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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1295
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 4 2264-2269
Copyright © 2005 by The Endocrine Society

Small, Dense Lipoprotein Particles and Reduced Paraoxonase-1 in Patients with the Metabolic Syndrome

Marie-Claude Blatter Garin, Barbara Kalix, Alfredo Morabia and Richard W. James

Clinical Diabetes Unit (M.-C.B.G., B.K., R.W.J.), Department of Endocrinology, Diabetes, and Nutrition, and Department of Clinical Epidemiology (A.M.), University Hospital, 1211 Geneva 4, Switzerland

Address all correspondence and requests for reprints to: Dr. Richard W. James, Clinical Diabetes Unit, Department of Endocrinology, Diabetes, and Nutrition, University Hospital, 1211 Geneva 4, Switzerland. E-mail: richard.james{at}hcuge.ch.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
The presence of the metabolic syndrome (World Health Organization definition) and its association with lipoprotein abnormalities suggestive of greater susceptibility to oxidative stress have been analyzed in patients with angiographically defined coronary artery disease. The odds ratio for the presence of the metabolic syndrome was significantly higher in coronary artery disease-positive patients (P < 0.001). The metabolic syndrome was also associated with more severe coronary disease (P < 0.01). Patients with the metabolic syndrome had significantly decreased low-density lipoprotein-cholesterol/apolipoprotein B and high-density lipoprotein-cholesterol/apolipoprotein AI ratios, indicative of the presence of small, dense lipoprotein particles. The syndrome was also associated with reduced concentrations and activities of the antioxidant enzyme, paraoxonase-1. The metabolic syndrome is characterized by smaller, denser lipoprotein particles that increase their susceptibility to oxidative modifications and diminished serum paraoxonase-1, which is a major determinant of the antioxidant capacity of high-density lipoproteins. These may be contributory factors to the increased presence and severity of coronary disease in such patients.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE OBSERVATION THAT certain risk factors (RFs) accumulate in coronary patients, suggestive of a common origin, was the subject of quite early reports in the clinical literature (1, 2). The concept has evolved through a number of synonyms (3) to its present status as the metabolic syndrome (4). The strongest candidate for the common origin is insulin resistance (4, 5), and although a growing number of metabolic anomalies are linked to insulin resistance (3), the core components are excess weight, dyslipidemia, and hypertension. These have recently been incorporated into guidelines by the World Health Organization (6) and the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) (7) to provide a definition of the syndrome, which should aid clinical studies. Insulin resistance (or indications of abnormal glucose metabolism) is the central feature of the WHO definition, whereas the NCEP ATP III recommendations do not require evidence of insulin resistance.

Although interest in the syndrome has risen rapidly in recent years, the absence of a consensus definition has hampered attempts to analyze its relevance to coronary disease. The recent recommendations correct this deficit, but at present there is a paucity of data on the prevalence of the syndrome particularly with respect to coronary patients. Such data are now beginning to accrue, based on the consensus guidelines (8, 9, 10, 11).

Both quantitative and qualitative changes to lipoprotein profiles contribute to the increased incidence of coronary disease (12). Another important contributor to increased coronary risk is oxidative stress (13). In addition, there may be a pathological link among these parameters because modified forms of low-density lipoprotein (LDL) are more susceptible to oxidative stress (14). The aim of the present study was to examine the metabolic syndrome in a Swiss population of patients with coronary disease verified by angiographic assessment. Attention was focused on qualitative changes to LDL and high-density lipoprotein (HDL) as well as the serum antioxidant enzyme, paraoxonase, which plays a major role in protecting LDL and HDL from oxidative stress (15).


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

Patients were recruited from those referred to the university hospital (Geneva), as previously described (16). Patients completed a questionnaire with an interviewer. It included details of personal and family medical history as well as current medication. The patients’ hospital files were also consulted. All patients gave written, informed consent to participate, and the Ethics Committee of the Department of Internal Medicine approved the study, which was carried out according to the requirements of the Helsinki Declaration.

The arteriographic examination was performed and assessed as described previously (16). Briefly, patients underwent biplane arteriography with the standard Judkin’s technique, and a stenosis greater than 20% in at least one epicardial artery was considered positive for the present study. Patients were further classified as having single, double, or triple vessel disease by the presence of a stenosis greater than 70% in one, two, or three major epicardial arteries, as described (16).

Control subjects also underwent arteriography and were found to be free of significant stenoses. They had been mainly referred for valve anomalies/replacements. In some instances chest pain was the reason for referral, but no coronary anomaly could be detected, and the pain was considered to be of noncardiac origin. The controls had no other clinical evidence of coronary disease.

Metabolic syndrome

The presence of the metabolic syndrome was defined according to the WHO guidelines (6). This was based on the presence of glucose intolerance or insulin resistance or type 2 diabetes together with two or more of the following: hypertension (systolic ≥ 160 mm Hg and/or diastolic ≥ 90 mm Hg) or proven treatment for hypertension; dyslipidemia [triglycerides ≥ 149 mg/dl (1.70 mmol/liter)]; HDL-cholesterol 34.6 mg/dl or less (0.9 mmol/liter) (men) or 38.5 mg/dl or less (1.0 mm/liter) (women); or obesity (body mass index ≥ 30 kg/m2). Glucose intolerance was taken as fasting glucose 110 mg/dl or more (6.1 mmol/liter) after an overnight fast (>12 h) or presence of type 2 diabetes. The latter was ascertained from the interview and confirmed by current medication and hospital records. Patients with type 1 diabetes were excluded from the study.

Laboratory tests

Basal paraoxonase activity was determined as described (17). Briefly, serum (10 µl) was added to 1.0 ml Tris HCl (100 mM; CaCl2, 2 mM; pH 8.0) containing paraoxon (5.5 mM, Sigma/Fluka, Buchs, Switzerland) and the production of p-nitrophenol (405 nm, 5 min) was monitored continuously (Uvikon 810, Kontron, Paris, France). Results are expressed as units per milliliter (1 U, 1 nmol p-nitrophenol formed per minute). Serum paraoxonase-1 (PON1) mass was determined by enzyme linked immunoassay (17). Plasma lipids and apolipoproteins were quantified as described (18). LDL-cholesterol was calculated according to the Friedewald formula (19). Glucose was determined by the glucose oxidase technique (20).

Statistical analysis

Group frequencies were compared by the {chi}2 test. Multiple logistic regression analysis was performed with coronary artery disease (CAD) as the dependent variable and gender, age, and the metabolic syndrome or its individual components as the independent variables. LDL-cholesterol and smoking were also included as independent variables. LDL and age were continuous variables and the other parameters were categorical variables. The group that was negative for the syndrome thus contained patients with one or several RFs (mean 1.3/patient). The metabolic syndrome negative (MS–ve) group was also subdivided into those with none of the component RFs (MS–ve, RF–ve) and those with some RFs (mean 1.5/patient; MS–ve, RF+).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Patients’ characteristics are shown in Table 1Go, according to the presence or absence of the metabolic syndrome. In the latter case, the MS–ve group included patients with CAD and RFs (i.e. those defined for the metabolic syndrome) as well as CAD-negative participants (a mean 1.3 RFs per participant for the subgroup).


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  		TABLE 1. Clinical and anthropometric characteristics of CAD and control subjects

 
Gender and smoking status did not differ between the groups, but those with the metabolic syndrome were older (Table 1Go). The metabolic syndrome subgroups did not differ significantly with respect to total and LDL-cholesterol or apolipoprotein (apo) B, whereas body mass index, the presence of diabetes, triglycerides, and hypertension were, as expected, significantly higher in the group positive for metabolic syndrome (MS+ve). HDL-cholesterol and apo AI were lower in the presence of the metabolic syndrome (Table 1Go). The incidence of CAD was also significantly greater in the MS+ve group.

The metabolic syndrome was present in 18.0% of the whole population (8.8% of the population if type 2 diabetic patients were excluded). In CAD-negative (CAD–ve) participants, the metabolic syndrome was present in 9.5% of the subgroup (4.6% in nondiabetic participants), whereas 20.4% CAD-positive (CAD+ve) patients had the metabolic syndrome (10.1% of nondiabetic patients). Table 2Go shows odds ratios for the presence of the metabolic syndrome in CAD–ve or CAD+ve patients. There was an increased presence (5-fold) of CAD in MS+ve patients, compared with those with no RFs. There was also a significantly increased presence (2.5-fold) of CAD in MS+ve participants when compared with all participants who were MS–ve. When MS–ve participants were categorized as RF+ or negative (RF–), there was a highly significant trend to an increased presence of CAD in the subgroups (Table 2Go). These conclusions were not altered when type 2 diabetic patients were excluded from the analysis.


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  		TABLE 2. Odds ratios for association of the MS with the presence or absence of CAD

 
To explore further the potential impact of the metabolic syndrome in coronary disease, we examined disease severity. The analysis was limited to patients with CAD and defined as one-, two-, or three-vessel disease. The metabolic syndrome was significantly associated with increased severity ({chi}2 for trend 9.82, P < 0.01), as illustrated in Fig. 1AGo. This trend was also apparent when MS–ve patients were subdivided into those with and without cardiovascular RFs (Fig. 1BGo). After excluding diabetic patients from the analysis, the trends test was no longer significant ({chi}2 2.52), although there were too few patients in the metabolic syndrome subgroup (n = 42) for a valid analysis. In logistic regression analysis, the metabolic syndrome was independently associated (P < 0.01) with disease severity (one-, two-, or three-vessel disease) after correction for cholesterol, age, gender, apo B, and smoking status. Conversely, when the individual components of the metabolic syndrome were tested, only triglycerides (P = 0.04) emerged as an independent determinant of disease severity.



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  		FIG. 1. The prevalence of single- (1), double- (2), or triple- (3) vessel disease as a function of the presence (MS+) or absence (MS–) of the metabolic syndrome. A, Categories MS+ and MS–. B, MS– patients subdivided as RF–ve (RF–, MS–) or RF positive (RF+, MS–).

 
Plasma cholesterol, and notably LDL-cholesterol, is considered to be the principal lipid RF for coronary disease. The presence of the metabolic syndrome was not associated with significant differences in plasma cholesterol or LDL-cholesterol concentrations (Table 1Go), whereas plasma triglycerides and HDL-cholesterol differed significantly (Table 1Go). Removal of diabetic patients from the analyses did not alter the conclusions [MS–ve vs. MS+ve: total cholesterol, 223.5 ± 47.7 vs. 218.1 ± 39.2 mg/dl (5.81 ± 1.24 vs. 5.67 ± 1.02 mmol/liter), P = 0.39; LDL-cholesterol, 151.9 ± 42.3 vs. 144.6 ± 38.1 mg/dl (3.95 ± 1.10 vs. 3.76 ± 0.99 mmol/liter), P = 0.22], whereas differences for triglycerides and HDL-cholesterol remained highly significant (data not shown). Because the MS–ve subgroup nevertheless also included patients with CAD RFs (a mean of 1.3 RFs/participant) this could contribute to the lack of difference in cholesterol concentrations. When participants without any component of the metabolic syndrome were compared with those with the syndrome (MS–ve, RF–ve), no significant differences in total cholesterol were observed [224.6 ± 47.3 vs. 220.3 ± 43.8 mg/dl (5.84 ± 1.23 vs. 5.73 ± 1.14 mmol/liter), P = 0.43]. There were significant differences in LDL-cholesterol, but this was due to lower concentrations in the metabolic syndrome group [154.6 ± 43.5 vs. 144.2 ± 39.6 (4.02 ± 1.13 vs. 3.75 ± 0.1.03 mmol/liter), P = 0.03]. Exclusion of patients on lipid-lowering medication (33.1% of participants) did not change the general conclusions.

Qualitative changes to LDL can be identified by the presence of small, dense LDL particles. The LDL-cholesterol to apo B ratio is used as a surrogate marker for this type of LDL particle. Table 3Go shows a comparison of the ratios for the subgroups with and without the metabolic syndrome. Highly significant differences were observed, with MS+ve patients having lower ratios, suggesting smaller, denser LDL particles. These conclusions held when type 2 diabetic patients were removed from the analyses (Table 3Go). A similar analysis of HDL showed a significantly lower HDL-cholesterol to apo AI ratio in MS+ve patients, again consistent with smaller denser forms of HDL particle (Table 3Go). As with LDL, the ratio remained significantly lower in MS+ve patients when diabetic patients were removed from the analysis.


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  		TABLE 3. The ratios of LDL-cholesterol/apo B and HDL-cholesterol/apo AI in patients with and without the MS

 
Another contributory factor to the incidence of coronary disease is oxidative stress. The HDL-associated enzyme, PON1 has been identified as an important determinant of the capacity of HDL to prevent oxidative modifications to LDL (21). We examined serum levels of PON1 in the patients according to their metabolic syndrome status. As shown in Table 4Go, serum concentrations and activities of PON1 were significantly reduced in patients with the metabolic syndrome. This conclusion also held when diabetic patients were excluded from the analysis (Table 4Go). Neither differences in genotype frequencies for the PON1 Q192R polymorphism nor changes to paraoxonase-specific activity could explain the observed differences between patients with and without the metabolic syndrome (results not shown).


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  		TABLE 4. Serum PON1 concentrations and activities in patients with and without the MS

 
To analyze the potential pathological interaction between low serum PON1 and the presence of small, dense LDL, the population was categorized into quartiles according to the presence of low PON1 mass and a low LDL-cholesterol to apo B ratio (presence of small dense LDL). As shown in Table 5Go, patients in the lowest quartile had a significantly increased risk of CAD, compared with those in the highest quartile. Equivalent results were obtained when patients in the lowest quartile were compared with all other patients (P = 0.021) and when the population was categorized according to low PON1 activity and small dense LDL (P = 0.009 for lowest vs. highest quartiles).


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  		TABLE 5. Risk of CHD as a function of presence of low serum PON1 and a low (LDLchol/apo B) ratio

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The present study demonstrates significant, qualitative changes to lipoproteins in patients with the metabolic syndrome. They are accompanied by significant decreases in serum activity of PON1, which can protect both LDL and HDL from oxidation. These changes represent a net deterioration of the cardiovascular profile, which would contribute to an increased risk of coronary disease. In this context, the metabolic syndrome was associated with an increased prevalence of CAD and greater disease severity. These conclusions largely held when diabetic patients were removed from the analysis.

Plasma and LDL cholesterol concentrations did not differ between those with and without the metabolic syndrome, suggesting that, with regard to quantitative aspects of cholesterol metabolism, they are essentially independent of the metabolic disturbances giving rise to the syndrome. Thus, although LDL-cholesterol is a primary RF, the metabolic syndrome would not appear to increase risk by quantitative modifications to cholesterol. However, when qualitative modifications to the cholesterol transport vector, LDL, are taken into account, a different picture emerges. The metabolic syndrome is associated with a significantly lower LDL-cholesterol to apo B ratio, highly suggestive of the presence of smaller, denser LDL particles. Small, dense LDL is a RF for coronary disease (22) and, in addition, has been associated with insulin resistance (23). A recent study also reported a decrease in the LDL-cholesterol to apo B ratio in patients with increased accumulation of components of the metabolic syndrome (11). Thus, qualitative changes to cholesterol metabolism appear to be associated with the metabolic syndrome and represent an increased risk of CAD.

There were significant reductions in HDL-cholesterol (expected, as one of the diagnostic components for the metabolic syndrome) as well as its structural peptide, apo AI, in MS+ve patients. Despite reductions of both, there was also a significant reduction in the HDL-cholesterol to apo AI ratio, again indicating the presence of smaller denser particles in MS+ve patients. Such qualitative changes to HDL have been associated with increased risk of CAD (24, 25). In addition, HDL size is a determinant of its catabolic rate, with smaller-sized HDL being more rapidly eliminated (26), leading to lower plasma concentrations of the lipoprotein.

One means by which small, dense LDL could increase risk of vascular disease is their greater susceptibility to oxidation (14). Diabetes is associated with increased oxidative stress (27), and antioxidant-protective mechanisms are suggested to be suboptimal in the metabolic syndrome (28). HDLs are known to limit lipid oxidation, a function that is particularly associated with the HDL-bound enzyme, PON1 (29). PON1 can prevent oxidation of both LDL and HDL. The present study showed that serum levels of the enzyme are reduced in patients with the metabolic syndrome. The degree of reduction we observed was sufficient, in a previous study we undertook (30), to influence the antioxidant capacity of HDL. Reduced serum PON1 activity has been previously reported in diabetic patients (30, 31), but our present analyses show that enzyme activity and concentration are also reduced in MS+ve patients in the absence of diabetes. Thus, in this population of patients, the metabolic syndrome is associated with qualitative changes to LDL, which render them more susceptible to oxidation, coupled with a reduction in the potential antioxidant activity of HDL. A recent study provided evidence for dysfunctional HDL in patients with the metabolic syndrome (32). A decreased, intrinsic antioxidant capacity was observed. Although no reduction in PON1 activity of MS patients was reported, the small sample size (n = 10) would mask any such difference. Of interest, the authors proposed modified HDL composition as one factor contributing to reduced, inherent antioxidant function. We have previously shown that HDL composition impacts on PON1 activity (33).

The metabolic syndrome was associated with CAD, even when diabetic patients were excluded from the analysis, with a greater than 2-fold increase in risk. It should be underlined that the MS–ve group (Table 2Go) was not devoid of RFs and had various combinations of dyslipidemia, hypertension, excess weight, and glucose abnormalities. Comparison of the observations with other studies concerning coronary risk is not feasible at present because few are available (for further information, see Refs. 8 , 34), and only one has adopted the recent WHO guidelines (8). Indeed, it was one of the reasons for the present study. In a preceding study, Isomaa et al. (8) observed in Scandinavian patients a prevalence of the metabolic syndrome of approximately 10% in nondiabetic, CHD patients and approximately 5% in controls, which is quite comparable with our observations. CHD was less stringently defined in the study, but it reported an increase of 2- to 3-fold in risk, which is of the magnitude that we observed in the present study. Thus, there is a certain concordance between the two studies in terms of increased presence of CAD associated with the metabolic syndrome. The syndrome was also associated with more severe CAD, whereas only triglycerides (of the individual metabolic syndrome components) were independently associated with severity. Data from recent studies (11, 35), one of which was based on angiographic examinations (11), also reported more severe disease with increasing accumulation of components of the metabolic syndrome (based on the NCEP ATP III definition). In this context, identification of the syndrome may be of importance in clinical practice. It could contribute to defining higher risk and modify the therapeutic attitude, i.e. when cholesterol levels alone (see below) may not merit a more aggressive treatment.

There are several caveats to the present study. Definition of abnormal glucose metabolism in the absence of proven diabetes was based on a single, fasting glucose determination. It was determined, however, after an overnight stay in hospital, in which a fasting period greater than 12 h was assured. Microalbuminuria, which is included in the WHO definition, was not measured, and thus, the prevalence of the syndrome may be somewhat underestimated. The parameter is not, however, frequently measured, and, moreover, its inclusion in the guidelines is a somewhat disputed issue (36). The controls underwent angiography, which suggests suspicion of coronary disease. They were mainly referred for heart valve problems; those with chest pain were found to be free of stenoses by angiography (and free of other clinical evidence of coronary disease). A misdiagnosis of controls as CAD–ve would, conversely, decrease the chances of observing differences between them and CAD patients. It should also be noted that LDL-cholesterol was not directly measured but calculated by the Friedewald formula (19), which is a commonly applied procedure. In addition, apo B was measured in whole serum but essentially reflects apo B in LDL.

In conclusion, the metabolic syndrome was associated with significant qualitative changes to the LDL and HDL profiles, which would increase risk of coronary disease. They were accompanied by a reduction in the capacity of one of the main antioxidant activities associated with HDL. These could be contributory factors to the increased incidence and severity of CAD observed in metabolic syndrome populations.


   Footnotes
 
This work was supported by grants from the Swiss Cardiology Society, the Swiss National Research Foundation, and the Stanley Thomas Johnson Foundation.

Current address for M.-C.B.G.: Swiss Institute of Bioinformatics, University Medical Center, Medical Faculty, Geneva, Switzerland.

First Published Online February 1, 2005

Abbreviations: apo, Apolipoprotein; CAD, coronary artery disease; CAD–ve, CAD-negative; CAD+ve, CAD-positive; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MS–ve, metabolic syndrome negative; MS+ve, metabolic syndrome positive; PON1, paraoxonase-1; RF, risk factor; RF–ve, RF negative; RF+, RF positive.

Received July 5, 2004.

Accepted January 24, 2005.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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