The pathological complications of atherosclerosis, namely heart attacks and strokes, remain the leading cause of mortality in the Western world. Preceding atherosclerosis is endothelial dysfunction. There is therefore interest in the application of non-invasive clinical tools to assess endothelial function. The flow-mediated dilation (FMD) test is the standard tool used to assess endothelial function. Reduced FMD is an early marker of atherosclerosis and has been noted for its capacity to predict future cardiovascular disease events. This review discusses the measurement of endothelial function using ultrasound, with a focus on the FMD technique.

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Aims: To determine whether low-dose calcitriol attenuates atherosclerosis in apoE-null mice and, if so, through which predominant mechanism.
Methods: Starting at the age of 6 weeks, mice received intraperitoneal injections of either 0.25 ng/g body weight of calcitriol or the vehicle, every other day for 8 weeks.
Results: Calcitriol treatment resulted in 35% reduction of atherosclerosis at the aortic sinus, and in a significant decrease in blood pressure. These effects were possibly mediated by downregulation of the renin-angiotensin system (RAS), as there was a 64% decrease in the aortic level of renin mRNA. None of the other components of the RAS or the prorenin receptor were affected by treatment. Low-dose calcitriol treatment did not modify the plasma level of monocyte chemoattractant protein-1, interferon γ, interleukin-4 and interleukin-10, which were similar in control and treated mice. Likewise, there was no difference in the percentage of splenic Foxp3⁺ regulatory T cells. Calcitriol treatment resulted in an unfavorable metabolic profile (glucose and lipids), as determined after a limited fast, a difference that disappeared after food was withheld for a longer time.
Conclusions: At a relatively low dosage, calcitriol attenuates the development of atherosclerosis in apoE-null mice, most probably by down regulation of RAS, and not through immunomodulation; however, even at this low dose, calcitriol appears to elevate calcium and to have potentially adverse metabolic effects. Exploring the potential antiatherogenic effects of non-calcemic and safer analogues is therefore warranted.

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Aim: Recent researches have shown that myeloperoxidase (MPO) is a potential inflammatory risk factor for coronary heart disease (CHD). In the present study, the possible associations of MPO with acute coronary syndrome (ACS), low density lipoprotein cholesterol (LDL-C) and other risk factors in CHD patients were investigated.
Methods: Five hundred thirty-six CHD patients [363 ACS and 173 stable angina pectoris (SAP)] and 181 non-CHD patients confirmed by coronary angiography were enrolled in this study. The association study was performed by logistic regression analysis.
Results: ACS patients had significantly higher MPO activities than SAP and non-CHD patients (p < 0.001). The area under the receiver operating characteristic (ROC) curve of MPO for diagnosing ACS was 0.84 (95% CI: 0.80-0.88, p < 0.001). The optimal cut-off value (sensitivity; specificity) of MPO was 164.77 ng/mL (79.1% and 82.1%). LDL-C (III versus I tertile, OR: 3.24, 95% CI: 1.67-6.29, p = 0.001) and ACS (yes versus no, OR 2.74, 95% CI: 1.71-4.39, p < 0.001) were significantly associated with elevated serum MPO activities, which had the highest odds ratio in quantitative and qualitative variables, respectively. There were significant increase trends in the prevalence of ACS and high LDL-C levels from I to III MPO tertile, which were 46.4% and 8.9% for I, 68.0% and 31.5% for II, 88.8% and 59.8% for III tertile, respectively (p < 0.001).
Conclusion: The present study provides epidemiological evidence that elevated serum MPO activities are significantly associated with the prevalence of ACS and high LDL-C levels in CHD patients, and MPO may be a potential early warning marker for ACS.

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Aim: Small dense low-density lipoprotein (sdLDL) has been suggested to be more atherogenic than large buoyant LDL. High-density lipoprotein (HDL) consists of two major subfractions (HDL2, HDL3), and just as controversy remains regarding which of the two is the more powerful negative risk factor for atherosclerosis, associations between sdLDL and these HDL subfractions are unclear.
Methods: We measured sdLDL cholesterol (sdLDL-C), HDL2 cholesterol (HDL2-C) and HDL3 cholesterol (HDL3-C) by a newly developed method in 481 Japanese-Americans who were not using lipid-lowering medication, and examined the associations of these cholesterol concentrations with variables related to atherosclerosis.
Results: In multivariate analysis, sdLDL-C was positively correlated with the body mass index (BMI), fasting glucose and insulin, 2-h glucose, HOMA-IR, high sensitivity C-reactive protein (hsCRP), and carotid artery intima-media thickness (IMT) after adjustment for age and sex. In particular, sdLDL-C was positively correlated with IMT, even after adjustment for sex, age, smoking status, hypertension, diabetes mellitus and hsCRP. HDL2-C was more closely inversely correlated than total HDL-C with BMI, fasting glucose and insulin, 2-h glucose, HOMA-IR, and hsCRP, whereas HDL3-C was not correlated with these factors. Additionally, HDL2-C was more closely correlated than total HDL-C or HDL3-C with sdLDL-C, LDL-C, triglycerides (TG), and apolipoprotein B (apoB).
Conclusions: SdLDL-C was closely associated with insulin resistance and glucose tolerance, lending credence to its potential as a useful risk marker in assessing carotid artery IMT and the present degree of atherosclerosis in Japanese-Americans. The findings also suggest that subjects with higher HDL2-C levels were better protected from atherosclerosis.

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Aim: The cardio-ankle vascular index (CAVI) is a new non-invasive marker of arterial stiffness and atherosclerosis. The purpose of this study was to compare CAVI in patients with heterozygous familial hypercholesterolemia (FH) and in healthy controls.
Methods: 82 FH subjects (27 males, 65 females), aged 53.7±13.6 years without clinical symptoms of cardiovascular diseases and 359 healthy controls (121 males, 238 females), aged 43.9±14.9 years, were examined. CAVI was measured using the system VaSera® 1500.
Results: CAVI in FH patients was significantly higher (8.0±1.4) than in healthy subjects (7.5±1.3) p = 0.002; however, age, sex and BMI adjusted CAVI did not differ significantly (p = 0.061) between the FH group (7.5, CI: 7.3; 7.7) and control group (7.7, CI: 7.6; 7.7).
Conclusion: The study showed no significant difference in CAVI between heterozygous FH and healthy controls.

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Aim: A simple, non-invasive medical device, using bioelectrical impedance analysis (BIA) for the evaluation of visceral fat level (VFL) was developed recently. The aim of this study was to investigate the utility of VFL by BIA in the screening of metabolic syndrome (MetS).
Methods: VFL was measured by the BIA device in 1,451 Japanese residents (546 men and 905 women, age range 30-69 years).
Results: VFL had significant positive correlations with waist circumference (WC) and body mass index (r=0.772 and 0.849, all P < 0.0001). The overall MetS prevalence using Japanese Diagnosis Criteria was 19.8%: men 36.3% and women 9.8%. The mean VFL of the participants with MetS was significantly higher than those without MetS (men; 12.1 and 9.4, women; 13.3 and 8.7) (both P < 0.001). VFL significantly correlated with blood pressure, lipid profiles, fasting plasma glucose, and hemoglobin A1c (all P < 0.001). Receiver operating characteristic curve analysis for a diagnosis of two or more MetS risk factors excluding WC resulted in the same cutoff values for the VFL (10.0) of men and women.
Conclusions: The VFL by BIA is useful for the detection of MetS because it is correlated with all metabolic parameters and shows the same normal limit in both sexes.

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Aim: A prothrombotic state is associated with organ damage in hypertensive patients. Carotid intima-media thickness (IMT) is an early marker of vascular damage that anticipates the development of atherosclerotic plaques. The aim of the present study was to investigate the relationships between subclinical carotid damage and markers of the prothrombotic state in hypertension.
Methods: In 258 essential hypertensive patients who were consecutively recruited at a hypertension clinic an ultrasound carotid scan was performed with assessment of the IMT and plasma levels of C-reactive protein, fibrinogen, fibrin D-dimer, prothrombin fragment 1+2, homocysteine, and lipoprotein(a) were measured.
Results: Patients with an IMT above the median of the distribution (800 µm) were older and had greater BMI, pulse pressure, duration of hypertension, and prevalence of coronary heart disease than patients with an IMT below the median. Patients with higher IMT had also greater levels of C-reactive protein, fibrinogen, fibrin D-dimer, and homocysteine. Regression analysis showed a direct relationship of IMT with age, waist circumference, pulse pressure, fibrinogen, fibrin D-dimer, and number of cigarettes smoked per day, and an inverse relationship with creatinine clearance. On multivariate analysis, age, pulse pressure, and fibrin D-dimer were independently related with IMT.
Conclusion: In hypertensive patients, subclinical carotid damage is related with evidence of activated coagulation system suggesting a prothrombotic state. This might contribute to the development of hypertensive arterial damage even in the earliest stages.

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Aim: A novel arterial stiffness index, the cardio-ankle vascular index (CAVI), has been proposed. To clarify the properties of CAVI, the effects of beraprost sodium (BPS), a prostaglandin (PG) I₂ analogue, which has a potent vasodilating effect, on CAVI were studied and comparing with brachialankle pulse wave velocity (baPWV) in healthy volunteers.
Methods: Male volunteers (n=18, 46.3±4.2 yr) were enrolled in this study and administered BPS (40 µg). CAVI and baPWV were measured every hour for 4 hours.
Results: When BPS was administered to 18 healthy volunteers, systolic blood pressure and diastolic blood pressure fluctuated slightly, but the means did not change. CAVI significantly decreased in the 1st hour from 8.3±0.34 (mean±SE) to 7.9±0.34 (p<0.05) and this decrease persisted for 3 hours, whereas baPWV did not significantly change. ΔbaPWV each time was significantly correlated with both Δsystolic blood pressure and Δdiastolic blood pressure, but ΔCAVI did not correlate with either Δsystolic blood pressure (r=−0.12, p=0.38) or Δdiastolc blood pressure (r=−0.22, p=0.10).
Conclusions: Beraprost sodium did not decrease blood pressure, but decreased CAVI, whereas baPWV did not change. These results indicate that CAVI partly reflected the contraction of arterial smooth muscle cells.

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Aim: This study compared the effect of doubling the dose of pravastatin with that of adding ezetimibe to low-dose pravastatin on the LDL cholesterol (LDL-C) level and on cholesterol absorption and synthesis markers. The tolerability of the 2 regimens was also compared.
Methods: This was a multicenter, open-label, parallel-group trial. Subjects were aged from 20 to 74 years and had an LDL-C ≥ 120 mg/dL despite pravastatin therapy at 5-10 mg/day. They were randomly allocated to receive either add-on ezetimibe (10 mg/day) or double-dose pravastatin, and follow-up was performed for 12 weeks. The primary endpoints were the changes of LDL-C and apolipoprotein (apo) B levels after 12 weeks of treatment. Cholesterol absorption and synthesis markers were also determined.
Results: LDL-C and apo B decreased by 16% and 14% in the ezetimibe add-on group versus 5.9% and 4.4%, respectively, in the pravastatin double-dose group. The between-group differences of these decreases were highly significant. Cholesterol absorption markers (sitosterol, campesterol, and cholestanol) were reduced by 48%, 36%, and 10%, respectively, in the ezetimibe add-on group, and were increased by 17%, 14%, and 6%, respectively, in the pravastatin double-dose group. Lathosterol (a cholesterol synthesis marker) increased by 76% in the ezetimibe add-on group and by 24% in the pravastatin double-dose group. The difference was statistically significant. No serious adverse effect was observed in either group.
Conclusions: Adding ezetimibe to low-dose pravastatin achieves greater decreases in LDL-C, apo B, and cholesterol absorption markers than doubling the dose of pravastatin.

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Aim: Platelet aggregates with white blood cells (WBC-platelet complex) have recently been proposed as a marker of activated platelets, in addition to well-known molecular markers. We aimed to investigate the colocalization of activated platelets and WBC-platelet complex by means of flow cytometry, in patients with ischemic stroke.
Methods: Eighty-six patients with cerebral infarction (CI) in the acute phase (58 males, 28 females; 65±14 years old) and 62 non-CI controls (23 males, 39 females; 53±14 years old) were registered. The appearance of WBC-platelet complex was quantified using 3-color flow cytometry.
Results: The appearance rate of WBC-platelet complex was significantly higher in the CI group than in the controls. The appearance rate of WBC-platelet complex was significantly higher in atherothrombotic infarction (AT) than in lacunar infarction (LA) (p < 0.05). Furthermore, positive rates of both monocyte-platelet complex and granulocyte-platelet complex, but not lymphocyte-platelet complex, were significantly higher in the AT group than in the controls.
Conclusion: We concluded that WBC-platelet complex, especially involving monocytes and granulocytes, is a novel marker of platelet activation in the acute phase of ischemic stroke, mainly in AT.

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