Summary
Background and purpose
Mean platelet volume (MPV), an indicator of platelet activation, has been shown to be elevated in patients with coronary artery disease (CAD) in some studies. Insulin resistance contributes to increased platelet activation and it is one of the risk factors for CAD. The aim of this study was to assess the relationship between insulin resistance and MPV in non-obese, non-diabetic patients with CAD.
Methods and subjects
Seventy-seven non-obese, non-diabetic CAD patients were divided into two groups, insulin resistant and insulin sensitive according to the homeostasis model assessment insulin resistance index (HOMA-IR). The insulin-resistant group was composed of 45 patients (30 males/15 females; mean age 59.8 ± 11.1 years). The insulin-sensitive group was composed of 32 patients (17 males/15 females; mean age 58.9 ± 12.2 years).
Results
Insulin and HOMA-IR values were significantly higher in insulin-resistant CAD patients than in insulin-sensitive CAD patients. The MPV values were significantly higher in insulin-resistant CAD patients than in insulin-sensitive CAD patients (8.6 ± 1.0 fl vs. 8.0 ± 0.7 fl; respectively, p = 0.01). The MPV was poorly correlated with HOMA-IR (r = 0.30, p = 0.054) and insulin (r = 0.22, p = 0.053).
Conclusions
We have shown that MPV was significantly elevated in insulin-resistant non-obese, non-diabetic CAD patients when compared to insulin-sensitive non-obese, non-diabetic CAD patients.
Keywords
Introduction
Insulin resistance is established to be one of the risk factors for coronary artery disease (CAD) [
[1]
]. Insulin resistance underlies the metabolic syndrome that includes central obesity, dyslipidemia, hyperglycemia, hypertension, impaired fibrinolysis, and atherosclerosis [1
, 2
].Recent studies showed that insulin resistance contributes to increased platelet activation in obesity [
3
, 4
, 5
].Mean platelet volume (MPV), an indicator of platelet activation has an important role in the pathophysiology of cardiovascular diseases [
6
, 7
]. MPV is an important biological variable and larger platelets have higher thrombotic potential [[8]
]. In comparison to smaller ones, larger platelets have more granules, aggregate more rapidly with collagen, have higher thromboxane A2 levels, and express more glycoprotein Ib and IIb/IIIa receptors [9
, 10
, 11
].Elevations of MPV values have been shown in patients with CAD [
12
, 13
]. Elevations of MPV values have also been shown in conditions that are closely related to insulin resistance such as metabolic syndrome, obesity, impaired fasting glucose, diabetes mellitus, and hypertension [14
, 15
, 16
, 17
]. These conditions are also risk factors for CAD. To the best of our knowledge, no study has investigated specifically the direct relationship between insulin resistance and MPV in patients with CAD. Accordingly, the aim of our study was to evaluate the relationship between insulin resistance and MPV in patients with CAD. Diabetes mellitus and obesity cause an increase in platelet size [14
, 15
, 16
]. To overcome this difficulty, we performed this study in non-obese, non-diabetic CAD patients.Patients and methods
We studied 77 consecutive non-obese, non-diabetic patients (47 males/30 females; mean age 59.4 ± 11.5 years) with CAD. All patients underwent coronary angiography. The indication for coronary angiography was either the presence of typical angina or positive or equivocal results of noninvasive screening tests for myocardial ischemia in both of the groups. Patients were divided into two groups, insulin resistant and insulin sensitive according to the homeostasis model assessment insulin resistance index (HOMA-IR). The insulin-resistant group was composed of 45 patients (30 males/15 females; mean age 59.8 ± 11.1 years). The insulin-sensitive group was composed of 32 patients (17 males/15 females; mean age 58.9 ± 12.2 years). Hypertension was considered to be present if the systolic pressure was >140 mm Hg and/or diastolic pressure was >90 mm Hg, or if the individual was taking antihypertensive medications. Diabetes mellitus was defined as plasma fasting glucose ≥126 mg/dl and/or the current use of diabetes medication. Obesity was defined as body mass index ≥30 kg/m2. Patients who were smoking before hospitalization were classified as smokers. Exclusion criteria were prior to myocardial infarction, valvular heart disease, heart failure, diabetes mellitus, peripheral vascular disease, renal and hepatic dysfunction, hematological disorders, history of malignancy, acute or chronic infection, and stroke. All patients gave informed consent and the study was approved by the institutional ethics committee.
Coronary angiography
Coronary angiography was routinely performed without the use of nitroglycerin. Selective coronary angiography was performed by means of the Judkins technique in multiple projections. We used iohexol (Omnipaque, GE Healthcare, Princeton, NJ, USA) as contrast agent during coronary angiography in all patients and control subjects. Coronary angiograms were analyzed by two blinded interventional cardiologists without knowledge of the clinical status and laboratory measurements of the subjects. CAD was defined as >50% stenosis in major epicardial vessels.
Biochemical measurements
Blood samples were drawn from the antecubital vein by careful vein puncture in a 21 G sterile syringe without stasis at 08:00–10:00 a.m. after a fasting period of 12 h. Glucose, creatinine, lipid profiles, and insulin levels were determined by standard methods. MPV was measured in a blood sample collected in dipotassium EDTA tubes within 30 min to prevent EDTA-induced swelling. An automatic blood counter (Beckman Coulter, Fullerton, CA, USA) was used for whole blood counts. The estimate of insulin resistance by homeostasis model assessment (HOMA-IR) was calculated with the formula: fasting serum insulin (mIU/l) × fasting plasma glucose (mmol/l)/22.5 [
[18]
]. Insulin resistance (HOMA-IR) was defined as an index >2.245, a cut-off that represented the 70th percentile in non-diabetic adults in the Turkish Adult Risk Factor Study [[19]
].Statistical analysis
Data were analyzed with the SPSS software version 10.0 for Windows (SPSS Inc., Chicago, IL, USA). Continuous variables from the study groups were reported as mean ± standard deviation, categorical variables as percentages. To compare continuous variables, the Student's t-test or Mann–Whitney U-test were used where appropriate. Categorical variables were compared with the chi-squared test. Statistical significance was defined as p < 0.05. Pearson correlation analysis was used to assess the association between MPV and HOMA-IR, insulin, and other laboratory parameters.
Results
The clinical and laboratory characteristics of the insulin-resistant and insulin-sensitive patients with CAD are presented in Table 1. There were no statistically significant differences between the two groups with respect to age, gender, smoking habit, levels of glucose, creatinine, total cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol, or high-density lipoprotein (HDL) cholesterol. Insulin and HOMA-IR values were significantly higher in insulin-resistant CAD patients than in insulin-sensitive CAD patients. The hematological parameters of the insulin-resistant and insulin-sensitive patients with CAD are shown in Table 2. There were no statistically significant differences between the two groups with respect to levels of white blood cells (WBC) and hemoglobin. The MPV values were significantly higher in insulin-resistant CAD patients than in insulin-sensitive CAD patients (8.6 ± 1.0 fl vs. 8.0 ± 0.7 fl; respectively, p = 0.01). The platelet count was significantly lower in insulin-resistant CAD patients than in insulin-sensitive CAD patients (226.7 ± 60.0 vs. 260.9 ± 63.3; respectively, p = 0.02). The MPV was poorly correlated with HOMA-IR (r = 0.30, p = 0.054) and insulin (r = 0.22, p = 0.053).
Table 1Comparison of the clinical and laboratory characteristics of the insulin-resistant and insulin-sensitive patients with coronary artery disease.
| Insulin resistant (n = 45) | Insulin sensitive (n = 32) | p-Value | |
|---|---|---|---|
| Age (years) | 59.8 ± 11.1 | 58.9 ± 12.2 | 0.74 |
| Sex (M/F) | 30/15 | 17/15 | 0.24 |
| BMI (kg/m2) | 27.2 ± 3.8 | 25.9 ± 2.8 | 0.10 |
| SBP (mmHg | 120.7 ± 12.5 | 116.4 ± 11.7 | 0.16 |
| DBP (mmHg) | 76.2 ± 8.3 | 73.8 ± 8.2 | 0.20 |
| Smoking (%) | 9 (28%) | 17 (37%) | 0.46 |
| HOMA-IR | 3.8 ± 1.3 | 1.3 ± 0.4 | <0.001 |
| Insulin (mIU/l) | 9.0 ± 2.9 | 3.3 ± 1.1 | <0.001 |
| Glucose (mg/dl) | 95.1 ± 5.3 | 92.7 ± 6.2 | 0.07 |
| Creatinine (mg/dl) | 1.0 ± 0.2 | 0.9 ± 0.2 | 0.14 |
| Total cholesterol (mg/dl) | 186.8 ± 46.5 | 198.5 ± 62.7 | 0.34 |
| Triglycerides (mg/dl) | 173.5 ± 81.7 | 150.5 ± 74.1 | 0.21 |
| LDL-cholesterol (mg/dl) | 108.0 ± 39.2 | 122.4 ± 56.80.19 | |
| HDL-cholesterol (mg/dl) | 44.0 ± 8.8 | 46.7 ± 13.1 | 0.29 |
| Medications | |||
| Beta blockers | 16 (35%) | 12 (37%) | 0.86 |
| ACE inhibitors | 12 (26%) | 7 (22%) | 0.63 |
| Ca channel blockers | 11 (24%) | 8 (25%) | 0.95 |
| ASA | 41 (91%) | 28 (87%) | 0.60 |
| Statin | 30 (66%) | 20 (62%) | 0.70 |
M/F, male/female; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; HOMA-IR, homeostasis model assessment insulin resistance index; LDL, low-density lipoprotein; HDL, high-density lipoprotein; ACE, angiotensin-converting enzyme; ASA, aspirin; p-value is for comparison between control and study population.
Table 2Comparison of the hematological parameters of the insulin-resistant and insulin-sensitive patients with coronary artery disease.
| Insulin resistant (n = 45) | Insulin sensitive (n = 32) | p-Value | |
|---|---|---|---|
| WBC (×103 mg/dl) | 7.7 ± 2.2 | 7.6 ± 2.9 | 0.78 |
| Hemoglobin (g/dl) | 14.8 ± 1.2 | 14.3 ± 1.3 | 0.09 |
| Platelet count (×109) | 226.7 ± 60.0 | 260.9 ± 63.3 | 0.02 |
| MPV (fl) | 8.6 ± 1.0 | 8.0 ± 0.7 | 0.01 |
WBC, white blood cell; MPV, mean platelet volume. p-Value is for comparison between control and study population.
Discussion
In the present study, we investigated the relationship between insulin resistance and MPV in non-obese, non-diabetic patients with CAD. We found that MPV, an indicator of platelet activation was higher in insulin-resistant CAD patients than in insulin-sensitive CAD patients.
It is known that increased platelet activation and aggregation are closely related to cardiovascular complications [
[7]
]. The determination of platelet size, usually via quantification of MPV, is a simple and easy method of accurately assessing platelet function. Platelets are heterogeneous in size, density, and reactivity. Larger platelets have a greater mass and are both metabolically and enzymatically more active than smaller platelets. In comparison to smaller ones, larger platelets have more granules, aggregate more rapidly with collagen, have higher thromboxane A2 levels, and express more glycoprotein Ib and IIb/IIIa receptors [9
, 10
, 11
].It has been reported that elevated values of MPV were associated with cardiovascular diseases [
12
, 13
]. However, the association of MPV with insulin resistance, which has been accepted as one of the risk factors for CAD, has gained little attention. Tavil et al. showed that patients with metabolic syndrome had higher MPV compared to control subjects with normal coronary angiograms. To evaluate the severity of coronary artery disease, they subdivided the patients with metabolic syndrome depending upon the coexistence of CAD: normal coronary arteries (group 1); having coronary stenotic lesions of <50% (group 2); and having coronary stenotic lesions of >50% (group 3). There was no statistically significant difference in MPV values among the groups with respect to CAD severity. They also found that metabolic syndrome patients with CAD had higher MPV compared to metabolic syndrome patients without CAD [[13]
]. However, they did not measure insulin resistance in patients with metabolic syndrome and its association with MPV and CAD. In our study we investigated the direct relationship between insulin resistance and MPV in patients with CAD. Muscari et al. reported that, in an unselected population of elderly subjects, percent body fat, blood glucose, and ischemic electrocardiographic changes were found to be the main determinants of MPV, and MPV tended to be higher in subjects with higher HOMA index (p = 0.09) [[20]
]. However, they did not perform coronary angiography in study patients especially in those having ischemic electrocardiographic changes. We selected all patients from individuals who underwent coronary angiography with suspicion of CAD. In an another study about the relationship between MPV and insulin resistance, Yazici et al. found significantly higher baseline MPV values in prehypertension subjects than in those with an optimal blood pressure and they found that MPV showed a modestly positive correlation with the insulin resistance index using HOMA in prehypertension subjects [[21]
]. Additionally, MPV values were significantly higher in patients with insulin resistance than in patients without insulin resistance in this study. After lifestyle modification, MPV and HOMA-IR values were significantly reduced in the prehypertension group. They suggested that reduction of insulin resistance may play a modest role in the decrease in MPV in this specific group of patients.A few studies have demonstrated a strong association between insulin resistance measured directly and CAD [
2
, 22
, 23
, 24
, 25
]. On the other hand, hyperinsulinemia has also been related to CAD [26
, 27
]. Insulin is associated with a functional change in platelets that promotes thrombosis [[5]
]. Human platelets have insulin receptors that participate in the regulation of platelet functions [[28]
]. In vitro and in vivo studies have demonstrated that insulin inhibits platelet aggregation and activation in insulin-sensitive subjects [5
, 29
]. In conditions of insulin resistance, a reduction in platelet sensitivity to the antiaggregating effects of insulin has been reported [5
, 29
, 30
].One of the other possible mechanisms is the increased platelet reactivity due to the direct effect of hyperglycemia via osmotic effects on platelets [
[31]
]. Another mechanism potentially contributing to increased platelet reactivity is vascular dysfunction. Decreased vascular endothelial production of prostacyclin and nitric oxide in patients with insulin resistance promotes increased activation of platelets [[32]
].Insulin resistance, diabetes mellitus, and other risk factors associated with endothelial dysfunction might trigger the series of cytokine production [
[32]
]. The cytokines produced by adipose tissue and the dysfunctioning endothelium may stimulate the production of large platelets in the bone marrow [[33]
]. Platelet size is regulated at the level of the megakaryocyte. Researchers have reported that cytokines such as interleukin-3 or interleukin-6 influence megakaryocyte ploidy and can lead to the production of more reactive and larger platelets [34
, 35
, 36
].Recently, Deveci et al. showed that insulin resistance is present in normoglycemic patients with CAD and HOMA-IR may be a more sensitive method than the definitions of metabolic syndrome for the evaluation of the relationship between insulin resistance and CAD in normoglycemic patients [
[37]
]. Our study population was also composed of non-obese, normoglycemic patients with CAD and we assessed the relationship between MPV and insulin resistance in this group of patients. We speculated that there might be close relationship between insulin resistance and MPV, an indicator of platelet activation, in patients with non-obese, non-diabetic patients with CAD.The small number of patients was the first limitation of the study. The second limitation of this study was that analysis was based on a simple baseline determination that may not reflect the patient status over long periods. As a third limitation, although we selected normoglycemic patients and excluded diabetes mellitus, we did not perform oral glucose tolerance test to exclude impaired glucose tolerance.
Conclusion
In this study, we have shown that MPV was significantly higher in insulin-resistant CAD patients than insulin-sensitive CAD patients. To overcome insulin resistance in CAD, patients could decrease the platelet activation and consequently morbidity and mortality. Further prospective studies are mandatory to establish the relationship between insulin resistance and platelet volume in CAD patients.
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Article info
Publication history
Accepted:
March 26,
2010
Received in revised form:
March 21,
2010
Received:
February 1,
2010
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© 2010 Japanese College of Cardiology. Published by Elsevier Inc.
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