Plasma concentration of high density lipoprotein (HDL) is one of the most reliable negative risk factors for CVD. There is however convincing experimental and clinical evidence that plasma concentration of HDL does not convey the full picture of atheroprotective properties of HDL. HDL functionality, i.e. the ability of HDL to perform its many atheroprotective functions, is partly independent of HDL concentration and may be as important, if not more important, in determining the atheroprotective capacity of HDL. The capacity of HDL to support cholesterol efflux, its anti-inflammatory, anti-oxidant, anti-thrombotic and other atheroprotective functions are affected dramatically in conditions like coronary artery disease, chronic and acute inflammation, diabetes as well as through various interventions. The mechanisms connecting changes in HDL functionality to HDL structure are only beginning to emerge. Modifications of HDL proteins and lipids, such as advanced glycation and oxidation, changes in HDL composition and size of HDL particles, changes in abundance of various proteins and lipids carried by HDL are among factors affecting HDL functionality. A single common denominator reflecting the multiple HDL functions is yet to be found and may not exist leaving direct measurements of each HDL function as the way to assess atheroprotective capacity of HDL.
Vascular calcification is clinically important in the development of cardiovascular disease. It has been suggested that apoptosis is one of the processes regulating calcification in vascular smooth muscle cells (VSMC). In this review, we discuss the role of apoptosis in inorganic phosphate (Pi)- induced calcification, focusing on regulation of the survival pathway mediated by growth arrest- specific gene 6 (Gas6). Further, we mention the beneficial effect of statins mediated by inhibition of apoptosis which is accompanied by restoration of the Gas6-mediated survival pathway. These findings indicate that Gas6 is a novel target of statins' effects to prevent vascular calcification.
Aim: The excessive proliferation and migration of vascular smooth muscle cells (SMCs) and angiogenesis of endothelial cells (ECs) participate in the growth and instability of atherosclerotic plaques. It is unclear whether Jun N-terminal kinase (JNK) is pro-or anti-atherogenic. Methods: We examined the direct effect of JNK inhibitor (JNK-I) on the proliferation and formation of tubes by human coronary SMCs and human coronary ECs. Results: Culture medium from JNK-I-treated SMCs prevented ECs from forming tubes in an in vitro model of angiogenesis indirectly by reducing the amount of vascular endothelial growth factor (VEGF) released from SMCs. In addition, JNK-I attenuated the expression of pro-matrix metalloproteinase-2 in ECs. When added back to the medium of SMCs treated with JNK-I, VEGF blocked the inhibitory effect on the formation of tubes. Conclusion: Our results indicate JNK-I to have a direct anti-atherogenic effect in SMCs and ECs.
Aim: Predictions of the onset of acute myocardial infarction (AMI) in high risk individuals are of great clinical importance. Among various risk factors, elevated levels of oxidized low density lipopro-tein (ox-LDL) in plasma have been shown to reflect unstable coronary plaques. Coronary calcifica-tion is a common finding in the elderly, however, its clinical implications as a risk factor for plaque rupture are controversial. This study was designed to investigate the clinical implications of plasma ox-LDL levels and coronary calcification detected by electron-beam computed tomography (EBCT), by comparing patients with AMI with those with stable angina pectoris (SAP). Methods: We measured plasma ox-LDL levels in AMI (n=34) and SAP (n=49) patients. In addition, a coronary calcium score was quantified with the Agatston system. The total coronary calcium score (TCS) was defined as the sum of the scores for each lesion. Results: TCS and total calcium area were significantly smaller in patients with AMI than in those with SAP. On the other hand, plasma ox-LDL levels were significantly higher in AMI patients than in SAP patients (p<0.0005). Conclusion: These results suggest that a combined assessment of coronary calcium and plasma ox-LDL levels may be useful for screening patients with unstable coronary plaques.
Aim: Homogeneous assay reagents for the determination of low-density lipoprotein cholesterol (LDL-C) have been available from several manufacturers. However, there has been considerable controversy due to uncertainty regarding their reactivity with intermediate-density lipoprotein (IDL), which is detected at an especially high frequency in patients with type III hyperlipemia. In this study, we examined the reactivity of a homogeneous assay, Cholestest LDL ® (CT-LDL), with hyperlipemic sera that were classified according to the WHO system. Methods: Sera from 6 normolipidemic and 22 hyperlipidemic patients classified according to the WHO system were used for this study. All serum specimens were fractionated by the ultracentrifugation method of Hatch and Lees, and subjected to lipid and protein measurements. Results: The percent bias of values measured by CT-LDL relative to those determined by the ultracentrifugation method was calculated and compared to the lipid/protein ratios of each lipoprotein fraction. Consequently, the coefficient of correlation between the bias and the Triglyceride/Total cholesterol (TG/TC) ratio in the IDL fraction was 0.742. There were also correlations with the TG/TC ratio and the apo-lipoprotein B/Total Cholesterol ratio in the LDL fraction and in the LDL+IDL fraction, respectively. Conclusion: Further testing will be required in order to know more about the clinical condition of hyperlipidemic patients, since CT-LDL may react differently with some beta lipoproteins having a diverse lipid/protein composition compared to those in normolipidemic specimens.
Aim: Resistin in serum is associated with high risk in patients with atherosclerosis. This clinical study aimed to investigate whether pitavastatin can regulate the serum level of resistin, together with levels of other inflammatory cytokines and adipocytokines. Methods: Forty two outpatients (mean age 65.2 ± 12.6 yr, M/F: 21/21) with hypercholesterolemia were administered 2 mg of pitavastatin and serum levels of resistin, together with serum levels of adiponectin, leptin, TNF-alpha and hsCRP, were measured before, and 12 weeks after enrollment. Results: There was no significant gender-related difference in initial serum resistin levels. Pitavastatin significantly decreased LDL-cholesterol after 12 weeks. Initial levels of resistin showed a significant correlation with those of hsCRP (r=0.38, p=0.013), but not TNF-alpha or HOMA-R. Serum resistin, but not adiponectin and leptin, levels were significantly decreased, dropping from 17.1 ± 9.9 ng/ dL to 15.2±10.0 (p=0.001) after 12 weeks of administration. The patient group with a baseline hsCRP ≥ 0.1 at enrollment (n=17) had decreased levels of both resistin and hsCRP (p=0.011 and p=0.022, respectively). Conclusion: This study showed the pleiotropic effect of pitavastatin on the serum resistin concentration, suggesting that it may assist in the prevention of atherosclerosis.
Aim: We reevaluated waist circumference as a diagnostic criterion of metabolic syndrome (MetS) in Japanese. Methods: We enrolled 5,571 subjects (3,148 men and 2,423 women) who had health check-ups in our center. The criterion was reevaluated using the positive predictive value of a receiver-operating characteristics (ROC) curve at 10 different hypothesized lengths of waist circumference with or without a cluster of risk factors. We also drew ROC curves based on the atherosclerotic findings of clinical examinations. Results: Based on the ROC curves, the optimal waist circumference cut-off was 85 cm in men and 80 cm in women. Using this 80 cm cut-off point in women, misdiagnosis rates of MetS were lowered (-19.1--56.6%) compared to the cut-off point currently in use. Integrating the influence of height, namely by using a waist-to-height2 ratio, misdiagnosis rates in shorter populations were decreased in both men and women. Conclusion: These data suggested an optimal waist circumference cut-off to improve the diagnostic probability of MetS in Japanese women of 80 cm, as well as the utility of an easily detected anthropometric index such as a waist-to-height (cm × 100/cm) or waist-to-height2 (cm × 10,000/cm2) ratio, determined as 51 in men and 52 in women, or 30 in men and 33 in women, respectively.
Aim: Small dense LDL particles are associated with an increased risk of coronary heart disease and are prevalent in obesity related dyslipidaemia. This study evaluated the effect of weight loss in nine children (BMI 33.4 ± 8.4 kg.m-2 and age 15.1 ± 2.9 years) on LDL peak particle size, and cholesterol concentrations within particular LDL sub-fractions. Methods: Each child undertook fun based physical activity, dietary restriction and modification and lifestyle education classes in a residential summer weight loss intervention. Blood was drawn before and after intervention and LDL heterogeneity measured by ultracentrifugation. Results: The mean change in body weight were -6.8 ± 4.9 kg, BMI units -2.5 ± 1.4 kg.m-2, and waist circumference -6.3 ± 6.3 cm (all p < 0.01). Absolute LDL-c concentration reduced from 106.2 mg/dL to 88.3 mg/dL (p < 0.01). The cholesterol contained within the small dense LDL sub-fraction (LDL-c III) reduced from 54.1 mg/dL to 40.4 mg/dL (p < 0.01). Peak particle density decreased from 1.041g/mL to 1.035g/mL (p < 0.01). At pre intervention 50.9% of absolute cholesterol was within LDL-c III particles, changing to 46.2%. Conclusion: Mean weight loss of -6.8 ± 4.9 kg lowers absolute LDL-c and the cholesterol specifically within LDL-c III particles. LDL peak particle size increased and a degree of LDL particle remodelling occurred. These favourable adaptations, accrued in a matter of 4 weeks, maybe associated with a reduction in CHD risk.