than with TRL particle triglyceride content. The relationship between TRL particle number and the severity of angiographic coronary disease was demonstrated in three ways: by comparing TRL apoB levels in individuals who were divided into groups (mild versus moderate and severe disease) according to the coronary score, by univariate correlation analysis, and by multivariate regression analysis.
The WHO Multinational Study found that the presence of ischemic ECG changes in diabetes was related to plasma triglyceride but not cholesterol levels.5 In men with impaired glucose tolerance or diabetes, the Paris Prospective Study observed that the relationship of coronary mortality with plasma triglyceride was stronger than with plasma cholesterol.6
We have shown that approximately three quarters of the increase in plasma triglyceride levels, at least in nondiabetic individuals with moderate hypertriglyceridemia, is due to an increase in the number, rather than the size, of the TRL particles and that the vast majority of these are the smaller TRLs (Sf 12 to 60).3 We have previously found that the presence of CAD is related to the number of Sf 12 to 60 particles in a population of nondiabetic men who were selected to have normal LDL levels.4
Interestingly, and in contrast to TRLs, the mean number of LDL particles, LDL density, and LDL cholesterol levels were not significantly different in the patients with mild coronary disease compared to those with moderate or severe coronary disease, and these three parameters were not related to CAD severity in univariate analysis. However, LDL cholesterol did add somewhat to the prediction of coronary score in multiple regression analysis. There are other studies in which the presence of CAD was more strongly related to TRL than to LDL.4
We observed that the apoA-I concentration, an indirect and imperfect reflection of the number of HDL particles, was inversely related to the severity of CAD. Multivariate analysis showed that the effect of apoA-I on CAD severity was independent of the TRL apoB and of the LDL cholesterol. No similar relationship was found for HDL cholesterol, except in a subgroup of women evaluated by univariate correlation analysis. Thus, in the case of HDL, as in the case of TRL, it appeared that the number of lipoprotein particles was more closely related to CAD score than was the HDL lipid content.
To the best of our knowledge, only one study has evaluated the severity of CAD specifically in type 2 diabetes.19 That study included only 36 patients. In contrast to our study, it reported that Lp(a), but no other measured lipid variables, was significantly related to the severity of CAD. We found no relationship between Lp(a) levels and CAD severity. The difference between the studies may reflect the numbers of patients examined (36 in their study versus 174 in ours).
Some studies of nondiabetic populations examined the relationship between Sf 12 to 20 lipoproteins and the severity of atherosclerosis. They found a relationship between the Sf 12 to 20 cholesterol levels and the severity of CAD10 or peripheral vascular disease.31 Reardon et al17 observed a positive relationship between Sf 12 to 60 lipoprotein apoB and the severity of CAD in nondiabetic women. They also found a positive relationship between CAD severity and triglyceride levels.
When we separately analyzed the men and women in our study, we found a stronger relation between the TRL particle numbers and the severity of coronary disease in women than in men. This may reflect previous reports that hypertriglyceridemia is more strongly related to the risk of coronary artery disease in women than in men.32 However, those observations were made in populations without diabetes. Another possible explanation for the gender differences may lie in the angiographic severity of the coronary disease in the women and men in this study. This may have reflected different types of individuals coming to angiography from each gender, perhaps as a consequence of the well-known gender differences in the connection between the chest pain syndromes and coronary disease.33
We observed the major difference of lipoproteins to be between the individuals with the mildest CAD and those with moderate CAD. There was little difference between those with moderate and those with severe CAD. That might be another reason why the relationship between TRL apoB and the severity of angiographic disease was stronger in women than in men, as a higher proportion of women examined had mild or moderate CAD. Similar to our observations, the ECAT study9 showed that in patients with zero to two stenotic vessels, the number of stenotic vessels was inversely related to apoA-I and positively related to triglycerides. However, there was no further change in triglyceride or apoA-I levels in patients with three or four stenotic coronary vessels. Likewise, the MARS study, which examined angiographic progression in a nondiabetic population, has shown that TRLs have more pronounced effect on mild-to-moderate than severe lesion progression.18 These observations raise the possibility that the TRLs play a more important role in milder disease than they do in more severe disease. This in turn leads to an intriguing speculation that different factors are responsible for the early stages of atherosclerosis than for its progression ultimately to vascular occlusion. Perhaps TRLs play a more important role in the former.
In conclusion, to the best of our knowledge, this is the first study that shows that the severity, not just the presence, of angiographically defined coronary artery disease is positively related to the number of triglyceride-rich lipoprotein particles in type 2 diabetes. This relationship is stronger in women than in men and is independent of HDL and LDL. These findings raise the possibility that reducing plasma triglyceride-rich lipoproteins might reduce the progression of CAD in type 2 diabetes mellitus. This hypothesis is currently being tested in the Diabetes Atherosclerosis Intervention Study.34
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Acknowledgments |
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This work was supported by a grant from the Canadian Diabetes Association in honor of Barbara Ann Johnson. I.T. is a Postdoctoral Fellow of the Center for Cardiovascular Research of the Toronto Hospital. G.L. is a Scholar of the Heart and Stroke Foundation of Canada. The authors wish to thank J. Ivanov for her statistical advice.
Received December 12, 1996; accepted March 28, 1997.
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