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Clinical Chemistry 49: 1873-1880, 2003; 10.1373/clinchem.2003.022558
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Right arrow Lipids, Lipoproteins, and Cardiovascular Risk Factors
(Clinical Chemistry. 2003;49:1873-1880.)
© 2003 American Association for Clinical Chemistry, Inc.

Lipids, Lipoproteins, and Cardiovascular Risk Factors

Fractional Esterification Rate of Cholesterol and Ratio of Triglycerides to HDL-Cholesterol Are Powerful Predictors of Positive Findings on Coronary Angiography

Jiri Frohlich1,a and Milada Dobiásová2

1 Department of Pathology and Laboratory Medicine, University of British Columbia, Healthy Heart Program/Lipid Clinic, St. Paul’s Hospital, Vancouver, BC V6Z 1Y6, Canada.

2 Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic 14220.

aAddress correspondence to this author at: Healthy Heart Program, St. Paul’s Hospital, B180-1081 Burrard St., Vancouver, BC V6Z 1Y6, Canada. Fax 604-806-8590/3; e-mail jifr{at}interchange.ubc.ca.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: We examined the predictive value of various clinical and biochemical markers for angiographically defined coronary artery disease (aCAD). Specifically, we assessed the value of the ratio of plasma triglyceride (TGs) to HDL-cholesterol (HDL-C) and the fractional esterification rate of cholesterol in plasma depleted of apolipoprotein B (apoB)-containing lipoproteins (FERHDL), a functional marker of HDL and LDL particle size.

Methods: Patients (788 men and 320 women) undergoing coronary angiography were classified into groups with positive [aCAD(+)] and negative [aCAD(-)] findings. Patient age, body mass index, waist circumference, blood pressure (BP), medications, drinking, smoking, exercise habits, and plasma total cholesterol (TC), LDL-cholesterol (LDL-C), HDL-unesterified cholesterol, HDL-C, TGs, FERHDL, apoB, log(TG/HDL-C), and TC/HDL-C were assessed. Lipids and apoproteins were measured by standard laboratory procedures; FERHDL was determined by a radioassay.

Results: Members of the aCAD(+) group were older and had a higher incidence of smoking and diabetes than those in the aCAD(-) group. The aCAD(+) group also had higher TG, apoB, FERHDL, and log(TG/HDL-C) and lower HDL-C values. aCAD(+) women had greater waist circumference and higher plasma TC and TC/HDL-C. aCAD(+) men, but not women, had higher plasma LDL-C. In the multivariate logistic model, the significant predictors of the presence of aCAD(+) were FERHDL, age, smoking, and diabetes. If only laboratory tests were included in the multivariate logistic model, FERHDL appeared as the sole predictor of aCAD(+). Log(TG/HDL-C) was an independent predictor when FERHDL was omitted from multivariate analysis.

Conclusions: FERHDL was the best laboratory predictor of the presence of coronary atherosclerotic lesions.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Several predictors of coronary atherosclerosis, such as age, male sex, smoking, presence of diabetes, hypertension, obesity, high serum LDL-cholesterol (LDL-C), 1 and low serum HDL-cholesterol (HDL-C) have been well established (1)(2)(3)(4)(5)(6). Many other predictors have been studied, including plasma concentrations of triglycerides (TGs) and TG-enriched lipoprotein particles (7)(8)(9)(10), lipoprotein particle size (11)(12), apolipoprotein B (apoB) (13), lipoprotein(a), homocysteine, C-reactive protein, and others (14). Various algorithms for predicting coronary atherosclerosis have been established (15), most of which are based on large epidemiologic, cohort, and cross-sectional studies (16).

We assessed both clinical and laboratory predictors of atherosclerosis in 1108 consecutive patients undergoing coronary angiography with the following objectives: (a) to compare the associations between the various clinical and laboratory indices and the presence or absence of angiographically defined coronary artery disease (aCAD); and (b) to examine the potential usefulness of a new functional test for indirect assessment of HDL and LDL particle size, i.e., the fractional esterification rate in apoB-depleted plasma (FERHDL) (17)(18)(19). FERHDL measures the rate of esterification of free cholesterol in HDL in plasma depleted of apoB-containing lipoproteins. The esterification is mediated by lecithin-cholesterol acyl transferase, an enzyme that transfers acyl of fatty acids from lecithin to unesterified cholesterol, which leads to the formation of cholesterol esters. The esterification rate is related to the particle size: it is fastest in the smallest HDL particles and slower in larger particles (17)(18)(19).

In this study we also compared the predictive power of two lipid indexes: the commonly used ratio of plasma cholesterol to HDL-C and the logarithmically transformed ratio of plasma TGs to HDL-C (20).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
patients
The participants were consenting individuals undergoing coronary angiography at Vancouver General and St. Paul’s Hospitals in 1993–1994. The indications for angiography included exercise-induced chest pain, previously diagnosed myocardial infarction (MI), atypical chest pain, aortic stenosis/regurgitation, and mitral regurgitation. Patients with unstable angina and MI within the preceding 2 months were excluded from the study. Coronary angiograms were obtained by the standard techniques with multiple views recorded. The angiograms were defined regarding the number of vessels involved (0, 1, 2, or 3) and the lesion severity, i.e., more than or less than 50% lumen obstruction. For the purpose of this study, angiograms with a >50% stenosis in one or more arteries were classified as aCAD(+). Those with a maximum stenosis of <=10% in any artery were defined as aCAD(-). Each participant in the study filled out a questionnaire that included their demographic data and presence/absence of the major risk factors, including personal and family history of vascular disease. Height, weight, and waist circumference were measured at the same time. All participants signed a consent form that had been approved by University of British Columbia and St. Paul’s Hospital ethics committees.

laboratory assays
Blood samples were collected after an overnight fast into EDTA-containing Vacutainer tubes on the day of the angiogram, kept at 4 °C, and centrifuged within 12 h. Aliquots of plasma were frozen at -70 °C until analyses. Plasma total cholesterol (TC), TGs, total HDL-C, and HDL-unesterified cholesterol (HDL-UC) were measured enzymatically. LDL-C was calculated using the Friedewald equation, and apoB was measured nephelometrically (Beckman Array System). The radioassay for FERHDL had been described previously (17)(18)(19). Briefly, apoB-containing lipoproteins are precipitated from EDTA plasma by phosphotungstic acid and MgCl2. To the supernatant, which contains plasma with HDL only, is added a filter-paper disk containing a trace of [3 H]cholesterol. After an overnight incubation at 4 °C, the disk is removed and the plasma with labeled HDL is heated to 37 °C and incubated for 30 min. After the incubation, lipids are extracted by ethanol and separated by thin-layer chromatography. FERHDL (%/h) is calculated from the ratio of radioactive unesterified to radioactive esterified cholesterol.

statistical analysis
The data are presented as means (SD) for all individuals and separately for men and women with positive [aCAD(+)] and with negative angiography findings [aCAD(-)]. Differences between those with positive and negative findings were tested by unpaired Student and Wilcoxon rank-sum tests. For variables with high interindividual variation (3 SD > mean), statistical analyses were performed on log-transformed values (as has been done for TGs, FERHDL, and TG/HDL). Correlation was tested by a bivariate Spearman nonparametric rank correlation test. The association of measured variables with the presence of aCAD(+) was evaluated in both univariate and multivariate logistic regression models. Stepwise logistic regression analysis was used to predict the presence or absence of aCAD. The model was based on values of the set of variables that had significant association on univariate analysis. Odds ratios and 95% confidence intervals (CIs) for aCAD(+) vs aCAD(-) were calculated (Table 5 ). Data were adjusted for the categorical variables, such as smoking and diabetes, and for continuous variables, such as age, body mass index (BMI), waist circumference, TC, LDL-C, apoB, TGs, HDL-C, HDL-UC, FERHDL, log(TG/HDL-C), and TC/HDL-C. The statistical packages SPSS, Base 11.0, and SPSS Regression Models 11.0 were used to analyze the data.


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  		Table 5. Stepwise logistic regression model for all study participants.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
characteristics of the study population
The study cohort consisted of 320 women and 788 men (age range, 18–88 years). Their characteristics are shown in Table 1 . Of the initial diagnoses, the most common was CAD (52% of women, 64% of men). Twenty-one percent of the women and 33% of the men had received a previous diagnosis of MI, whereas peripheral vascular disease or cerebral vascular disease was previously diagnosed in 15% and 9% of the women and 10% and 6% of the men, respectively. Eighty-one percent of the men and 58% of the women had positive findings on coronary angiography. Adult-onset diabetes was diagnosed in 17% of women and 16% of men, hypertension in 42% of women and 36% of men, and the BMI was >30 in 27% of both genders. More than 80% of the women were postmenopausal. Fifty-seven percent of the women and 76% of the men were current or former smokers, ~11% of both men and women did not exercise regularly, and 20% the men and 40% of the women were nondrinkers. Only ~15% of the men and women in this cohort were using lipid-lowering medications.


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  		Table 1. Characteristics of patient cohort.

univariate analyses
The mean (SD) for each continuous variable in the negative [aCAD(-)] and positive angiography [aCAD(+)] groups are shown in Tables 2 and 3 . Analyses of these variables were carried out separately for men (Table 2 ) and women (Table 3 ). The P values indicate the results of independent sample t-tests for differences between those with positive and negative angiographic findings. In the whole cohort, CAD(+) and aCAD(-) individuals differed significantly in age; TG, apoB, and HDL-C concentrations; FERHDL; and log(TG/HDL-C). However, there were no significant differences in systolic BP and BMI. Men, but not women, with positive findings had higher LDL-C and lower HDL-UC. Women, but not men, with positive findings had significantly increased waist circumference, TC, unesterified cholesterol, and TC/HDL-C ratio.


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  		Table 2. Univariate analysis of CAD risk factors for men with negative and positive angiographic findings.


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  		Table 3. Univariate analysis of CAD risk factors for women with negative and positive angiographic findings.

Of the categorical variables, both smoking and diabetes were significantly higher in the cohort members with positive findings (P <0.001). In addition, women with CAD(+) had a significantly higher frequency of hypertension (P <0.04). Neither alcohol consumption nor physical inactivity were significantly associated with positive findings.

correlation analysis
The relationships between plasma lipid/apoprotein measurements and FERHDL are shown in Table 4 . There was a strong correlation between FERHDL, plasma TGs, HDL-C, and HDL-UC. Whereas the correlation between FERHDL and either total or unesterified cholesterol was rather weak (albeit significant), the correlation between FERHDL and apoB was much stronger. There was an even stronger correlation between FERHDL and both calculated indexes [log(TG/HDL-C) and TC/HDL-C]. There was no significant difference in any the above correlations between the aCAD(+) and CAD(-) groups.


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  		Table 4. Pearson correlations (r) between logFERHDL and anthropometric and biochemical variables.

Conversion of the continuous variables (TGs, HDL-C, and apoB) into quartiles may better illustrate the relationships between these specific markers and FERHDL: FERHDL increased from 13.2%/h to 35.7%/h between the first and fourth quartiles of logTG and HDL-C. This increase was related independently to both of these variables (Fig. 1 ). The relationship between FERHDL and apoB and HDL-C was similar (Fig. 2 ).



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  		Figure 1. Three-dimensional model relating FERHDL values to the quartiles of logTG and HDL-C.

The columns indicate the means. Error bars, 95% CIs of the means.



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  		Figure 2. Three-dimensional model relating FERHDL values to the quartiles of apoB and HDL-C.

The columns indicate the means. Error bars, 95% CIs of the means.

logistic stepwise regression model
The results of logistic regression analysis of the differences between the aCAD(+) and aCAD(-) groups are shown in Table 5Up . Although the univariate models demonstrated significant differences in several variables between the aCAD(+) and aCAD(-) groups (Tables 2Up and 3Up ), many did not appear in the model adjusted for age, BMI, waist circumference, diabetes, smoking, logTG, LDL-C, apoB, HDL-C, HDL-UC, logFERHDL, and the indices log(TG/HDL-C) and TC/HDL-C. In the logistic regression model that included the whole cohort, the most powerful predictors were FERHDL, age, smoking, and diabetes (Table 5Up ). When log FERHDL was omitted from the model, the logarithmically transformed ratio of TGs to HDL-C became the best independent predictor of aCAD(+). The model examining the predictive power of laboratory tests [TC, logTG, LDL-C, apoB, HDL-C, HDL-UC, logFERHDL, log(TG/HDL-C), and TC/HDL-C] only indicated that FERHDL was the sole significant predictor (odds ratio = 28.33; P <0.0001).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We examined the predictive value of different demographic, clinical, and biochemical indices for findings on selective coronary angiography in a cohort of 1108 patients.

We have shown that individuals with positive angiographic findings tend to be older, smokers, have a history of diabetes, and also have higher TG and apoB concentrations, lower HDL-C, and only mildly increased TC and LDL-C. These results are in agreement with previous reports of association of these "classic" markers with angiographically confirmed CAD (21). We have shown that FERHDL, an indirect measure of lipoprotein particle size (22)(23)(24), is a better predictor of positive angiographic findings than the classic markers. Recent reports confirmed that the smallest LDL (25) and small HDL (26) particles are most strongly related to coronary disease progression. In our cohort, FERHDL was the most effective predictor of positive angiographic findings among all clinical and biochemical markers assessed (Table 5Up ). In women, in agreement with previous findings (8), there was a strong relationship between plasma TGs and positive coronary findings. In the logistic regression model in which FERHDL was omitted, the ratio of TGs to HDL-C was the most effective predictor. This index, log(TG/HDL), strongly correlated with FERHDL and several other risk factors for CAD (20). In the current study, log(TG/HDL-C) appeared to be a better predictor of positive angiographic findings than the commonly used ratio TC/HDL-C (27)(28).

The value of FERHDL is strongly related to changes in HDL-C, TGs, and apoB (Figs. 1Up and 2Up ). The concentrations of all these analytes are known to influence lipoprotein particle size and number. For example, higher TG concentrations are associated with the presence of small VLDL and LDL particles (29), and the apoB concentration is directly linked to the number of LDL particles (13).

It has been well documented that small, dense LDL particles are more susceptible to oxidation and are a better substrate for formation of foam cells than large cholesterol-rich LDL particles (6). On the other hand, increased HDL-C is usually associated with an increase in protective HDL2b particles (30), which inhibit esterification of cholesterol, i.e., reduce FERHDL (23), whereas low HDL-C is seen in the presence of small particles (11), which increase FERHDL (23). The value of FERHDL as an independent indicator of angiographic endpoints was reported recently in the HDL-atherosclerosis study (31).

The size of our cohort and the number of markers measured compare favorably with other studies in this field (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80)(81)(82)(83)(84). Most of these studies were limited in the number of patients examined, relative to one gender or age or race group, and many of them examined only some of the markers assessed in our study.

There are several limitations to our findings. The angiographic assessment of vascular disease, although currently an accepted "gold standard", is less sensitive and specific than newer methods, such as intravascular ultrasound. Furthermore, the assessment of the angiographic findings was only semiquantitative. The effects of beta-blockers and lipid-lowering drugs when taken into account in both the CAD(+) and CAD(-) groups had no effect on statistical analyses; however, they may have influenced several of the biochemical markers measured. Finally, it may be disputed that our control group (patients with negative findings on angiography) were not truly healthy individuals because they had risk factors that led to their angiography in the first place. We believe that this actually makes our data stronger because the differences observed might have been much greater if a control group of patients without any risk factors have been used. There were only 25 patients with 10–50% obstruction.

In conclusion, after correcting for the presence of classic risk factors and several other variables, FERHDL, age, smoking, and diabetes were the best independent predictors of the presence of angiographically confirmed CAD in both genders. In women, serum TGs were also an independent predictor. Thus, the particle size of lipoproteins assessed by a functional test (FERHDL) appeared to be the superior biochemical predictor of positive findings on coronary angiography.


   Acknowledgments
 
This study was supported by grants from the British Columbia Heart & Stroke Foundation and Grant NA/6590-3 from the Ministry of Health of the Czech Republic. We would like to acknowledge the competent technical assistance of L. Adler.


   Footnotes
 
1 Nonstandard abbreviations: LDL-C and HDL-C, LDL-and HDL-cholesterol, respectively; TG, triglyceride; apoB, apolipoprotein B; aCAD, angiographically defined coronary artery disease; FERHDL, fractional esterification rate of cholesterol in plasma depleted of apoB-containing lipoproteins; MI, myocardial infarction; BP, blood pressure; TC, total cholesterol; HDL-UC, HDL-unesterified cholesterol; CI, confidence interval; and BMI, body mass index.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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