Microparticles (MPs) are small membrane vesicles that are released from many different cell types by exocytotic budding of the plasma membrane in response to cellular activation or apoptosis. MPs may be involved in both physiological processes and clinical treatments because they express phospholipids, which function as procoagulants. Elevated levels of platelet-derived MPs, endothelial cell-derived MPs, and monocyte-derived MPs are observed in almost all thrombotic diseases occurring in venous and arterial beds. Several studies have shown that the quantity, cellular origin, and composition of circulating MPs depend on the type of disease, the disease state, and medical treatment. Although MPs were initially thought to be small particles with only procoagulant activity, they are now known to have many different functions. An increasing number of studies have identified new implications of elevated MPs in clinical disorders. On the basis of evidence available till date, the present review suggests that MPs may be a useful biomarker in identifying atherothrombosis.
Macrophage activation is one of the major immunological events in the pathogenesis of various diseases. Recent studies have disclosed that complicated mechanisms are involved in macrophage activation and polarization, and many published research articles have been based on the M1/M2 polarization concept. It is considered that M1- and M2-like macrophages are associated with T helper (Th)1-type and Th2-type immune responses, respectively, via several immune mediators. In this article, we summarize the correlations between macrophage polarization and metabolic disorders in both humans and mice and discuss the contribution of macrophage polarization to the pathogenic process of metabolic diseases.
The carotid intima-media thickness (IMT) is a widely used surrogate marker for atherosclerosis worldwide. The carotid IMT can be simply, noninvasively, and reproducibly measured through B-mode carotid ultrasound. The carotid IMT is also a strong predictor of future cerebral and cardiovascular events. In addition, regressions of increased carotid IMT by lipid-lowering and antihypertensive drugs have been reported. Despite the strong association between increased carotid IMT and cardiovascular disease, it remains unclear whether routine carotid IMT measurement is useful for the detection of subclinical atherosclerosis in clinical practice. Researches should consider other methodological aspects, such as the definition of carotid plaques, the choice of measurement sites on the common or internal carotid artery, and the assessment of maximum or minimum IMT. The detailed guidelines for measuring carotid IMT vary by county. Thus, the usefulness of the carotid IMT may be assessed in different countries taking racial differences into account. Other important parameters revealed by carotid ultrasound, such as artery stenosis and the characteristics and size of plaques, should also be considered. Physicians should comprehensively interpret the results of carotid ultrasonography. Therefore, carotid ultrasonography is an essential tool for assessing cardiovascular risk in clinical settings.
To prevent obesity in middle age, early precautions and interventions are required during childhood. Therefore, it is very important to accurately evaluate the degree of overweight in children. Body mass index (BMI) is widely used worldwide in adults, but not in children. Because standard BMI, which is calculated using the average height and weight for age, changes widely during growth, a constant cut-off point cannot be set for children. An international unified method defining childhood obesity has not been established. In many countries, BMI-for-age percentile (BMI%) value or Z (standard deviation) score is used, whereas in Japan, the percentage of overweight (POW), which is the modified weight-for-height method, is used. We compared BMI% values with POW values obtained using the anthropometric data of elementary and junior high school students based on the Japanese school survey conducted in 2000 and found that the values for the degree of overweight were significantly different between the two methods. It became clear that tall students were easily defined as being overweight, whereas short students tended to be evaluated as being underweight when using BMI%. POW method seemed to be more appropriate than BMI% for school-age children. Abdominal obesity, excess visceral adipose tissue (VAT), is highly associated with obesity-related complications. Waist circumference (WC) is now accepted as an appropriate guide to VAT accumulation. The cut-off value of WC defining excess VAT is 80 cm at the umbilical level in Japanese school-age children. It is not easy to decide the obesity criteria and optimum WC in school-age children. Childhood obesity should be discussed more internationally.
Aim: The purpose of this study was to evaluate the efficacy and safety of LIVALO® tablets (pitavastatin) in Japanese male children with heterozygous familial hypercholesterolemia (FH). Methods: A multicenter, randomized, double-blind, parallel study was conducted in 14 male children 10-15 years of age with heterozygous FH. Pitavastatin (1 mg/day or 2 mg/day) was administered orally for 52 weeks. The primary endpoint was the percent change in the LDL-cholesterol (LDL-C) concentrations from baseline to endpoint (repeated measures ANCOVA at Weeks 8 and 12). Secondary endpoints included the percentage of patients who achieved the target LDL-C concentration and percent changes in the levels of lipoprotein and lipid parameters at the visit performed at 52 weeks. Results: The percent change in LDL-C from baseline (mean 258 mg/dL for all patients) to the endpoint was －27.3% (95%CI; －34.0, －20.5) and －34.3% (95%CI; －41.0, －27.5) in the patients receiving 1 mg and 2 mg of pitavastatin, respectively. Stable reductions in the total cholesterol (TC), non-HDL cholesterol (non-HDL-C), apolipoprotein B (Apo-B) and LDL-C levels and non-HDL-C/HDL-C and Apo-B/Apo-A1 ratios were observed up to 52 weeks in both groups. One patient in each dose group (14%) reached the treatment target level of 130 mg/dL. Adverse events were observed in seven (100%) patients receiving 1 mg and five (71%) patients receiving 2 mg of pitavastatin, although none were considered related to the study treatment. One patient in the 1 mg group reported a musculoskeletal AE; however, it was attributed to recent excessive exercise. Conclusions: Pitavastatin significantly reduced the LDL-C levels and was well tolerated when administered at usual adult doses in 14 male children 10-15 years of age with heterozygous FH. Pitavastatin is a promising therapeutic agent for pediatric dyslipidemia with few safety concerns.
Aim: The optimal fractional flow reserve (FFR) measurement method for superficial femoral artery (SFA) lesions remains to be established. We clarified the optimal measuring procedure for FFR for SFA lesions and investigated the necessary dose of papaverine for inducing maximal hyperemia in SFA lesions. Methods: Forty-eight patients with SFA lesions who underwent measurement of peripheral FFR (pFFR: distal mean pressure divided by proximal mean pressure) after endovascular treatment by the contralateral femoral crossover approach were prospectively enrolled. In the pFFR measurement, a guide sheath was placed on top of the common iliac bifurcation and pressure equalization was performed. After advancing the pressure wire distal to the SFA lesion, sequential papaverine administration selectively to the affected common iliac artery was performed. Results: There were no symptoms, electrocardiogram changes, and significant pressure drops at the guide sheath tip with increasing papaverine dose. pFFR changes following 20, 30, and 40 mg of papaverine were 0.87±0.10, 0.84±0.10, and 0.84±0.10, respectively (P＜0.001). Although not significantly different, pFFR decreased more in several patients at 30 mg of papaverine than at 20 mg. The pFFR at 40 mg of papaverine was almost similar to that at 30 mg of papaverine. The necessary papaverine dose was not changed according to sex and number of run-off vessels. Conclusions: The contralateral femoral crossover approach is useful in FFR measurement for SFA lesions, and maximal hyperemia is induced by 30 mg of papaverine.
Aim: Vascular endothelial-cadherin (VE-cadherin) is specifically expressed by outgrowth endothelial cells (OECs). Zwitterionic stent showed high antifouling and excellent blood compatibility. Therefore, we hypothesized that anti-VE-cadherin antibody-coated zwitterionic stents (VE-cad-Z stents) would promote re-endothelialization, reduce neointimal formation, and resist thrombus. Methods: VE-cad-Z stents were examined using platelet adhesion test, platelet activation, and OEC capture ability in vitro. In vivo effect of VE-cad-Z stents on re-endothelialization, thrombus-resistance, and neointima hyperplasia was investigated in left common carotid arteries of rabbits (n=15). Results: In vitro, VE-cad-Z stents showed better platelet-resistance and OEC-capture ability (DNA concentration: 297.23±22.71 versus 67.49±15.26 ng/µL, P＜0.01). In vivo, VE-cad-Z stents exhibited better patency rate than bare metal stents (BMS) (15/15 versus 12/15), and it significantly reduced platelet adhesion and neointima formation (neointima area: 1.13±0.05 versus 1.00±0.05mm2, P＜0.01 and 3.04±0.11versus 1.05±0.06mm2, P＜0.01, at 3 and 30 days, respectively; % stenosis: 20.99±0.98 versus 18.72±0.97, P＜0.01 and 56.46±2.20 versus 19.45±1.24, P＜0.01, at 3 and 30 days, respectively). Conclusion: These data suggested that VE-cad-Z stents could specifically capture OECs, consequently promote endothelial healing, and also reduce platelet adhesion and neointima formation.
Aim: Chronic kidney disease (CKD) may lead to reduced concentrations of high-density lipoprotein (HDL) and its subfractions (HDL2 and HDL3), and damage them via inflammation and oxidative stress. The present study aimed to determine the contribution of such changes to cardiovascular disease (CVD) in patients with CKD. Methods: The levels of total cholesterol, low-density lipoprotein cholesterol, HDL-C, HDL2, HDL3, apolipoproteins, malondialdehyde-modified LDL (MDA-LDL), oxidized (ox) HDL, oxHDL2, and oxHDL3 were measured in blood samples from patients with CKD (stages 2–5, n=86) who were not on dialysis and from patients undergoing hemodialysis (CKD stage 5D, n=25). The patients were followed up for 28±9 months after baseline examinations and CVD events were recorded. Result: The levels of HDL3 and ApoA1 in HDL3 fraction decreased according to CKD severity, whereas those of HDL2 and ApoA1 in HDL2 fraction did not differ. The levels of oxHDL were similar across CKD stages. The levels of oxHDL3 and MDA-LDL were decreased, whereas those of oxHDL2 increased according to CKD severity. Multivariate analyses using the Cox proportional hazards model selected high levels of oxHDL and its subfractions, and those adjusted with HDL-C and HDL subfractions or ApoA1 in HDL fractions respectively, compared with HDL-C and HDL subfractions or ApoA1 in HDL fractions alone as independent risk factors for CVD events. Conclusion: The levels of HDL subfractions and their oxidized subfraction particles differed among patients with CKD. The increasing levels of oxHDL subfractions might cause a high frequency of CVD events in such patients.
Aim: This study aimed to evaluate the cross-sectional association between serum phosphorus and arterial stiffness among a health checkup population. Methods: The study population included 26791 individuals without impaired kidney function. Arterial stiffness was measured by brachial-ankle pulse wave velocity (baPWV), ankle brachial index (ABI), and augmentation index (AI) by the radial artery waveform analysis. Linear or logistic regression model was used to appropriately evaluate the association between phosphorus levels and arterial stiffness markers. Results: The mean age of the population was 49 years and 67% were male. The phosphorus level was divided into quintiles. After multivariate adjustments, participants in the fourth (3.90-4.17 mg/dL) and fifth quintile (≥ 4.18 mg/dL) of serum phosphorus had increased the level of baPWV with linear regression coefficients of 11.9 [95% confidence interval (CI): 5.6-18.2] and 17.2 (95% CI: 10.9-23.5), respectively, compared with those in the first quintile (＜3.34 mg/dL). No significant associations were found between each quintile of phosphorus and ABI ＜0.9. However, participants in the fifth quintile of phosphorus had an increased risk of ABI ≥ 1.3 with an odds ratio (OR) of 1.2 (95% CI: 1.0-1.5) compared with the reference quintile. Furthermore, the increased risks could be observed for AI ＞97% throughout the second to fifth quintile of phosphorus and the ORs were 1.1 (95% CI: 1.0-1.3), 1.2 (95% CI: 1.0-1.4), 1.3 (95% CI: 1.1-1.5), and 1.5 (95% CI: 1.3-1.7), respectively. Conclusions: Higher serum phosphorus levels, even within the normal range, are associated with markers of arterial stiffness among general population with normal kidney function.
Aim: To investigate the relationship between the clustering of metabolic syndrome (MetS) components and non-high-density lipoprotein cholesterol (non-HDL-C) levels in Japanese obese boys. Methods: Subjects were 58 obese boys aged 12.0±2.6 years, which were categorized into three subgroups: abdominal obesity, pre-MetS (abdominal obesity＋1 component), and MetS (abdominal obesity＋2 or more components). Results: Sixteen (27.6%) and 32 (55.2%) of the obese boys were diagnosed as pre-MetS and MetS, respectively. The mean non-HDL-C level in total subjects was 139.0±36.4 mg/dl and that in boys with abdominal obesity, pre-MetS, and MetS were 112.9±34.4, 135.4±37.9, and 149.0±32.6 mg/dl, respectively (p=0.0183, ANOVA). Conclusions: Japanese obese boys with MetS exhibited elevated non-HDL-C levels, suggesting that they may have a higher risk for the development of atherosclerotic diseases.
Familial hypercholesterolemia (FH) is characterized by a high level of low-density lipoprotein cholesterol (LDL-C) and is inherited as an autosomal dominant trait. We report 4-year-old dichorionic diamniotic twins (boy and girl) with FH who presented with multiple xanthomas on the face, both knees, both feet, and buttocks. Family history revealed vertical transmission of hypercholesterolemia from father to patients, thereby suggesting dominant inheritance. Lipid data of their mother did not match the criteria of FH. However, lipid data of maternal grandmother and maternal sister matched the criteria of FH. LDL receptor gene analysis of the family revealed that their father was heterozygous for a missense mutation, L547V, their mother was heterozygous for a nonsense mutation, C675X, and patients were compound heterozygous for L547V and C675X. After 10 months of treatment with pitavastatin (2 mg/day) and ezetimibe (10 mg/day), LDL-C decreased from 595 mg/dL to 267 mg/dL in the boy and from 530 mg/dL to 182 mg/dL in the girl. These findings suggest that lipid-lowering therapy with statin may be considered in pediatric patients with compound heterozygous FH (hetero FH) before inducing LDL apheresis, and gene analysis for true diagnosis in pediatric patients with multiple xanthomas should be considered, though they appear to be hetero FH from the family history and lipid data of parents.