Hypertensive patients with carotid artery plaque exhibit increased platelet aggregability

Thrombosis Research (2006) 117, 615 — 622

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Hypertensive patients with carotid artery plaque exhibit increased platelet aggregability Yuichi Fusegawa a,*, Hiromi Hashizume a, Toshiaki Okumura a, Yoshiaki Deguchi b, Yutaka Shina b, Yuji Ikari b, Teruhisa Tanabe b a

Atherosclerosis Prevention Center, Sagamidai Hospital, 6-24-28, Sagamigaoka, Zama, Kanagawa, Japan Division of Cardiology, Department of Internal Medicine, School of Medicine, Tokai University, Bohseidai, Isehara Kanagawa, Japan

b

Received 6 December 2004; received in revised form 18 April 2005; accepted 8 May 2005 Available online 1 July 2005

KEYWORDS Platelet aggregation; Carotid artery plaque; Hypertension

Abstract Background: Platelets play an important role in myocardial infarction and ischemic stroke events, but whether platelet aggregability is related to early stage arteriosclerosis remains unclear. Methods: We used a novel platelet counting system which makes it possible to detect spontaneous platelet aggregation, to evaluate the relationship between platelet aggregability and carotid artery arteriosclerosis in 125 outpatients with primary hypertension (46—73 years old: 65 men, 60 women). All subjects underwent carotid artery ultrasonography to determine whether plaque was present and to estimate intima-media thickness. Results: Patients with carotid artery plaques (Plaque(+), n = 63) were older and had higher systolic blood pressures than patients without plaques (Plaque( ), n = 62), but no significant differences in sex, body mass index, diastolic blood pressure, plasma concentrations of glucose, total cholesterol, triglyceride, lipoprotein cholesterol, fibrinogen or the platelet count in whole blood were observed between Plaque(+) and Plaque( ) groups. Plaque(+) subjects showed greater spontaneous platelet aggregability and platelet aggregation induced by 2 AM or 0.5 AM of ADP or 0.3 AM of epinephrine than the Plaque( ) group. When age and systolic blood pressure were matched (n = 52 in both groups), the Plaque(+) subjects exhibited greater platelet aggregability than the Plaque( ) subjects. Platelet aggregation induced by 2 AM of ADP showed statistical significant positive correlation coefficients with age, HbA1c and diastolic blood pressure.

* Corresponding author. Tel.: +81 463 93 1121; fax: +81 463 93 6679. E-mail address: [email protected] (Y. Fusegawa). 0049-3848/$ - see front matter D 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2005.05.011

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Y. Fusegawa et al. Conclusion: Our results indicate that hypertensive patients with carotid artery plaque have increased platelet aggregability. A prospective study is recommended to clarify whether this increase in platelet aggregability promotes the progression of arteriosclerosis. D 2005 Elsevier Ltd. All rights reserved.

Introduction Platelets are known to play an important role in acute coronary syndrome and cerebrovascular events. Some studies have indicated that enhanced platelet aggregability might accelerate the atherogenic events in patients with ischemic heart disease [1—3]. However, it is still unclear whether platelet aggregability is related to the early stage of atherosclerosis before any occurrence of acute coronary syndrome or cerebrovascular events. Hypertension is a major risk factor for arteriosclerosis, and high blood pressure has been shown to be associated with increased platelet aggregability [4,5]. In subjects with carotid artery atherosclerosis, pro-thrombotic states characterised by increased concentrations of platelet factor 4, beta thromboglobulin and von Willebrand factor have been reported [6]. These studies indicated that subjects with carotid artery atherosclerosis might have enhanced platelet aggregability. However, a previous study showed no significant association between carotid artery atherosclerosis and platelet aggregation as detected using a method using a light transmission based method [7]. Spontaneous platelet aggregation and small platelet aggregates detected using a novel laser light scattering method are useful indicators for the study of arteriosclerosis and thrombogenic disease. This method has in fact been broadly used in clinical studies and has clarified the relationship between platelet aggregation and atherogenic disease [8—12]. We retrospectively investigated the relationship between platelet aggregability, measured using the laser light scattering method [13], and carotid artery arteriosclerosis, evaluated using ultrasonography in hypertensive patients without coronary heart disease or stroke.

the World Health Organization/International Society of hypertension definitions for Hypertension (systolic and diastolic blood pressure N 140 mm Hg and N 90 mm Hg, respectively). Patients with ischemic heart disease or stroke diagnosed by clinical examination were excluded. Patients with more than 220 mg/dl of plasma total cholesterol were considered to have hypercholesterolemia, and those whose fasting blood glucose exceeded 125 mg/dl or whose HbA1c exceeded 6.5% were considered to have diabetes. Habitual smokers were excluded since smokers have been shown to have increased spontaneous platelet aggregability [14,15]. All subjects were treated with betablockers, calcium antagonists, angiotensin converting enzyme inhibitors or angiotensin receptor blockers. Some patients with hypercholesterolemia, diabetes or both were treated with statins, fibrate, sulfonylurea or alpha-glucosidase inhibitor. Patients treated with anti-platelet or anti-coagulant medications, and diabetic patients receiving subcutaneous insulin injections were excluded from the study. The Sagamidai Hospital Ethics Committees approved the study.

Assessment of carotid artery The extracranial (common, internal and external) carotid arteries were examined bilaterally in all patients using high-resolution B-mode and color Doppler/pulsed-wave Doppler ultrasonography (Sonos 5500, Philips, 5—10 MHz linear-array transducer) to evaluate the maximum intima-media thickness (IMT) and the presence of plaques. All plaques were defined as focal widenings of the vessel wall relative to the adjacent wall, that protruding into the lumen. Three ultrasonographers (B.K., Y.K. and T.M.) collected the retrospective data. All patients were classified according to Salonen et al.’s criteria [16].

Subjects and methods

Blood sampling

Subjects

Venous blood was collected after the subjects had fasted early in the morning and rested for 1 h. Blood was obtained using a 21-gauge needle and rapidly transferred to test tubes containing 3.13%

One hundred twenty-five patients with primary hypertension participated in this study. We used

Hypertensive patients with carotid artery plaque exhibit increased platelet aggregability sodium citrate (Sigma Co, St. Louis). The blood samples were centrifuged at 100g for 10 min to obtain platelet-rich plasma (PRP). The supernatant obtained after centrifugation at 900g for 10 min was used as platelet-poor plasma (PPP). PRP was diluted with PPP to adjust the platelet count to 200,000/Al.

Measurement of platelet aggregation Epinephrine (0.3 AM) and ADP (0.5 and 2.0 AM) (Sigma Co, St. Louis, U.S.A.)-induced platelet aggregation and spontaneous platelet aggregation without any chemical stimulants were measured by evaluating the maximum percent decrease in optical density, and by assessing the laser light scattering intensity using an AG10 system (KOWA, Tokyo, Japan). The details of this method were previously described by Ozaki et al. [13]. In short, a laser beam measuring 40 Am in diameter was generated using a 20-mW diode laser (675 nm, Toshiba, Japan), and passed through PRP (300 Al) stirred at 37 8C in a cylindrical glass cuvette with a 5 mm internal diameter. The light scattered from the observation volume (48  140  20 Am) was detected using a photocell array. The resulting light intensity corresponds to the particle size, with an intensity of 25—499 mV representing small aggregates (9—25 Am), 400—1000 mV representing medium aggregates (25—50 Am) and 1000—2048 mV representing large aggregates (50—70 Am). Data were recorded every 10 s. A quantitative estimation was performed by determining the area under the curve of the light scattering intensity. Optical density was simultaneously detected by measuring light transmission using the AG10 system [17]. The platelet counts in the whole blood and PRP samples were measured using a flow cytometer (Coulter AcT, Beckman, Miami, USA). The concentration of plasma fibrinogen was measured using a CA530 system (Sysmex, Tokyo, Japan) and the thrombin coagulating method. The plasma concentrations of glucose and lipoprotein cholesterol were measured using an AU1000 (Olympus, Tokyo, Japan), and the HbA1c was measured using an HA8150 (Arkray, Kyoto, Japan) with HPLC.

Statistical analysis Inter-group differences between the results were evaluated using an ANOVA, an unpaired Student’s ttest and a v 2 test. A p-value of b 0.05 was considered significant.

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Results In PRP from patients with enhanced platelet aggregability, the addition of 2 AM of ADP initially induced small platelet aggregates followed by medium and large aggregates; these aggregates persisted in patients with enhanced platelet aggregability. Blood from these patients also had a high optical density. On the other hand, PRP samples from patients with low platelet aggregability exhibited the transient formation of small, medium and large aggregates in response to the addition of ADP, but these aggregates immediately disappeared. Blood samples from these patients had a low optical density. Five patients exhibited more than 20% stenosis with plaques in their right, left or both carotid arteries (class 4 according to Salonen’s criteria), meanwhile, 58 patients had plaques without artery stenosis (class 3), 7 patients had an IMT of more than 1 mm of IMT but did not have any plaques (class 2) and 55 patients had an IMT of less than 1 mm of IMT (class 1). All patients were categorized according to the presence of carotid artery plaque (class 3 + 4, n = 63) or the absence of plaques (class 1 + 2, n = 62) for the statistical analyses. Patients with carotid artery plaques (Plaque(+)) were older and exhibited significantly higher systolic blood pressures than those without carotid artery plaques (Plaque( )). No significant differTable 1 Characteristics of patients with or without carotid artery plaques N Age (years) Sex (male %) BMI (kg/m2) Glucose (mg/dl) HbA1c (%) TC (mg/dl) TG (mg/dl) HDL (mg/dl) LDL (mg/dl) Fibrinogen (mg/dl) Platelets (1000/mm3) SBP (mm Hg) DBP (mm Hg)

Plaque( )

Plaque(+)

p-value

62 60.8 F 8.8 53 25.1 F 3.3 112 F 21.5 5.49 F 0.64 213 F 29.6 143 F 82.6 61.3 F 16.7 125 F 30.4 271 F 55.0 257 F 71.1 133 F 12.7 77.6 F 8.84

63 64.3 F 6.9 52 24.2 F 3.2 117 F 39.8 5.69 F 1.01 207 F 25.7 134 F 65.5 57.4 F 14.1 124 F 24.2 251 F 53.4 244 F 81.6 140 F 14.5 80.0 F 8.01

0.0127 n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. 0.0207 n.s.

Plaque(+); patients with carotid artery plaque, Plaque( ); patients without plaque, BMI; body mass index, TC: total cholesterol, TG: triglyceride, HDL: high density lipoprotein cholesterol, LDL: low density lipoprotein cholesterol, SBP: systolic blood pressure, DBP: diastolic blood pressure, Platelets: platelets counts in whole blood. All values represent the means F S.D. Inter-group differences between the results were evaluated using an unpaired Student’s t-test. A p-value of b0.05 was considered significant.

618

Y. Fusegawa et al.

Table 2 Comparison of platelet aggregation in patients with or without carotid artery plaque Plaque( ) Spontaneous aggregation Small aggregates 25.4 F 33.8 ( 105 counts)

Plaque(+)

p-value

66.6 F 118

0.0089

ADP 2 lM Small aggregates Medium aggregates Large aggregates Optical density (%)

338 F 146 106 F 90.7 57.7 F 88.4 39.8 F 16.1

385 F 188 179 F 97.2 147 F 144 51.8 F 18.4

n.s. b0.0001 b0.0001 0.0020

ADP 0.5 lM Small aggregates Medium aggregates Optical density

125 F 160 1.93 F 3.75 16.9 F 6.59

241 F 168 3.58 F 6.42 22.3 F 6.22

0.0001 n.s. b0.0001

Epinephrine 0.3 lM Small aggregates Medium aggregates Optical density

260 F 177 12.7 F 37.6 20.2 F 6.88

374 F 164 38.3 F 68.9 26.6 F 15.1

0.0004 0.0159 0.0046

Small, medium and large aggregates of platelets detected by laser light scattering are expressed as the area under the curve representing 60 determinations, and optical density is expressed as the maximum percent reduction in optical density. A p-value of b0.05 was considered significant.

ences in sex, body mass index, diastolic blood pressure, plasma concentrations of glucose, total cholesterol, triglyceride, high- and low-density lipoprotein cholesterol, fibrinogen, or the whole blood platelet counts were observed between the two groups (Table 1). In the spontaneous platelet aggregation experiments, more than twice as many small platelet aggregates formed in samples from Plaque(+) patients than in samples from Plaque( ) patients. Plaque(+) patients exhibited more medium to large aggregates and a higher optical density than

Plaque( ) subjects when 2 AM of ADP was used to induce platelet aggregation. More small and medium-sized aggregates were induced by 0.5 AM of ADP or 0.3 AM of epinephrine in the samples from Plaque(+) patients than in the samples from Plaque( ) subjects (Table 2). When platelet aggregability was compared in age and systolic blood pressure matched groups (n = 52 each in Plaque(+) and Plaque( )) (Table 3), the Plaque(+) patients exhibited more small aggregates in spontaneous aggregation, more medium and large aggregates and higher optical density induced by 2 AM of ADP, more small aggregates and higher optical density induced by 0.5 AM of ADP, and more small and medium aggregates and higher optical density induced by 0.3 AM of epinephrine than the Plaque( ) patients (Table 4). Pearson’s correlation coefficients for platelet aggregability and atherogenic factors were analyzed (Table 5). In blood samples where aggregation was induced by 2 AM of ADP, the formation of medium aggregates was positively correlated with age, the formation of large aggregates was positively correlated with diastolic blood pressure, and the optical density was positively correlated with HbA1c and diastolic blood pressure. Spontaneous platelet aggregation, and platelet aggregation induced by 0.5 AM of ADP or 0.3 AM of epinephrine were not significantly associated with any atherogenic factors. Patients with hypercholesterolemia and/or diabetes complications had significantly higher body mass indices, systolic blood pressures, fibrinogen concentrations, and IMT values, and a larger Table 4 Comparison of platelet aggregation in age and systolic blood pressure matched patients with or without carotid artery plaque Plaque( )

Table 3 Characteristics of age and systolic blood pressure matched patients with or without carotid artery plaques N Age (years) Sex (male %) BMI (kg/m2) Glucose (mg/dl) HbA1c (%) TC (mg/dl) TG (mg/dl) HDL (mg/dl) LDL (mg/dl) Fibrinogen (mg/dl) Platelets (1000/mm3) SBP (mm Hg) DBP (mm Hg)

Plaque( )

Plaque(+)

p-value

52 62.2 F 8.2 52 25.2 F 3.5 111 F 19.8 5.51 F 0.66 213 F 30.7 142 F 83.1 63.1 F 16.2 123 F 30.6 277 F 57.6 257 F 71.1 137 F 11.2 79.0 F 8.82

52 62.6 F 6.3 57 24.4 F 3.1 113 F 30.3 5.53 F 0.84 208 F 25.8 138 F 69.6 57.7 F 14.1 124 F 25.9 257 F 44.1 244 F 81.6 138 F 14.7 79.9 F 8.81

n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s.

Spontaneous aggregation Small aggregates 22.9 F 29.7 ( 105 counts)

Plaque(+)

p-value

74.8 F 128

0.0055

ADP 2 lM Small aggregates Medium aggregates Large aggregates Optical density (%)

337 F 136 110 F 93.7 59.3 F 89.4 39.8 F 16.1

398 F 192 174 F 103 146 F 150 51.8 F 18.4

n.s. 0.0014 0.0005 0.0020

ADP 0.5 lM Small aggregates Medium aggregates Optical density

126 F 170 1.98 F 4.01 16.8 F 6.91

245 F 178 3.98 F 7.00 22.6 F 6.53

0.0007 n.s. b0.0001

Epinephrine 0.3 lM Small aggregates Medium aggregates Optical density

248 F 171 8.93 F 20.9 19.7 F 6.29

359 F 157 40.5 F 73.8 25.8 F 14.2

0.0013 0.0052 0.0082

Hypertensive patients with carotid artery plaque exhibit increased platelet aggregability Table 5

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Person’s correlation coefficients for platelet aggregation and atherogenic factors Age

Glucose

HbA1c

TC

LDL

SBP

DBP

Spontaneous aggregation Small aggregates ( 105 counts)

0.081

0.096

0.027

0.026

0.014

0.019

0.004

ADP 2 lM Small aggregates Medium aggregates Large aggregates Optical density

0.008 0.269# 0.122 0.018

0.013 0.017 0.009 0.073

0.024 0.116 0.122 0.219#

0.022 0.121 0.096 0.057

0.002 0.025 0.027 0.040

0.053 0.079 0.100 0.166

0.075 0.118 0.234# 0.249#

ADP 0.5 lM Small aggregates Medium aggregates Optical density

0.096 0.013 0.018

0.005 0.143 0.088

0.118 0.031 0.027

0.062 0.058 0.072

0.109 0.144 0.158

0.010 0.036 0.051

0.095 0.061 0.180

Epinephrine 0.3 lM Small aggregates Medium aggregates Optical density

0.186 0.003 0.156

0.075 0.059 0.060

0.134 0.006 0.142

0.082 0.005 0.174

0.002 0.072 0.161

0.003 0.010 0.042

0.013 0.064 0.023

Statistical significance is indicated by #, indicating a p-values b0.05.

percentage of these patients were Plaque(+), compared with patients who did not have these complications (Table 6). However, the presence of hypercholesterolemia and/or diabetes had no influence on platelet aggregability except for the formation of small and medium-sized aggregates induced by 2 AM of ADP (Table 7).

Discussion Examination of the carotid arteries using ultrasonography is a common and widespread method of clinically evaluating arteriosclerosis. Usually, arterial plaques are analyzed for extension and echo-

genic composition. However, we classified carotid artery arteriosclerosis into only two categories to enable an accurate statistical analysis, and to exclude the possibility of differences in analytical technique among the ultrasonographers. No significant relationship was in fact seen between plaque composition and platelet aggregability (data not shown). With more subjects and one ultrasonographer analyzing all the carotid artery plaques, however some relationship between platelet aggregability and the composition of carotid artery plaques might be possible. Carotid artery arteriosclerosis has shown some associations with atherogenic factors, like the interleukin-6 level [18], systolic blood pressure

Table 6 Comparison of characteristics among patients with (+) or without ( ) hypercholesterolemia (HC) and diabetes (DM) HC N Male (%) Age (years) BMI (kg/m2) Glucose (mg/dl) HbA1c (%) TC (mg/dl) TG (mg/dl) HDL (mg/dl) LDL (mg/dl) SBP (mm Hg) DBP (mm Hg) Platelets ( 104/mm3) Fibrinogen (mg/dl) Plaque(+) (%) IMT ( 10 2 mm)

DM

51 63a 62.8 F 7.7 23.8 F 3.1a 103 F 10.8a 5.16 F 0.36a 205 F 29.6a 125 F 60.6a 57.8 F 15.8 123 F 28.4 138 F 15.2 79.3 F 9.9 27.3 F 9.5 246 F 46a 55 76.0 F 15.3a

HC+ DM

HC

46 42b 62.9 F 8.1 24.7 F 3.7a 104 F 16.7a 5.26 F 0.36a 218 F 27.7b 156 F 72.6b 60.9 F 14.4 131 F 25.8a 136 F 13.5a 79.1 F 7.9 26.9 F 6.4 266 F 36 39a 80.6 F 19.5a

24 63 61.5 F 7.2 25.0 F 2.8 135 F 23.5b 6.42 F 0.88b 199 F 22.3a 126 F 76.5 62.3 F 17.5 110 F 27.7b 132 F 9.16a 75.6 F 7.0 26.6 F 7.6 266 F 88 41a 75.0 F 14.7a

DM+

HC+ DM+ 14 50 61.3 F 2.7 27.1 F 3.2b 174 F 50.7c 7.06 F 0.89c 212 F 22.1 165 F 108 56.6 F 13.3 127 F 20.7 146 F 14.7b 82.1 F 8.1 27.0 F 4.6 321 F 21b 79b 99.0 F 37.5b

Inter-group differences between the results were evaluated using ANOVA. Statistically significant differences are indicated by a, b, and c, with p-values b0.05.

620 Table 7

Y. Fusegawa et al. Platelet aggregability in patients with or without hypercholesterolemia and/or diabetes or neither HC

DM

HC+ DM

HC

DM+

HC+ DM+

N

51

46

24

14

Spontaneous aggregation Small aggregates ( 105 counts)

54.0 F 120

43.4 F 62.8

39.6 F 42.2

41.8 F 51.3

ADP 2 lM Small aggregates Medium aggregates Large aggregates Optical density

358 F 186a 136 F 102a 96.6 F 130 44.4 F 20.3

362 F 134a 142 F 104 103 F 137 44.2 F 15.8

350 F 174a 146 F 91.4 110 F 109 49.0 F 21.4

465 F 204b 200 F 108b 111 F 123 50.7 F 12.4

ADP 0.5 lM Small aggregates Medium aggregates Optical density

167 F 179 3.17 F 6.24 19.2 F 6.76

195 F 169 2.52 F 5.03 20.4 F 6.7

199 F 187 2.25 F 4.09 20.5 F 7.38

209 F 157 2.00 F 1.41 19.4 F 6.75

Epinephrine 0.3 lM Small aggregates Medium aggregates Optical density

316 F 186 24.5 F 49.3 23.1 F 13.3

325 F 172 27.3 F 39.6 23.3 F 9.34

295 F 173 17.2 F 36.3 23.8 F 15.6

350 F 182 12.4 F 22.5 21.6 F 4.35

Inter-group differences between the results were evaluated using an ANOVA. Statistically significant differences are indicated by a, and b, with p-values b0.05.

and the oxidized low-density lipoprotein concentration [19], but no association with polymorphisms in the hemostatic pathway genes including fibrinogen have been found [20]. The Plaque(+) group actually had a higher systolic blood pressure but no significant differences in fibrinogen concentration were found in this study. However, a few previous studies evaluated the relationship between carotid artery plaque and platelet aggregability in humans. In the present report, we demonstrated that hypertensive patients with arterial plaques exhibited enhanced platelet aggregability. Enhanced platelet aggregability was observed in the Plaque(+) group. However it might be hard to state conclusively that hypertensive patients with artery plaque have enhanced platelet aggregability, because the Plaque(+) group also had a higher mean age and systolic blood pressure than Plaque( ) group. Actually, high blood pressure and aging have been shown to influence platelet aggregability [4,5]. On the other hand, age and diastolic blood pressure were positively correlated with some of platelet aggregation induced by 2 AM of ADP in this study. Nevertheless, the statistically significant associations were not strong (r b 0.3) and low dose ADP-induced, epinephrine-induced, and spontaneous platelet aggregation were not significantly associated with age or blood pressure. Moreover, in age and systolic blood pressure matched groups, the Plaque(+) patients showed enhanced platelet aggregability. From these results, we concluded that the effects of high blood pressure and aging on platelet aggregation

(especially, on spontaneous platelet aggregation) might be limited in our study. Diabetic patients with enhanced platelet function [21,22] and hyperglycemia after glucose tolerance tests have also been shown to have an elevated spontaneous platelet aggregability [23,24]. Moreover, oxidized LDL is known to cause irreversible platelet aggregation [25]. These previous studies indicate that hypertensive patients with hypercholesterolemia, diabetes or both conditions should have enhanced platelet aggregability. In the present study, however, hypercholesterolemia was well controlled using statins, and no great difference in the LDL cholesterol concentration was seen between the hypercholesterolemia(+) and hypercholesterolemia( ) groups. Moreover, a significant association among platelet aggregability and total cholesterol and LDL cholesterol concentrations was not observed in our study. Based on these findings, we considered that LDL cholesterol might not have as great an influence on platelet aggregation in the present study as in previous studies. On the other hand, diabetic patients did not show enhanced platelet aggregability except for the formation of small and medium aggregates induced by 2 AM of ADP. HbA1c was only positively correlated with optical density after the addition of 2 AM of ADP, and low dose ADP-induced, epinephrine-induced and spontaneous platelet aggregability were not significantly associated with blood glucose or HbA1c. It is hard to explain the inconsistency between our study and previous stud-

Hypertensive patients with carotid artery plaque exhibit increased platelet aggregability ies. Almost all of the diabetic and hypercholesterolemic patients in this study were treated with statin, sulfurnylurea and/or alpha-glucosidase inhibitor. In previous studies, anti-hypertensive medicine, cholesterol lowering therapy and oral medication for diabetes have suppressed platelet aggregability [26—31]. However, some studies have shown a lack of inhibited platelet aggregability in patients with hypertension, hypercholesterolemia and diabetes who were treated with oral medication [32—34]. The different effects of different medication on platelet aggregability might have complicated the results. Despite the enhanced platelet aggregability observed in the Plaque(+) group, we cannot claim that increased platelet aggregability results in arterial plaques formation, and because our data were analyzed retrospectively; thus, the conclusions that can be based on these data are limited. Arterial stenosis has been demonstrated to enhance the interaction of platelets with damaged arterial walls under conditions of abnormal shear stress in an animal model [35]. Our results and those of this previous study have led us to hypothesize that Plaque(+) subjects might have more irregularities or a higher degree of arterial lumen stenosis than Plaques( ) subjects, and that these irregularities or degree of stenosis might increase the shear stress exerted on platelets. On the other hand, increased platelet aggregability might promote the formation and rupture of arterial plaques, based on the fact that coronary heart disease patients with increased platelet aggregability often experience more cardiovascular events [1,2,36]. If both mechanisms influence the relationship between platelet aggregability and arterial plaque formation, platelet aggregability may be enhanced in vascular lumen with plaques, and this enhanced platelet aggregability may cause more vascular events in hypertensive patients with arterial plaques. To break this batherogenic cycleQ, anti-platelet medication might be considered as a first line of preventive treatment for hypertensive patients with arterial plaques. However, this hypothesis has not been proven, and prospective studies are needed to clarify the mechanism underlying the enhanced platelet aggregability seen in patients with arterial plaque.

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