Accumulating clinical evidence has suggested serum triglyceride (TG) is a leading predictor of atherosclerotic cardiovascular disease, comparable to low-density lipoprotein (LDL)-cholesterol (C) in populations with type 2 diabetes, which exceeds the predictive power of hemoglobinA1c. Atherogenic dyslipidemia in diabetes consists of elevated serum concentrations of TG-rich lipoproteins (TRLs), a high prevalence of small dense low-density lipoprotein (LDL), and low concentrations of cholesterol-rich high-density lipoprotein (HDL)2-C. A central lipoprotein abnormality is an increase in large TG-rich very-low-density lipoprotein (VLDL)1, and other lipoprotein abnormalities are metabolically linked to increased TRLs. Insulin critically regulates serum VLDL concentrations by suppressing hepatic VLDL production and stimulating VLDL removal by activation of lipoprotein lipase. It is still debated whether hyperinsulinemia compensatory for insulin resistance is causally associated with the overproduction of VLDL. This review introduces experimental and clinical observations revealing that insulin resistance, but not hyperinsulinemia stimulates hepatic VLDL production. LDL and HDL consist of heterogeneous particles with different size and density. Cholesterol-depleted small dense LDL and cholesterol-rich HDL2 subspecies are particularly affected by insulin resistance and can be named “Metabolic LDL and HDL,” respectively. We established the direct assays for quantifying small dense LDL-C and small dense HDL(HDL3)-C, respectively. Subtracting HDL3-C from HDL-C gives HDL2-C. I will explain clinical relevance of measurements of LDL and HDL subspecies determined by our assays. Diabetic kidney disease (DKD) substantially worsens plasma lipid profile thereby potentiated atherogenic risk. Finally, I briefly overview pathophysiology of dyslipidemia associated with DKD, which has not been so much taken up by other review articles.

Sitosterolemia is a rare inherited disease characterized by increased levels of plant sterols, such as sitosterol. The cause of this disease is ATP-binding cassette (ABC) subfamily G member 5 or member 8 (ABCG5 or ABCG8, respectively) gene mutations. Recent advances in genetics have revealed that the prevalence of subjects with deleterious mutations in ABCG5 and/or ABCG8 genes could be more than 1 in ~200,000 individuals among the general population. Furthermore, accumulated evidence, including infantile cases exhibiting progression/regression of systemic xanthomas associated with LDL cholesterol levels, have shown that the elevation of LDL cholesterol seems to be the major cause of development of atherosclerosis and not the elevation of sitosterol. Regarding therapies, LDL apheresis, as well as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, could be useful for sitosterolemia, in addition to ezetimibe and/or colestimide. In this study, we provide the current understanding and future perspectives of sitosterolemia, which is currently considered an extremely rare disorder but is expected to be much more prevalent in clinical settings.

Aim: The arterial pressure–volume index (API) and arterial velocity–pulse index (AVI) are novel measurement indices of arterial stiffness. This study was performed to examine the screening validity of the API and AVI for preclinical atherosclerosis in Japanese community-dwelling adults.

Methods: We conducted a cross-sectional study of 2,809 participants aged ≥40 years who underwent Japanese national medical check-ups from 2014 to 2016. Preclinical atherosclerosis was defined as a mean carotid intima–media thickness (CIMT) of ≥1.0 mm. Multivariable linear regression analysis was performed to investigate the association of CIMT with API and AVI, adjusting for body mass index, sex, and the Framingham–D'Agostino score. We also examined receiver operating characteristic curves, sensitivity, and specificity to predict preclinical atherosclerosis defined by the CIMT. The cardio-ankle vascular index was also measured for comparison with the API and AVI.

Results: Of 2,809 participants, 68 (2.4%) had preclinical atherosclerosis. In the multivariable linear regression analysis, the API and AVI maintained a positive association with the mean CIMT (B=2.6, P=0.009 and B=3.7, P=0.001, respectively). The cut-offs of the API and AVI that demonstrated better sensitivity and specificity for detection of subclinical atherosclerosis were 31 [area under the curve (AUC), 0.64] and 29 (AUC, 0.60).

Conclusions: The API and AVI were positively associated with preclinical carotid atherosclerosis independent of the participants' cardiovascular risk. The ability of these scores to predict carotid atherosclerosis could make them a useful screening tool for atherosclerosis.

Aim: To investigate the long-term clinical outcome of endovascular therapy (EVT) or bypass surgery in patients on hemodialysis (HD) with critical limb ischemia due to isolated infrapopliteal disease.

Methods: We enrolled 254 consecutive HD patients successfully undergoing infrapopliteal revascularization by EVT (126 patients) and bypass surgery (128 patients). They were followed up for five years. Amputation-free survival (AFS) and incidence of any re-intervention were evaluated. A propensity score from all baseline variables was incorporated into Cox analysis.

Results: In the EVT group, age was higher (p=0.039), diabetes and coronary artery disease were more frequent (p=0.004 and p=0.0052, respectively), and tissue loss was more rarely observed (p＜ 0.0001) than in the bypass group. During the follow-up period, 21 major amputations and 64 deaths occurred. The propensity score-adjusted AFS rate at 5 years was comparable between groups (61.0% in EVT group vs. 55.1% in the bypass group, adjusted hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.52–1.42, p=0.58). The adjusted survival rates were also similar between groups for amputation and all-cause mortality. However, freedom from any re-intervention was markedly lower in the EVT than in the bypass group (48.6% vs. 84.6%, adjusted-HR, 3.56, 95% CI 1.95-6.75, p＜ 0.0001).

Conclusions: The rate of AFS was broadly comparable between the two strategies, although compared with bypass surgery, EVT had much higher rates for re-intervention.

Aim: Ischemia-reperfusion (I-R) produces reactive oxygen species (ROS) that damage cells and favour cytotoxicity and apoptosis in peripheral artery disease (PAD) patients. Since brief episodes of I-R (ischemic conditioning) protect cells against ischemic harms, we evaluated whether a short-course of supervised treadmill training, characterized by repeated episodes of I-R, makes peripheral blood mononuclear cells (PBMCs) from PAD patients with intermittent claudication more resistant to I-R injuries by reducing oxidative stress and by inducing an adaptative response of unfolded protein response (UPR) and nuclear factor-E2-related factor (Nrf2) pathway expression.

Methods: 24 PAD patients underwent 21 sessions of treadmill training and a treadmill test as indicator of acute response to I-R.

Results: Maximal and pain free walking distance improved (p＜0.01), whereas LDH leakage and apoptosis of PBMCs decreased (p＜0.01); plasma malondialdehyde and ROS generation in PBMCs declined, while plasma glutathione augmented (p＜0.01). Moreover we demonstrated an up-regulation of UPR and Nrf2 expression in PBMCs (p＜0.01). To understand whether treadmill training may act as a trigger of ischemic conditioning, we examined the effect of repeated episodes of I-R on adaptative response in PBMCs derived from the patients. We showed an up-regulation of UPR and Nrf2 gene expression (p＜0.01), while oxidative stress and cytotoxicity, after an initial increase, declined (p＜0.01). This positive effect on cytotoxicity was reduced after inhibition of UPR and Nrf2 pathways.

Conclusions: Treadmill training in PAD patients through UPR and Nrf2 up-regulation may trigger hypoxic adaptation similar to conditioning, thus modifying cell survival.

Aim: Fibroblast growth factor-21 (FGF-21) is a metabolic regulator with beneficial effects on glucolipid metabolism. Since FGF-21 has lipid-lowering, anti-inflammatory and anti-oxidant properties, it may play a protective role against atherosclerosis. However, blood FGF-21 levels in coronary artery disease (CAD) or peripheral artery disease (PAD) have not been elucidated.

Methods: We measured plasma FGF-21 levels in 417 patients undergoing coronary angiography, who also had ankle-brachial index test for PAD screening.

Results: CAD was found in 224 patients (1-vessel [1-VD], n=92; 2-vessel [2-VD], n=65; 3-vessel disease [3-VD], n=67). No significant difference was found in the FGF-21 levels between 224 patients with CAD and 193 without CAD (median 26.0 vs. 25.9 pg/mL). FGF-21 levels in 4 groups of CAD(-), 1-VD, 2-VD, and 3-VD were 25.9, 37.2, 19.4, and 0.0 pg/mL. FGF-21 tended to be highest in 1-VD and lowest in 3-VD, but the difference did not reach statistical significance. PAD was found in 38 patients. Compared to the 379 patients without PAD, 38 with PAD had CAD more often (87% vs. 50%), especially 3-VD (P＜0.001). FGF-21 levels were lower in patients with PAD than in those without PAD (0.0 vs. 30.7 pg/mL, P＜0.02). In multivariate analysis, the FGF-21 level was an independent factor for PAD, but not for CAD. Odds ratio for PAD was 2.13 (95%CI=1.01-4.49) for a low FGF-21 level (＜15.6 pg/mL).

Conclusion: No significant difference was found in the FGF-21 levels between patients with and without CAD. However, FGF-21 levels were low in patients with PAD, and were a factor for PAD independent of atherosclerotic risk factors.

Aim: To analyze associations among the serum endostatin level, renal function, and carotid atherosclerosis of healthy residents of Japan.

Methods: Among 1,057 Japanese residents who attended free public physical examinations between 2010 and 2011, we evaluated the data of 648 healthy residents (200 men and 448 women, age 24 to 84 years) for whom the serum endostatin level and common carotid intima-media thickness (IMT) were measured. Renal function was assessed by estimated glomerular filtration rate (eGFR). Multiple linear regression analysis was done to determine the association of eGFR and serum endostatin level after adjustment for known covariates. Mediation analysis was done using Baron and Kenny's regression approach.

Results: The median endostatin level was 63.7 ng/mL (interquartile range: 49.7–93.2). The mean eGFR was 78.4±14.8 mL/min/1.73m². Univariate analysis showed that age (r=－0.37, P＜0.01), non current smoking (85.8±13.0 vs. 77.5±14.8 mL/min/1.73 m², P＜0.01), hemoglobin A1c (r=－0.08, P=0.05), low-density lipoprotein-cholesterol (r=－0.13, P＜0.01), uric acid (r=－0.15, P＜0.01), carotid IMT (r=－0.11, P＜0.01), and log-transformed endostatin (r=－0.36, P＜0.01) were significantly associated with eGFR. In multiple linear regression analysis, log-transformed endostatin was significantly associated with eGFR (beta=－0.24, P＜0.01). While, carotid IMT was no longer significant. Mediation analysis showed serum endostatin level to be a mediator in the association between carotid IMT and eGFR.

Conclusions: The association between carotid IMT and eGFR is mediated by the serum endostatin level of healthy individuals.

Aims: Smoking impairs endothelial function as an acute effect. However, few population-based studies have examined the association between smoking status and endothelial function or the dose–response and duration–response association of smoking with endothelial function. We examined whether smoking habits were associated with impaired endothelial function depending on smoking dose and duration.

Methods: We conducted a cross-sectional study of 910 men and women aged 30–79 years from 2013 to 2016. Statistical analyses of the data were conducted between 2016 and 2017. Endothelial function was assessed by brachial artery flow-mediated dilation (FMD) measurement. Low FMD was defined in two ways as the cutoff point based on the lowest quartile of %FMD (＜5.1%) and median of %FMD (＜6.8%), regarding as impaired endothelial function. We investigated the smoking status in terms of cigarettes consumed per day and the duration of smoking.

Results: Heavy and chronic smokers were associated with a high prevalence of impaired endothelial function. Those associations did not change substantially after adjustment for other cardiovascular risk factors. Among all participants, the multivariable-adjusted ORs (95% CIs) of low FMD (＜5.1%) with reference to never smokers were 2.23 (1.00–5.14) for current heavy smokers of ≥ 30 cigarettes per day, 1.83 (1.04–3.20) for heavy smokers of ≥ 40 pack-years, and 2.16 (1.15–4.06) for chronic smokers of ≥ 40 years. For low FMD (＜6.8%) those values was 2.17 (1.01–5.05), 1.70 (1.01–2.86), and 1.98 (1.07–3.69), respectively.

Conclusions: Similar associations were observed among only men. Heavy or long-term tobacco smoking may induce impaired endothelial function.