© 1997 American Heart Association, Inc.
Articles |
Relation of LDL Size to the Insulin Resistance Syndrome and Coronary Heart Disease in American Indians
The Strong Heart Study
From the Medlantic Research Institute, Washington, DC (B.V.H., D.C.R., R.S.G.); the Department of Biostatistics and Epidemiology, University of Oklahoma, Oklahoma City (L.D.C., E.T.L.); the Center for Epidemiologic Research, Oklahoma City, Okla (J.L.Y., W.W.); the National Heart, Lung, and Blood Institute, Bethesda, Md (R.R.F.); and the Ernest Orlando Lawrence Berkeley National Laboratory, Berkeley, Calif (R.M.K.).
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Abstract |
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Abstract Small, dense LDL has been shown to be associated with the insulin resistance syndrome and coronary heart disease (CHD). We examined the distribution of LDL size and phenotype within a population-based sample of American Indians to determine the relationships with prevalent CHD and to examine associations with hyperinsulinemia and other components of the insulin resistance syndrome. Data were available for 4505 men and women between 45 and 74 years of age who are members of 13 American Indian communities in three geographic areas. Diabetes, CHD, and CHD risk factors were assessed by standardized techniques, and LDL size was measured by gradient gel electrophoresis. LDL size was smaller in men than in women and in individuals with diabetes than in those without diabetes. In multivariate analysis, LDL size was significantly related to several components of the insulin resistance syndrome, including triglycerides (inversely) and HDL cholesterol (positively). Although univariate relations were positive, LDL size was not significantly related to fasting insulin concentrations or body mass index in the multivariate model. LDL size also showed no relationship to apolipoprotein E phenotype. When LDL size was compared in individuals with and without CHD, no significant differences were observed, either in nondiabetic or diabetic individuals. We conclude that LDL size is most strongly related to lipoprotein components of the insulin resistance syndrome, especially plasma triglycerides. However, in this population with low LDL, it is not related to cardiovascular disease.
Key Words: American Indians • LDL size • coronary heart disease • diabetes mellitus, • Strong Heart Study
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Introduction |
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The Strong Heart Study, a study of 13 American Indian communities, has shown that the prevalence of CHD varies greatly among different groups of American Indians. The Strong Heart Study is assessing the relative importance of diabetes and other CHD risk factors in explaining these differences in CHD prevalence.1 Some characteristics that might be expected to diminish the risk of CHD are found to be prevalent among American Indians, including low concentrations of total and LDL cholesterol and relatively lower rates of hypertension.1 The varied prevalence rates of CHD among American Indians deserve further examination to identify those additional punitive or protective factors of relevance.
Several abnormal lipid patterns are known to be associated with CHD, including an elevation in LDL cholesterol, apo B, and TGs in conjunction with a reduced concentration of HDL cholesterol.2 Recently, it has been shown that LDL is heterogeneous with respect to size and density.3 Small, dense LDL particles have been found in highest concentration among individuals with premature CHD in white populations from North America4 5 6 7 8 and Europe.9 10 The relation between LDL subfractions and CHD in other ethnic groups has not yet been studied.
Small, dense LDL has been associated with a cluster of metabolic and other risk factors for CHD, including hypertriglyceridemia, low HDL cholesterol, insulin resistance, diabetes, central obesity, and hypertension.11 12 13 14 15 16 The association between small, dense LDL and CHD may reflect a yet stronger and possibly causative link between hypertriglyceridemia and/or other associated factors and CHD. When account is taken of concurrent hypertriglyceridemia, the relation between small, dense LDL and CHD sometimes8 11 but not always5 6 7 is no longer significant. This association between small, dense LDL, elevated TGs and insulin resistance has been predominantly described in non-Hispanic white populations, although one study demonstrated a similar relationship in Mexican Americans.17 No information is yet available concerning the significance of small LDL size as a risk factor for macrovascular disease in populations other than whites.
For these reasons, we have examined the distribution of LDL size within a large and geographically diverse population of American Indians in the Strong Heart Study who have already been comprehensively characterized with regard to cardiovascular disease and many other risk factors known to be related to cardiovascular disease. We have examined the distribution of LDL size and phenotype within the American Indian population in relation to the prevalence of CHD to see whether an association is evident with hyperinsulinemia and other components of the insulin resistance syndrome.
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Methods |
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The study design, survey methods, and laboratory techniques of the Strong Heart Study have been previously reported.18 19 20 The population for the clinical examination included American Indians aged 45 to 74 years who were examined during the period from July 1989 through January 1992 and who were resident members of the following tribes: Pima/Maricopa/Papago Indians of central Arizona who live in the Gila River, Salt River, and Ak Chin Indian communities; the seven tribes of southwestern Oklahoma (Apache, Caddo, Comanche, Delaware, Fort Sill Apache, Kiowa, and Wichita); the Oglala and Cheyenne River Sioux in South Dakota; and the Spirit Lake Sioux in the Fort Totten area of North Dakota. Approximately 1500 individuals from each center were included. For the prevalence rates of CHD and risk factors, the denominators were all 4549 tribal members aged 45 to 74 years who attended the clinical examination.
The clinical examination consisted of a personal interview and a
physical examination. Participants reported in the morning after at
least a 12-hour overnight fast, and blood samples were obtained. A 75-g
oral glucose tolerance test was performed on all of the cohort except
for diabetic persons who were being treated with insulin or oral
hypoglycemic agents or participants with a fasting glucose level
12.5 mmol/L (225 mg/dL) as determined by an Accu
Check II (Baxter Healthcare Corp).21 Diabetes was
diagnosed using World Health Organization criteria.22
Standard assays were used to measure lipoproteins,23 cholesterol,24 TGs,24 glucose,24 apo B,25 fibrinogen,26 HbA1c,27 urinary albumin,28 urinary creatinine,29 and apo E phenotype.30 31
LDL size and subclass assessment were determined on plasma samples by the method of Krauss and Burke3 in the laboratory of the Medlantic Research Institute (Washington, DC). Gradient gels were obtained from Isolab Inc and standardized by using LDL subfractions whose molecular diameter was confirmed by gradient gel electrophoresis at the Donner Laboratory (courtesy of Dr R. Krauss, Donner Laboratories, Berkeley, Calif). A peak LDL size <253.5 Å was classified as pattern B, >257 Å as pattern A, and 253.5 to 257.0 Å as intermediate (I) unless the size was very close to and the peak had the shape of the A or B pattern.
The interassay coefficient of variation for eight control pools (247
through 263 Å) ranged from 1.8% to 3.6%. Data on LDL size were
available for 4468 participants. Controls monitored during the same
time period did not show drift. LDL size measures were made in 1994 on
plasma samples that had been stored at -70°C. Insulin was measured
by a modification of the method of Morgan and Lazarow.32
The cross-reactivity with proinsulin, des 31,32 split proinsulin, and
des 64,65 split proinsulin (b50) were 38%, 47%, and 72%,
respectively. The limits of quantification and detection were 
2
µU/mL.
Anthropometric measurements included weight, height, and waist and hip circumferences. These were measured with participants wearing light clothing and with their shoes removed. Percent body fat was estimated with an RJL impedance meter (model B14101, RJL Equipment Co) utilizing an equation based on total body water (M. Singer, RJL Equipment Co, personal communication, 1992). After participants had been seated for 5 minutes, three consecutive measurements of blood pressure, using the first and fifth Korotkoff sounds, were made on the right arm with the appropriate size cuff and a Baum mercury sphygmomanometer (W.A. Baum Co). The mean of the last two measurements was used to estimate blood pressure. A 12-lead ECG was taken using a Marquette system (MAC-PC or MAC-12, Marquette Electronics). All ECGs were read clinically by three staff cardiologists at the Fitzsimons Medical Center; all ECGs were then forwarded to the University of Minnesota ECG center for application of Minnesota codes.33
Criteria used to define prevalent disease have been previously described.1 Definite MI was determined by Minnesota-coded Q-wave changes on the ECG or by a history of MI verified by chart review and confirmed by a Strong Heart Study cardiologist.18 Possible MI included ECGs with a broader range of Minnesota codes or a history of MI verified as possible MI by chart review and confirmed by a Strong Heart Study cardiologist.18 Criteria for definite CHD included definite MI, evidence in the medical record of coronary angioplasty or bypass surgery, thrombolytic therapy, a positive angiogram, or angina pectoris by Rose questionnaire34 when accompanied by Minnesota code 4.1 or 5.1 or a verified history of possible MI. Possible CHD included an ECG with a broad range of Minnesota codes, angina pectoris by Rose questionnaire, or a history of MI by interview.
Statistical methods included Student's t test and ANOVA. Logarithms of TGs and urinary albumin/creatinine were used in the analysis because of their skewed distributions. Simple linear regression was used to describe the relationship between LDL size and continuous risk factor variables. Multiple linear regression and logistic regression methods were used to determine the independent associations of LDL size with continuous risk factor variables after adjustment for potential confounding variables. Correlations with P<.01 and comparisons with P<.05 were considered significant.
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Results |
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Table 1
shows the mean age and LDL
size in each center according to sex. When participants from all
centers were considered together, women had a statistically
significantly larger mean LDL size (259.8±9.3 Å) than men (258.5±9.3
Å) (P<.001). On a by-center basis, a similar sex
difference in LDL size was observed in participants from Oklahoma and
South/North Dakota but not from Arizona. LDL size varied significantly
among the three centers when men (P<.001) or women
(P<.001) were considered, with women from Arizona and men
from Arizona and Oklahoma having the smallest LDL size. LDL size was
not significantly related to age in either sex. The mean LDL size in
the 577 premenopausal women (260.2±9.7 Å) was not significantly
different from that of the 2042 postmenopausal women (259.6±9.2
Å).
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A univariate comparison of mean LDL size and subclass
pattern in men and women with NGT, IGT, and diabetes is shown in Table 2. In men, mean LDL size was
significantly related to diabetic status (P<.001): LDL size
was largest in those with NGT and smallest in those with diabetes. The
percentage of men having LDL subclass pattern B was also related to
diabetic status (P<.001), being highest in diabetic
subjects and lowest in those with NGT. Similarly in women, mean LDL
size and LDL subclass distribution were significantly related to
diabetic status (P<.001 for both). The difference in mean
LDL size in diabetic subjects when compared with nondiabetic subjects
(NGT and IGT combined) was somewhat greater in women (4.62 Å) than in
men (3.63 Å). Because of the association of diabetes with LDL size,
associations of LDL size/subclass with other metabolic
characteristics were examined separately for diabetic and nondiabetic
subjects.
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Tables 3 and 4
show mean
values for anthropometric and metabolic characteristics of
nondiabetic men and women, respectively, by LDL subclass pattern.
Probability values are for comparison of subclasses A and B, for the
univariate correlation between LDL size and each
characteristic, and for the correlation between LDL size and each
characteristic adjusted for confounding variables. For men and
women, the following parameters showed a significant,
univariate, inverse correlation with LDL size: BMI, percent
body fat, WHR, TGs, TC, VLDL cholesterol, apo B, insulin
concentration, and diastolic blood pressure, with HDL
cholesterol showing a significant, univariate,
positive correlation with LDL size. In women, there was also a
significant inverse correlation between LDL size and systolic
blood pressure, smoking, and percent Indian blood. When mean values for
each parameter were compared between participants with LDL
subclass patterns A and B, similar relations were observed in men,
except that the difference in diastolic blood pressure was
not significant. When parameters for women in subclasses A
and B were compared, BMI, percent body fat, diastolic blood
pressure, smoking, and percent Indian blood were not significant, but
differences in relation to LDL cholesterol and urinary
albumin/creatinine reached significance.
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Table 5 shows LDL size in relation to
center, sex, and diabetic status, following adjustment for confounding
variables by multivariate analysis. Mean
LDL size in nondiabetic women (261.9±0.2 Å) was significantly larger
(P<.001) than in nondiabetic men (260.3±0.2 Å). There was
no significant difference (P=.07) between mean LDL size in
diabetic women (257.2±0.2 Å) and diabetic men (256.6±0.3 Å). Mean
LDL sizes in nondiabetic women (260.5±0.2 Å) and men (258.8±0.2 Å)
were significantly (P<.001 and <0.05) larger than in
diabetic women (259.1±0.2 Å) and men (257.9±0.3 Å). A statistically
significant difference in LDL size was still evident among the three
centers for nondiabetic women and for diabetic women and men. For
diabetic men and women, the following parameters showed a
significant, univariate, inverse correlation with LDL size:
TGs, TC, VLDL cholesterol, apo B, HbA1C,
diastolic blood pressure, and urinary
albumin/creatinine, with HDL
cholesterol showing a significant, univariate,
positive correlation with LDL size. Similar findings were observed for
diabetic men and women when mean values for each parameter
were compared between participants with LDL subclass patterns A and B,
except that in diabetic women, additional differences were observed
with percent body fat and systolic and diastolic
blood pressures (data not shown).
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The associations of those variables showing significant,
univariate correlations with LDL size were further
assessed by a multivariate analysis after
adjustment for center, BMI, percent body fat, WHR, TGs, TC, VLDL
cholesterol, HDL cholesterol, apo B, insulin,
HbA1C, blood pressure, and percent Indian blood. Among
nondiabetic subjects (Tables 3
and 4), LDL size was significantly
inversely related to TGs and VLDL cholesterol, positively
related to HDL cholesterol in women and men, and inversely
related to apo B in men. Among diabetic men and women, LDL size was
significantly inversely related to TGs and VLDL cholesterol
and positively related to HDL cholesterol; in diabetic men,
LDL size was inversely related to apo B (data not shown).
Table 6 compares mean LDL size and
subclass pattern by diabetic status and sex in participants with and
without CHD (definite and possible). Unadjusted values are shown as
well as values adjusted for BMI, WHR, TGs, HDL cholesterol,
and HbA1C by multivariate analysis.
CHD was not related, either in the univariate
analysis or after adjustment, to LDL size in nondiabetic men or
women or in diabetic men. Diabetic women with CHD had a significantly
larger (P=.009) mean LDL size than those without CHD
(258.3±0.4 Å versus 257.0±0.5 Å). When the criterion of definite
CHD was used (data not shown), there was again no significant
difference in LDL size in nondiabetics or diabetics of either sex.
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When mean LDL size was compared according to apo E phenotype by diabetic status and sex after adjustment for confounding variables by multivariate analysis, no significant relation was observed between LDL size and apo E phenotype (data not shown).
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Discussion |
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A large population-based study such as this permits a detailed examination of the relation of LDL size and other components of the insulin resistance syndrome and the possible association of LDL size with premature macrovascular disease. Some selection biases are avoided, particularly in regard to diabetic status, because all participants were characterized according to conventional glucose tolerance test criteria. We have confirmed a difference in LDL size when men and women are compared, as previously described,12 17 but this difference of 1.3 Å is small—only 0.5% of the mean LDL particle size in men. We did not observe a significant reduction in LDL size with increasing age12 15 possibly because of the relatively narrow age range of the study population. Nor did we observe a smaller LDL size in postmenopausal women.35
This study confirms that LDL size is consistently related to diabetic status.15 17 36 37 Thus, mean LDL size decreases and subclass distribution progressively changes when NGT subjects are compared with those with IGT through to diabetes. Similarly in the diabetic population, LDL size varies with glycemic control, as judged by HbA1C. In both men and women, therefore, LDL size is lower in those with worse carbohydrate tolerance, even after adjustment for TGs. The relation between LDL size and diabetic status was only slightly stronger for women than for men. This is in contrast to a recent study of whites and Mexican Americans that showed a significantly greater association of diabetes and LDL size in women.38
To the extent that insulin action also declines with progressive worsening of glucose tolerance,39 the inference might be drawn that LDL size is inversely related to the prevailing degree of insulin resistance. The inverse, univariate correlation between insulin concentration and LDL size observed in both nondiabetic men and women is consistent with the proposition that LDL size is lowered by insulin resistance.16 However, multivariate analysis showed no relation between insulin concentration and LDL size in either nondiabetic or diabetic participants. In diabetic subjects, fasting insulin concentrations decline with progressive deterioration in carbohydrate tolerance beyond a fasting glucose concentration of 140 mg%,40 a phenomenon referred to as Starling's curve of the pancreas.41 As such, in the more severely diabetic subjects, fasting insulin concentrations no longer reflect the degree of insulin resistance and could not be expected to be related to LDL size.
In nondiabetic subjects, lipoproteins and other covariates may be stronger correlates of insulin action than a single fasting insulin concentration. An inverse correlation between LDL peak density and both insulin concentration and a direct measure of insulin resistance has, nevertheless, been reported in nondiabetic16 and diabetic42 subjects by other investigators, although these relationships were not assessed after adjustment for other covariates. In a recent study, Haffner et al43 concluded that LDL size was significantly related to specific insulin, proinsulin, and the fasting proinsulin-insulin ratio, even after adjustment for obesity, body fat distribution, sex, ethnicity, and proinsulin and insulin concentrations. Conversely, Lahdenpera et al44 were unable to demonstrate any relation between LDL size and insulin action using the insulin clamp technique across a range of glucose tolerance.
Additional metabolic components of the insulin resistance syndrome include hypertriglyceridemia and elevated concentrations of TC, VLDL cholesterol, and apo B and a reduced concentration of HDL cholesterol.11 12 13 14 15 16 Univariate analysis suggested that these features were associated with LDL size in men and women, whether diabetic or nondiabetic, whereas LDL cholesterol concentration was unrelated to LDL size. Similarly, univariate analysis suggested that LDL size was inversely proportional to BMI, percent body fat, and WHR in nondiabetic men and women. However, when account is taken of confounding variables, only log TGs, HDL cholesterol, and VLDL cholesterol are related to LDL size in nondiabetic subjects of each sex, with apo B being significantly correlated with LDL size in nondiabetic men only. The correlations between LDL size and TGs (r=.54) and HDL cholesterol (r=.37) were weaker than in some other studies.11 12 13 14 15 16 Among diabetic subjects of both sexes, LDL size remained related to log TGs, HDL cholesterol, and HbA1C.
Studies of Mexican-American17 and white populations11 12 13 14 15 16 have shown an association of LDL size with the cluster of metabolic characteristics associated with the insulin resistance syndrome. The present study now shows a similar relation among American Indians, although we were unable to demonstrate an independent relation between LDL size and fasting insulin, BMI, or WHR. A direct measure of insulin action might have demonstrated a relation to LDL size, but we were unable to show such a relationship with a single measure of fasting insulin. Similarly, our failure to show a correlation between LDL size and measures of obesity, including WHR, may reflect the relatively narrow range of body fat distribution exhibited by the Strong Heart Study population, of whom almost all participants were centrally obese.45 This obesity, combined with a higher prevalence of insulin resistance in the study population and subsequent exploration of insulin sensitivity, provides one explanation for the weaker relations between LDL size, TGs, and HDL in this study compared with previous reports. The observation that a clustering of metabolic abnormalities is found in such ethnically diverse populations supports the hypothesis that the alteration in LDL size is a fundamental part of the pathogenesis of the insulin resistance syndrome, wherever it appears. The concept that insulin resistance has a primary etiologic role in this pathogenesis is attractive but remains unconfirmed.
Microalbuminuria has been reported to be associated with dyslipidemia, including hypertriglyceridemia, reduced HDL concentrations, and elevated concentrations of apo B and LDL cholesterol in insulin-treated46 47 48 and non–insulin treated49 diabetic subjects, although no such relation was found in non–insulin treated diabetics by Haffner et al.50 The present study demonstrates a univariate correlation between small LDL size/subclass B and albuminuria among diabetic participants. Among nondiabetics, women with LDL subclass pattern B demonstrated a modest but significantly greater albuminuria than those with subclass A.
The proposition that insulin resistance is responsible for the pathogenesis of premature CHD is persuasive when account is taken of the many reports associating the clustering of insulin resistance–related metabolic risk factors with premature CHD in white populations.51 In the Strong Heart Study population, elevated CHD prevalence was significantly associated with low HDL cholesterol but not with high TG concentrations in most centers.52 Notwithstanding the clear association between LDL size and lipoprotein risk factors in American Indians, we have failed to show an independent relation between small LDL size and CHD on a cross-sectional basis in this population. Moreover, the center with the lowest cardiovascular mortality (Arizona) had the smallest LDL size. It seems likely that risk factors for CHD may differ in relative importance in different ethnic populations, especially in this population in which LDL concentrations are low.45 By analogy, hypertension is found within the insulin resistance syndrome in whites, among whom it is also clearly a potent risk factor for premature CHD,53 although it appears to be independent of insulin action in American Indians.54 To the extent that LDL size appears to be unrelated to hypertension in American Indians, there may yet be features of the insulin resistance syndrome common to American Indians to be contrasted with those of whites. In whites, a relation has been observed55 56 57 between hyperinsulinemia and subsequent CHD on prospective review, whereas this relationship has not yet been explored in other races. It could be argued that the criteria on which the diagnosis of CHD in American Indians were based were insufficiently exacting, at least with reference to those individuals with possible CHD. There was no association, however, even when definite CHD was used. It is of interest that LDL size is not a risk factor for CHD in individuals with diabetes. This may imply that the diabetes-associated changes in lipoprotein composition often invoked as an explanation for their excess CHD risk may involve characteristics other than LDL size. It is at least theoretically possible that our failure to show a difference in LDL size when participants with and without CHD are compared relates to the fact that ours is a cross-sectional study, and we have therefore only been able to consider a surviving population. Thus, it might be argued that participants who died of premature CHD prior to this study might have had a significant reduction in LDL size that would not have been taken into account by our analysis. Overall, our results clearly show that LDL particle size is the reflection of altered metabolic abnormalities, principally related to TG-rich lipoprotein and low HDL cholesterol. Thus, at least among American Indian populations, it remains a research tool, and measurement would not be indicated or cost effective for clinical care. Prospective review of our study population should either confirm or cast doubt on the conclusions, based on this cross-sectional survey, that macrovascular disease and small LDL size are not independently related in American Indians.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was conducted by cooperative agreement grants (U01-HL41642, No. U01HL41652, and No. UL01HL41654) from the National Heart, Lung, and Blood Institute (NHLBI). The work performed in the laboratory of R.M.K. was supported by the National Institutes of Health Program Project Grant HL 18574 from the NHLBI and by a grant from the National Dairy Promotion and Research Board. This study was administered in cooperation with the National Dairy Council and was conducted at the Ernest Orlando Lawrence Berkeley National Laboratory through the US Department of Energy under contract No. DE-AC03-76SF00098. A Wellcome Research Travel Grant and financial support through the Myre Sim Travel and Education Fund were provided to R.S.G. The authors acknowledge the assistance and cooperation of the AkChin Tohono O'odham (Papago)/Pima, Apache, Caddo, Cheyenne River Sioux, Comanche, Delaware, Spirit Lake Tribe, Fort Sill Apache, Gila River, Pima/Maricopa, Kiowa, Oglala Sioux, Salt River Pima/Maricopa, and Wichita Indian Communities, without whose support this study would not have been possible. The authors also wish to thank the Indian Health Service hospitals and clinics at each center and Betty Jarvis, Martha Stoddart, and Beverly Blake, Directors of the Strong Heart Study Clinics and their staffs and acknowledge the assistance of Dr Oscar Go in data analysis, Ellen Shair in editing the manuscript, and the secretarial assistance of Ruth Ross-Hunley.
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Footnotes |
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Reprint requests to Dr Barbara V. Howard, Medlantic Research Institute, 108 Irving St NW, Washington, DC 20010-2933.
The views expressed in this article are those of the authors and do not necessarily reflect those of the Indian Health Service.
Received July 31, 1996; accepted November 18, 1997.
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