Obesity, particularly excess visceral fat accumulation, is highly associated with the development of metabolic syndrome and atherosclerotic cardiovascular disease. Adipose tissue produces a variety of secreted proteins, referred to as adipocytokines, which directly affect nearby or remote organs. Dysregulation of adipocytokines caused by obese conditions contributes to the pathogenesis of various metabolic and cardiovascular disorders. This review focuses on the significance of several adipocytokines that potentially exert beneficial actions on obesity-related diseases, including atherosclerosis and ischemic heart disease.

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Acute inflammation is a fundamental, protective response that orchestrates immune system to address harmful stimuli both from within and via invasion. New evidences indicate that the resolution of acute inflammation is not simply passive but active and highly regulated processes coordinated by new families of potent bioactive lipid mediators (LMs), coined specialized proresolving mediators (SPMs). These SPMs are biosynthesized from n-3 polyunsaturated fatty acids. Low concentrations of SPM (nM range) stimulate proresolving cellular processes, such as inhibition of neutrophil infiltration, enhancement of macrophage phagocytosis of bacteria and efferocytosis of cellular debris, and reduction of inflammatory pain through specific G-protein coupled receptors.
Of the many bioactive mediators that regulate inflammation resolution, low-dose carbon monoxide (CO) functions as a tissue-protective gaso-transmitter that is endogenously produced by the heme oxygenase (HO) system. Specific SPMs activate the HO system, which in turn enhances endogenous CO production locally, thus establishing a protective feed-forward circuit between SPMs and CO. In addition, treatment with low-dose CO and SPMs exerts protective effects against ischemia/reperfusion injury by decreasing leukocyte–platelet interaction and proinflammatory LM levels.
Recent studies reviewed herein assessed the impact of SPMs and low-dose inhaled CO on inflammatory diseases. LM metabololipidomics approach allows the assessment of the efficacy of novel treatments with SPMs and low-dose CO. Moreover, this approach indicates the regions where the action of individual LMs may be physiologically relevant and when these LMs are produced in vivo to serve their proresolving mediator functions that may also permit new directions for treating human diseases.

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Aim: Asymptomatic visceral artery aneurysms (VAAs) have increasingly been found, with most being either atherosclerotic VAAs or fibromuscular dysplasia (FMD)-associated VAAs. However, little is known about the pathogenesis of both diseases. We aimed to identify the differences in the distribution pattern of lipid molecules between atherosclerotic VAAs and FMD-associated VAAs.
Methods: We conducted a histological study of VAAs using imaging mass spectrometry (IMS) to assess the accumulation of lipid molecules in both the aneurysmal sac and the adjacent arteries without aneurysmal changes in 17 VAA samples, which were resected during the surgery.
Results: IMS revealed characteristic distributions of cholesterol ester in intima and media in the atherosclerotic VAAs, which was hardly detected in FMD-associated VAAs. However, lysophosphatidylcholine (lysoPC), a proinflammatory and proapoptotic lipid mediator, was accumulated in the medial ridge of the adventitia of FMD-associated in the aneurysmal sac, and it was also diffusely accumulated in the adjacent arteries. In contrast, lysoPC was accumulated in the area of intimal hyperplasia in atherosclerotic VAAs and the adjacent arteries.
Conclusion: The distribution patterns of lipid molecules were different between the FMD-associated and atherosclerotic VAAs. The diffuse accumulation of lysoPCs in the visceral arteries may be a predisposition for the formation of FMD-associated VAAs.

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Aim: Observational studies have reported that elevated homocysteine (Hcy) levels are associated with the risk of cardiovascular disease (CVD). However, interventions that lower Hcy do not provide a corresponding risk reduction. Therefore, the causal role of Hcy in CVD remains unclear. This 5-year prospective study investigated the associations of Hcy levels, folate intake, and host factors with arterial stiffness among the general Japanese population.
Methods: We prospectively recruited 658 participants (40–69 years old) from the general population during regular health checkup examinations. Arterial stiffness was evaluated using the cardio-ankle vascular index (CAVI) at baseline and the 5-year follow-up. Folate intake was estimated using a structured questionnaire. Genotyping was used to evaluate the MTHFR C677T and MS A2756G gene polymorphisms. Ultrafast liquid chromatography was used to measure total plasma Hcy levels. Association between these variables and CAVI values was evaluated using general linear regression and logistic regression models that were adjusted for atherosclerosis-related factors.
Results: Men had higher Hcy levels and CAVI values and lower folate intake than women (all, p＜0.001). At baseline, Hcy, folate intake, and the two genotypes were not associated with CAVI values for both sexes. Among men, Hcy levels were positively associated with CAVI values at the 5-year follow-up (p=0.033). Folate intake and the two genotypes were not associated with the 5-year CAVI values.
Conclusion: Plasma Hcy may be involved in arterial stiffness progression, as monitored using CAVI, among men.

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Aim: To investigate the relationship between serum uric acid levels and cardiovascular disease in Asians.
Methods: We examined the above relationship using the data of Evidence for Cardiovascular Prevention from Observational Cohorts in Japan (EPOCH-JAPAN Study). The data of 36,313 subjects (15,628 men and 20,685 women aged 35–89 years without histories of stroke, coronary heart disease, or cancer at baseline) were used for the analyses.
Sex-specific hazard ratios (HRs) of mortality from cardiovascular disease were estimated according to the quintiles of serum uric acid using Cox hazard models stratified by cohorts.
Results: During 441,771 person-years of follow-up, we documented 1,288 cardiovascular deaths. A J- or U-shaped relationship between serum uric acid level and cardiovascular disease mortality was observed. Compared with the lowest quintile of serum uric acid levels, the highest quintile was associated with an increased cardiovascular disease mortality in men [HR: 1.28; 95% confidence interval (CI): 1.01–1.63] and women (HR: 1.51; 95% CI: 1.14–1.99). However, there was no significant association with mortality from stroke, coronary heart disease or heart failure in both men and women.
Conclusion: This large pooled analysis in Japan suggested a J- or U-shaped relationship between serum uric acid levels and cardiovascular mortality. The highest quintile of serum uric acid levels was associated with increased cardiovascular disease mortality in both Japanese men and women.

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Aim and Methods: The high-density lipoprotein 2 cholesterol (HDL₂-C) to HDL₃-C ratio is associated with insulin resistance, high-molecular-weight adiponectin (HMW-Ad), and metabolic syndrome (MetS) components and is useful for evaluating MetS in Japanese individuals. We investigated potential associations between changes in HDL₂-C/HDL₃-C and changes in MetS components, insulin resistance, adipocytokine, lipids, and lifestyle habits in 892 Japanese subjects who underwent annual health examinations twice at a mean interval of 1.1 years. Study subjects were divided into three groups on the basis of HDL₂-C/HDL₃-C changes.
Results: Average changes in waist circumference (WC) and HDL-C were significantly lower and higher, respectively, in the 0 to ＜0.5 and ≥0.5 HDL₂-C/HDL₃-C change groups compared with those in the reference group (＜0 HDL₂-C/HDL₃-C change). Among MetS components, average changes in HDL₂-C/HDL₃-C were associated with changes in WC and HDL-C. Average changes in HMW-Ad and the homeostasis model assessment of insulin resistance were significantly higher and lower, respectively, in the ≥0.5 HDL₂-C/HDL₃-C change group compared with those in the reference group. In addition, the average low-density lipoprotein cholesterol (LDL-C) gradually decreased as HDL₂-C/HDL₃-C increased. The average change in LDL-C was significantly lower in the 0 to ＜0.5 and ≥0.5 HDL₂-C/HDL₃-C change groups than in the reference group. Moreover, a ≥0.5 HDL₂-C/HDL₃-C change positively correlated with good lifestyle statuses in terms of smoking, physical activity, and alcohol consumption.
Conclusion: Changes in HDL₂-C/HDL₃-C inversely correlated with changes in WC, insulin resistance, and LDL-C and positively correlated with HMW-Ad and good lifestyle habits. Therefore, HDL₂-C/HDL₃-C changes comprise a useful marker for both MetS and atherogenic conditions in Japanese population.

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Aim: Malnutrition has been identified to be an independent predictor of morbidity and mortality in patients with chronic heart failure (CHF). However, the pathophysiological mechanisms underlying this pathway remain unclear.
Methods: Nutritional screening was performed using the controlling nutritional status (CONUT) score, which was calculated using the serum albumin and total cholesterol levels and lymphocyte number, in 114 CHF patients with a mean left ventricular ejection fraction of 26.6%±6.4%. The carotid intima-media thickness (CIMT) is correlated with carotid atherosclerosis and is a significant predictor of future cardiovascular events. Peripheral blood mononuclear cells (PBMCs) were isolated, and the production of monocyte tumor necrosis factor (TNF)-α was measured and expressed as mean±SD (pg/mL/10⁶ PBMCs).
Results: A multivariate linear regression analysis showed that the production of monocyte TNF-α (β coefficient=0.434, p＜0.001) and mean CIMT (β coefficient=0.204, p=0.006) were independent determinants of the CONUT score. During a median follow-up of 67.5 months, 45 patients experienced cardiac events, including 16 cardiac deaths and 29 readmissions for worsening CHF. A multivariate Cox hazard analysis demonstrated that a monocyte TNF-α level of ≥4.1 pg/mL/10⁶ PBMCs (hazard ratio (HR), 14.10; 95% confidence interval (CI), 2.55–77.92; p=0.002) and CONUT score of ≥3 (HR, 11.97; 95% CI, 2.21–64.67; p=0.004) were independently associated with the incidence of cardiac events.
Conclusions: These data indicate that a poor nutritional status as assessed using the CONUT score and atherosclerosis as indicated by CIMT is significantly associated with inflammation and predicts poor outcomes in patients with CHF.

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Aim: Although neck circumference (NC) is thought to predict obesity-related metabolic abnormality, its causal role in cardiometabolic risk is unclear. The aim of this study was to clarify the impact of changes in NC on cardiometabolic risk in healthy postmenopausal women through a community-based longitudinal study.
Methods: From a local community in Japan, 63 generally healthy postmenopausal women were recruited. All participants received an assessment of obesity-related anthropometric markers, biochemical parameters, and hemodynamic measures and were followed on average for 3 years.
Results: At baseline analysis, larger NC was positively associated with atherosclerosis-related markers, brachial-ankle pulse wave velocity (baPWV) and blood pressure, as well as some lipid parameters. After the follow-up period, change in NC was associated with changes in body mass index (BMI), body fat percentage, and waist circumference (WC). Interestingly, significant correlations of change in NC with changes in baPWV and blood pressure were observed, whereas changes in WC and BMI were only associated with changes in low-density lipoprotein cholesterol and/or total cholesterol. In multivariate linear regression analysis, change in NC was significantly associated with changes in baPWV and systolic blood pressure, independent of changes in BMI, WC, and biochemical parameters. In addition, an increase in NC was associated with a 2.69-fold increased odds ratio of accelerated baPWV.
Conclusions: Change in NC was independently associated with changes in atherosclerosis-related markers. These observations suggest that NC is an important predictor of the risk of developing obesity-related atherosclerosis in healthy postmenopausal women.

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Aim: Atherosclerosis (AS) characterized as a chronic inflammatory disease. Multiple immune cells and inflammatory cytokines, such as high mobility group protein (HMGB1), regulatory T (Treg) cells, T helper (Th17) cells, and inflammation-related cytokines, play a key role in its pathophysiology. A large number of studies report that HMGB1 and Th17 cells may promote atherosclerosis progression, whereas Treg cells may play a protective role in atherosclerosis; thus, alterations in the Treg/Th17 ratio may exist in atherosclerosis diseases. Up till now, the relationships between HMGB1 levels and the Treg/Th17 ratio remain incompletely understood. The major purpose of this study was to investigate the relationship between HMGB1 levels and the Treg/Th17 ratio in patients with coronary artery atherosclerotic plaques.
Methods: We enrolled patients with coronary atherosclerosis and normal coronary artery as the research subjects. Flow cytometry was used to analyze the Treg cells, the Th17 cells frequency, and the Treg/Th17 ratio. Otherwise, real-time polymerase chain reaction was used for assays the mRNA expressions of HMGB1, retinoic acid-related orphan nuclear receptor C (RORC), and forkhead-winged helix transcription factor (Foxp3). Moreover, enzyme-linked immunosorbent assays were used to detect the level of protein and cytokines, such as HMGB1, IL-10, TGF-β1, IL-17A, and IL-23.
Results: Using flow cytometry, we observed a significantly increased of Th17 cell frequency, whereas Treg cell frequency significantly decreased in atherosclerotic patients. Consistently, the levels of RORC mRNA were significantly increased in coronary atherosclerosis (AS) group compared to normal coronary artery (NCA) group (P＜0.01). In contrast, the expression of Foxp3 mRNA was markedly lower in the AS group than in the NCA group (P＜0.01). Furthermore, we observed the serum concentrations of HMGB1, IL-17A, and IL-23 were significantly higher in the AS group than in the NCA group (P＜0.01, respectively), whereas the concentrations of serum IL-10 and TGF-β1 were significantly lower in the AS group than in the NCA group (P＜0.01, respectively). In addition, we also found that HMGB1 levels showed negative correlation with the Treg/Th17 ratio in the two groups (r=－0.6984, P＜0.01).
Conclusions: The data in our study indicated that HMGB1 may promote atherosclerosis progression via modulating the imbalance in the Treg/Th17 ratio.

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Background: Reduction of serum LDL-cholesterol by statins was shown to improve clinical outcomes in patients with coronary heart disease (CHD). Although intensive statin therapy significantly reduced cardiovascular risks, atherosclerotic cardiovascular events have not been completely prevented. Therefore, effective pharmacologic therapy is necessary to improve “residual risks” in combination with statins. Probucol has a potent antioxidative effect, inhibits the oxidation of LDL, and reduces xanthomas. Probucol Trial for Secondary Prevention of Atherosclerotic Events in Patients with Prior Coronary Heart Disease (PROSPECTIVE) is a multicenter, randomized, prospective study designed to test the hypothesis that the addition of probucol to other lipid-lowering drugs will prevent cerebro- and cardiovascular events in patients with prior coronary events and high LDL cholesterol levels.
Study Design: The study will recruit approximately 860 patients with a prior CHD and dyslipidemia with LDL-C level ≥140 mg/dl without any medication and those treated with any lipid-lowering drugs with LDL-C level ≥100 mg/dl. Lipid-lowering agents are continuously administered during the study period in control group, and probucol (500 mg/day, 250 mg twice daily) is added to lipid-lowering therapy in the test group. The efficacy and safety of probucol with regard to the prevention of cerebro- and cardiovascular events and the intima-media thickness of carotid arteries as a surrogate marker will be evaluated.
Summary: PROSPECTIVE will determine whether the addition of probucol to other lipid-lowering drugs improves cerebro- and cardiovascular outcomes in patients with prior coronary heart disease. Furthermore, the safety of a long-term treatment with probucol will be clarified.

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