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European Heart Journal Advance Access originally published online on January 24, 2006
European Heart Journal 2006 27(7):817-823; doi:10.1093/eurheartj/ehi746
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Elevated levels of remnant lipoproteins are associated with plasma platelet microparticles in patients with type-2 diabetes mellitus without obstructive coronary artery disease

Hidenobu Koga1, Seigo Sugiyama1,*, Kiyotaka Kugiyama2, Hironobu Fukushima1, Keisuke Watanabe1, Tomohiro Sakamoto1, Michihiro Yoshimura1, Hideaki Jinnouchi3 and Hisao Ogawa1

1Department of Cardiovascular Medicine, Graduate School of Medical Sciences Kumamoto University, 1-1-1 Honjo, Kumamoto City, Kumamoto 860-8556, Japan
2Second Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan
3Department of Internal Medicine, Jinnouchi Clinic, Kumamoto, Japan

Received 4 January 2005; revised 21 October 2005; accepted 5 January 2006; online publish-ahead-of-print 24 January 2006.

* Corresponding author. Tel: +81 96 373 5175; fax: +81 96 362 3256. E-mail address: ssugiyam{at}kumamoto-u.ac.jp


   Abstract
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 Abstract
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Aims Platelets participate in the pathogenesis of arterial thrombosis and it has been demonstrated that enhanced platelet activation occurs in patients with diabetes mellitus (DM). Dyslipidaemia is a common feature of diabetes. We investigated the association between certain lipid fractions and plasma platelet-derived microparticle (PMP) levels in patients with type-2 DM.

Methods and results We measured fasting serum levels of remnant-like lipoprotein particles-cholesterol (RLP-cholesterol) and assessed in vivo platelet activation by quantifying the number of PMP in the plasma detected as CD42b-positive microparticles by flow cytometry in Japanese type-2 DM patients without obstructive coronary artery disease who were more slender when compared with Western diabetic patients. The levels of total cholesterol, triglycerides, RLP-cholesterol, and plasma glucose were significantly higher in patients with type-2 DM (n=105) than in non-diabetic patients (n=92). The plasma levels of PMP were elevated significantly in type-2 DM patients when compared with non-diabetic control subjects [7.41(5.39–10.50)x106 vs. 3.44(2.43–4.41)x106, P<0.001]. We found that RLP-cholesterol levels were the best predictor of PMP in multivariable linear regression analyses (ß=0.375, P<0.001). Lipid-lowering medication with bezafibrate successfully reduced levels of both RLP-cholesterol and PMP in patients with type-2 DM (P<0.05).

Conclusions RLP-cholesterol and platelet microparticles are both elevated in type-2 DM patients when compared with controls. RLP-cholesterol is the primary and only predictor of platelet microparticles in the multivariable analysis, which include several standard atherosclerosis risk factors. This suggested that reducing elevated RLP-cholesterol with lipid-lowering therapy may be an effective strategy to prevent thrombogenic vascular complications in type-2 DM.

Key Words: Remnant lipoprotein • Diabetes mellitus • Platelet-derived microparticles

Type-2 diabetes mellitus (DM) is associated with frequent atherothrombogenic complications and patients with the disorder have a two- to four-fold increased risk of developing coronary artery disease (CAD) compared with normal subjects. In fact, the risk of a coronary event is as high in diabetic patients without a previous myocardial infarction (MI) as it is in non-diabetic patients with a previous MI.1 Therefore, primary prevention of cardiovascular events in diabetic patients without previous CAD is very important.2 Dyslipidaemia is a common feature of diabetes and is known to increase the mortality of patients with diabetes and CAD.3 Several large clinical trials have demonstrated the benefit of lipid-lowering therapy in patients with DM, as in all these trials, a reduction in LDL-cholesterol levels was associated with a decrease in the prevalence of cardiovascular events.2,4,5

Serum levels of remnant-like lipoproteins cholesterol (RPL-cholesterol) are increased in patients with DM.6,7 Using an immunoseparation method for measuring RLP-cholesterol, recent clinical studies have demonstrated that these particles are closely associated with atherosclerosis.6,8–10 We have also shown that there is a relationship between RLP-cholesterol and coronary instability in patients with CAD,10 and also with increased gene expression of atherothrombogenic molecules.11

Activated platelets participate in the pathogenesis of arterial thrombosis12–14 and atherosclerosis.15 It is well documented that patients with DM have enhanced platelet activation,14 and platelet activation is associated with increased thrombogenic vascular complications in these patients. Several in vitro studies have shown that triglyceride-rich very-low density lipoprotein (VLDL) causes platelet activation by binding to the CD36 receptor on platelets,16 and RPL fraction may also directly activate human platelets.17–19 However, the involvement of lipid fractions in the enhanced thrombogenicity in patients with DM remains uncertain.

Previous reports have defined circulating platelet microparticles (PMPs) as particles <1.5 µm in diameter that are released from platelets into the extra-cellular space in response to platelet activation.20 Several studies have shown that PMPs assessed by flow cytometry is a useful marker for evaluating platelet activation.20–22

In this study, we measured serum levels of lipid parameters including RLP-cholesterol and plasma levels of PMPs in order to test the hypothesis that RLP-cholesterol may contribute to platelet activation in diabetic patients without CAD.

Methods
Clinical study population
This study involved consecutive enrolment of Japanese patients who had angina-like chest symptoms or ECG abnormalities who underwent elective and diagnostic cardiac catheterization in Kumamoto University Hospital. On the basis of the coronary angiographical evaluations, we enrolled 236 patients without obstructive CAD (≤10% stenosis in coronary arteries) or peripheral artery disease (ankle brachial pressure index ≥1.0) to undergo initial assessments for inclusion into the study. Thirty-nine patients with unstable conditions such as severe valvular diseases,5 acute infection,2 untreated malignant disease,1 active autoimmune disease,1 and severe congestive heart failure,7 or those taking any lipid-lowering medications,11 or anti-platelet drugs12 were excluded after the initial assessments for study. We finally enrolled 197 patients without obstructive CAD in the study and then separated this population into two groups; a type-2 diabetes group (n=105) and a non-diabetic group as control (n=92). Type-2 DM was diagnosed using WHO criteria. Informed consent was obtained from all patients prior to the study and this study was carried out in accordance with the guidelines approved by the Ethics Committee at our institution.

Measurement of lipoproteins and other biochemical parameters
Measurement of all the parameters with the exception of RLP-cholesterol was carried out at our hospital laboratory. RLP-cholesterol was measured as described in our earlier report.10 The arbitrary cut-off point defining high levels of RLP-cholesterol was set at 4.6 mg/dL, a value that corresponded to the median in patients with DM. We also measured plasma levels of plasminogen activator inhibitor-1 (PAI-1), fibrinogen, and homocysteine in patients with DM.

Measurement of circulating plasma levels of PMPs
Blood samples were drawn by venipuncture into vacutainer tubes containing sodium citrate after a 12-h overnight fast, prior to any mechanical intervention. The blood samples were assayed immediately after venipuncture. Platelet-rich plasma (PRP) was prepared by centrifuging whole blood at 160 g for 10 min. The PRP was then centrifuged at 6000 g for 1 min to obtain platelet-poor plasma (PPP). For the PMP assay, 50 µL of PPP in TruCount tubes (Becton Dickinson, NJ, USA) was incubated with CD42b-phycoerythrin (PE) (BD Pharmingen, San Diego, USA) for 30 min. Then, 1 mL of phosphate-buffered saline was added, and the samples were analysed using flow cytometry. PMPs were defined as elements with CD42b-positivity and a diameter <1.5 µm.21,23 The absolute number of PMPs were calculated as described previously.24 The arbitrary cut-off point that defined a high level of PMP was set at 7.26x106 counts/mL that corresponded to the 90th percentile of the PMP distribution in the control patients. The intra- and inter-assay variations for the PMP assay were 1.8±1.5% and 3.1±1.7% (mean±SD), respectively.

Bezafibrate treatment and follow-up study
DM patients with elevated levels of both RLP-cholesterol (>4.6 mg/dL) and PMPs (>7.26x106/mL) were recruited for a pharmacological intervention follow-up study. The 20 patients enrolled had not used any lipid-lowering drugs before entering the study. Informed consent was obtained from all the patients and they were then divided randomly into two groups, a control group not taking any lipid-lowering medications (n=10), and a group treated with bezafibrate at a dose of 400 mg per day for 6 weeks (bezafibrate group, n=10). The serum levels of lipid-parameters and plasma levels of PMPs were measured at baseline and after 6 weeks of treatment. As we were interested in the relative changes from baseline, we investigated whether the percentage change in PMPs had correlation with the percentage change in any lipid parameters.

Statistical analysis
The statistical analyses were performed with Stat View-V software (SAS Institute, NY, USA). The results of normal distributed data were expressed as mean±SE, whereas non-normally distributed data such as triglycerides, fasting plasma glucose, haemoglobin A1c (HbA1c), RLP-cholesterol, PAI-1, and PMP levels were expressed as median and inter-quartile range. The frequencies for gender, smoking, and hypertension were compared between the two groups using {chi}2 analysis. Comparisons between the two groups were carried out using the unpaired two-sided t-test for normally distributed variables (age, body mass index, total cholesterol, LDL-cholesterol, HDL-cholesterol, fibrinogen, and homocysteine) and the Mann–Whitney U test for non-normally distributed data (triglyceride, fasting plasma glucose, HbA1c, RLP-cholesterol, PAI-1, and PMPs). In order to reduce the experiment-wise type I error due to multiple testing, we performed multivariable linear regression analysis using only the covariates that showed more significant association (r>0.35, P<0.01) in the univariate linear regression analysis. The PMP data were logarithmically transformed (log-PMP) in order to obtain a normal distribution and were then analysed using linear regression analysis. A P-value <0.05 was considered as statistically significant.

Results
Elevated plasma levels of PMP in patients with DM
The clinical characteristics of the patients at baseline are summarized in Table 1. Fasting serum levels of total-cholesterol, triglyceride, RLP-cholesterol, plasma glucose, and HbA1c were significantly higher in patients with DM when compared with the non-DM controls. Patients with DM also had significantly lower HDL-cholesterol levels than the non-diabetic control group (Table 1). The levels of circulating PMPs were significantly higher in patients with DM (n=105) than in the non-diabetic controls (n=92) [7.41(5.39–10.50)x106 counts/mL vs. 3.44(2.43–4.41)x106 counts/mL, P<0.001, Figure 1A).


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  		Table 1 Clinical characteristics of the subjects in the study
 

Figure 7461
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  		Figure 1 (A) A box and whisker plot showing plasma PMP levels in patients with (n=105) and without DM (n=92). In this plot, lines within boxes represent median values, the upper and lower lines of the boxes represent the 25th and 75th percentiles, respectively, and the upper and lower bars outside the boxes represent the 90th and 10th percentiles, respectively. (B) A graph demonstrating the significant correlation between RLP-cholesterol and PMP levels in patients with DM (n=105) assessed using linear regression analysis.

 
Clinical characteristics of DM patients grouped according to RLP-cholesterol levels
The clinical and biochemical characteristics of the DM patients grouped according to high (>4.6 mg/dL) and low RLP-cholesterol levels are summarized in Table 2. The high RLP-cholesterol group had significantly increased levels of PMPs, body mass index, total-cholesterol, LDL-cholesterol, triglyceride, HbA1c, PAI-1, fibrinogen, and homocysteine compared with the group with low levels of RLP-cholesterol.


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  		Table 2 The clinical characteristics of the patients with DM grouped according to RLP-cholesterol levels
 
RLP-cholesterol is the most significant risk factor for elevated platelet microparticles in patients with DM
In the patients with DM, univariate linear regression analysis showed that there was a significant correlation between PMP levels and serum levels of RLP-cholesterol (r=0.465, P<0.001), total-cholesterol (r=0.376, P<0.001), LDL-cholesterol (r=0.370, P<0.001), homocysteine (r=0.273, P<0.03), PAI-1 (r=0.261, P<0.04), and HbA1c (r=0.251, P=0.01). However, HDL-cholesterol did not have correlation with PMP levels (Table 3). In the multivariable linear regression analysis, risk factors were found to have striking significance (r>0.35, P<0.01) with the univariate analysis. RLP-cholesterol was one of the risk factors that showed a significant association with elevated levels of PMPs as a marker of platelet activation in patients with DM (ß=0.375, P<0.001, Table 3).


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  		Table 3 Analyses between biochemical parameters and platelet microparticles in patients with DM
 
The effect of bezafibrate treatment on serum levels of RLP-cholesterol and plasma levels of PMP
Although there was no difference in lipid parameters and PMP levels between the two groups of DM patients at baseline, the levels of RLP-cholesterol, PMP, and triglyceride were decreased significantly in the bezafibrate group at the end of follow-up when compared with the control group. Moreover, levels of triglyceride (33%), RLP-cholesterol (45%), and PMP (53%) were significantly decreased and HDL-cholesterol levels (12%) were significantly increased in the bezafibrate group when compared with the control group (Table 4). Figure 2 shows the relationship between the percentage changes from baseline to follow-up in plasma PMP levels and RLP-cholesterol, triglyceride, total-cholesterol, and LDL-cholesterol. The percentage change in RLP-cholesterol correlated significantly with the percentage change in PMPs (r=0.561, P=0.01), whereas there was no significant relationship between the percentage change in PMPs and the percentage change in triglyceride (r=0.258, P=0.2), total-cholesterol (r=0.135, P=0.6), or LDL-cholesterol (r=0.231, P=0.3).


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  		Table 4 Baseline and follow-up data of the patients with DM in the intervention study
 

Figure 7462
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  		Figure 2 Relationship between the percentage changes from baseline to follow-up in plasma PMP levels and RLP-cholesterol (A), triglyceride (B), total-cholesterol (C), and LDL-cholesterol (D). The percentage change in RLP-cholesterol correlated significantly with the percentage change in PMPs. In contrast, there was no correlation between the percentage changes in plasma PMP levels and either triglyceride, total-cholesterol, or LDL-cholesterol.

 
Discussion
This study demonstrated that patients with type-2 DM without CAD have enhanced platelet activation, assessed by quantifying the number of PMPs in the plasma. Furthermore, we observed that among traditional cardiovascular risk factors and various lipid parameters, a high level of RLP-cholesterol was the only significant determinant of platelet activation, whereas pharmacological intervention with bezafibrate to decrease serum RLP-cholesterol resulted in successful reduction of PMP levels in patients with DM. Taken together, these findings indicate that remnant lipoproteinaemia may contribute partly to platelet-activation in patients with DM without obstructive CAD, and that RLP-cholesterol may therefore be a therapeutic lipid target with the potential to decrease enhanced thrombogenicity and also to prevent cardiovascular events in patients with DM.

It is well established that patients with type-2 DM develop more atherothrombogenic complications when compared with non-diabetic patients.1 Several clinical trials have indicated that lipid-lowering therapies have an important role in the primary prevention of cardiovascular events in diabetes patients.2,4,5 Although the possible involvement of specific lipid-fractions in these thrombogenic complications remains unclear, there is evidence that serum levels of RLP-cholesterol are elevated in patients with DM and CAD and that this lipoprotein fraction predicts future coronary events.6,7 These findings indicate that RLP-cholesterol may play a crucial role in the pathogenesis of vascular thrombogenic events in these patients and there are several lines of evidence showing the atherogenic nature of RPL.6,8,9

In the present study, we assessed activation of platelets by measuring the number of CD42b-positive PMPs in the plasma using flow cytometry. CD42b is a 170 kDa two-chain membrane glycoprotein GPIb found only on platelets and megakaryocytes.25 Previous reports have defined circulating PMPs as particles <1.5 µm in diameter that are released from platelets into the extra-cellular space in response to platelet activation.20 Elevated levels of PMPs in the plasma have been associated with acute coronary syndrome, DM, and hypertension.21,22,26 Given that platelet activation is associated with thrombus formation,12,14 PMPs may therefore represent a new clinical marker for evaluating the degree of platelet activation.20 Furthermore, PMPs play an important role in clinical diseases as they contain phospholipids and membrane proteins that have procoagulant potential and are involved in inflammatory processes.27 Therefore, PMPs may not only be a marker of platelet activation but also a pathophysiological mediator leading to atherothrombosis.

We have shown in patients with DM that serum levels of RLP-cholesterol are associated closely with PMPs as a new marker of platelet activation. We therefore consider that high RLP-cholesterol may be linked, in part, to the initiation and progression of atherogenesis and thrombogenesis as a result of its ability to induce platelet activation in patients with type-2 DM without obstructive CAD. Although the mechanism leading to this activation is yet to be established, it has been demonstrated that RLP-cholesterol increases intracellular oxidative stress thereby causing impairment of in vitro endothelial-dependent vasorelaxation,11,28 whereas other studies have shown that oxidative stress and reduction of nitric oxide (NO) induces platelet activation.29–31 Furthermore, Englyst et al.16 showed that CD36 is a receptor/transporter that binds the fatty acids of VLDL to platelets and enhances in vitro production of platelet thromboxane A2. These findings therefore indicate that raised levels of RLP-cholesterol in diabetes may potentially contribute to platelet activation by increasing oxidative stress, reducing NO bioavailability, and binding lipoprotein fatty acid to the CD36 receptor. Moreover, RLP-cholesterol also directly activate human platelets.17–19 However, the molecular mechanisms involved in the activation of platelets by RLP-cholesterol require further investigation.

Type-2 DM patients with higher RLP-cholesterol levels had a significantly higher BMI and HbA1c levels in the present study
Several studies have reported that weight loss in obese women and metabolic control by intensive insulin treatment reduced in vivo platelet activation and triglyceride levels.32–35 Thus, better glycaemic control or of weight loss might have good effects on RLP-cholesterol and PMP levels. Tenenbaum et al.36 reported that bezafibrate reduces the incidence of myocardial infarction in patients with metabolic syndrome In the present study, a decrease in RPL by treatment with bezafibrate successfully reduced plasma PMP levels (Table 4 and Figure 2). We therefore propose that monitoring changes in plasma PMP and serum RLP-cholesterol levels may be useful for evaluating thrombogenic disease activity in DM patients with the aim of preventing cardiovascular complications.

This study had several limitations, the first being the small size of the patient groups. The second limitation was that Japanese diabetic patients generally have a more slender body shape when compared with Western diabetes patients. However, regardless of ethnicity it is well established that diabetes patients have an increased prevalence of cardiovascular diseases and thrombogenic complications than non-diabetic patients, indicating that the presence of DM is of primary importance in the development of these vascular disorders. We consider our results are therefore also applicable to Western DM patients who may even have a higher risk of atherothrombosis because of elevated levels of RLP-cholesterol in combination with increased BMI. The third limitation was the suppression of cardiovascular events in patients with DM treated by bezafibrate could not be verified because of the short duration of follow-up. A longitudinal prospective study of platelet activity assessed by measuring PMP levels in a large number of patients is therefore required.

In summary, our results demonstrate that platelets are activated in patients with type-2 DM without CAD and that an elevated level of RLP-cholesterol is one of the risk factors with a significant relationship with this enhanced platelet activation. Furthermore, a reduction in RLP-cholesterol by bezafibrate treatment was associated with a decrease in platelet activation. These findings imply that platelet activation induced by increased RLP-cholesterol levels may play an important role in vascular thrombogenic complications in patients with type-2 DM. Treatment of remnant lipoproteinaemia therefore has the potential not only to improve the disorder of lipoprotein metabolism but also to suppress the enhanced thrombogenicity that occurs in patients with type-2 DM.

Acknowledgements
This study was supported in part by grants-in-aid C(2)-17590753 from the Ministry of Education, Science, and Culture, Tokyo; 14C-4 and 1116004 from the Ministry of Health, Labour, and Welfare, Tokyo; The Naito Foundation; Mochida Memorial Foundation for Medical and Pharmaceutical Research; and the Suzuken Memorial Foundation, Tokyo, Smoking Research Foundation, Tokyo, Japan Heart Foundation.

Conflict of interest: none declared.


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E. Herczenik, B. Bouma, S. J.A. Korporaal, R. Strangi, Q. Zeng, P. Gros, M. Van Eck, T. J.C. Van Berkel, M. F.B.G. Gebbink, and J.-W. N. Akkerman
Activation of Human Platelets by Misfolded Proteins
Arterioscler. Thromb. Vasc. Biol., July 1, 2007; 27(7): 1657 - 1665.
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 HypertensionHome page
C. M. Boulanger, N. Amabile, and A. Tedgui
Circulating Microparticles: A Potential Prognostic Marker for Atherosclerotic Vascular Disease
Hypertension, August 1, 2006; 48(2): 180 - 186.
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