Aim: Research shows that subclinical hypothyroidism (SCH) is related to an increased carotid intima–media thickness (CIMT), a surrogate marker of subclinical cardiovascular disease (CVD). It is controversial whether or not SCH should be treated to reduce CVD morbidity and mortality. This meta-analysis aimed to determine whether SCH is associated with an increase in CIMT as compared to Euthyroidism (EU) and whether thyroxin (T4) treatment in SCH can reverse the change in CIMT.

Methods: Two independent reviewers conducted an extensive database research up to December 2016. A total of 12 clinical trials discussed the effect of Thyroxin on CIMT values at pre- and post-treatment in subjects with SCH.

Results: CIMT was significantly higher among SCH (n=280) as compared to EU controls (n=263) at baseline; the pooled weighted mean difference (WMD) of CIMT was 0.44 mm [95% confidence interval (CI) 0.14, 0.74], p=0.004; I²=65%. After treatment with thyroxin in subjects with SCH (n=314), there was a statistically significant decrease in CIMT from pre- to post-treatment; the pooled WMD of CIMT decrease was [WMD －0.32; 95% CI (－0.47, －0.16), p=＜0.0001; I²=2%], and it was no longer different from EU controls [WMD 0.13 mm; 95% CI (－0.04, 0.30); p=0.14; I²=27%]. The total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL) were higher in SCH as compared to EU controls and decreased significantly after treatment with thyroxin.

Conclusion: This meta-analysis shows that thyroxin therapy in subjects with SCH significantly decreases CIMT and improves lipid profile, modifiable CVD risk factors. Thyroid hormone replacement in subjects with SCH may play a role in slowing down or preventing the progression of atherosclerosis.

Intestinal flora (microbiota) have recently attracted attention among lipid and carbohydrate metabolism researchers. Microbiota metabolize resistant starches and dietary fibers through fermentation and decomposition, and provide short chain fatty acids (SCFAs) to the host. The major SCFAs acetates, propionate and butyrate, have different production ratios and physiological activities. Several receptors for SCFAs have been identified as the G-protein coupled receptor 41/free fatty acid receptor 3 (GPR41/FFAR3), GPR43/FFAR2, GPR109A, and olfactory receptor 78, which are present in intestinal epithelial cells, immune cells, and adipocytes, despite their expression levels differing between tissues and cell types. Many studies have indicated that SCFAs exhibit a wide range of functions from immune regulation to metabolism in a variety of tissues and organs, and therefore have both a direct and indirect influence on our bodies. This review will focus on SCFAs, especially butyrate, and their effects on various inflammatory mechanisms including atherosclerosis. In the future, SCFAs may provide new insights into understanding the pathophysiology of chronic inflammation, metabolic disorders, and atherosclerosis, and we can expect the development of novel therapeutic strategies for these diseases.

Aims: Elevated carotid intima-media thickness (cIMT) is a preclinical phenotype of atherosclerotic diseases. There are significant sex differences in the morbidities of cardiovascular diseases and their major determinants, and we explored the sex-specific effects of cardiovascular factors on cIMT by a community-based study.

Methods: We measured the cIMT and cardiovascular profiles of 1579 residents aged 40–74 years in northern Taiwan. Multivariate regression analyses were used to assess the effects and contributions of these factors on cIMT.

Results: Males had significantly higher mean (±SD) of cIMT than females (0.668±0.113 vs. 0.632± 0.100 nm, p＜0.0001). The common factors of the best-fit regression models in both sexes were age, BMI, and LDL-/HDL-C ratio; however, their contributions and effects were different. The partial coefficients of determination (r²) were 17.9, 5.8, and 4.1%, respectively, for males and were 27.8, 1.4, and 1.2%, respectively, for females. Test statistics showed that the regression coefficients of BMI and LDL-/HDL-C ratio of males were significantly higher than those of females. As compared with females, per 1.0 SD increases of BMI and LDL-/HDL-C in males resulted in 0.0971 (p=0.030) and 0.1177 (p=0.0087), respectively, SD increases in cIMT. There was no difference in the means of cIMT between pre- and post-menopausal women of the same age groups.

Conclusions: There was a significant sex difference in cIMT. The contributions and effects of LDL-/HDL-C ratio and BMI on cIMT were more profound in males. Our findings indicate that sex-specific factors, but possibly not menstrual status-related factors, contribute to thicker cIMT.

Aim: To investigate the association of retinal vascular changes with a risk of dementia in longitudinal population-based study.

Methods: We performed a nested case-control study of 3,718 persons, aged 40–89 years, enrolled between 1983 and 2004. Retinal vascular changes were observed in 351 cases with disabling dementia (average period before the onset, 11.2 years) and in 702 controls matched for sex, age, and baseline year. Incidence of disabling dementia was defined as individuals who received cares for disabilities including dementia-related symptoms and/or behavioral disturbance. Conditional logistic regression analysis was used to calculate odds ratio (OR) and multivariable adjusted OR (Models 1 and 2) for incidence of disabling dementia according to each retinal vascular change. Regarding confounding variables, Model 1 included overweight status, hypertension, hyperglycemia, dyslipidemia, and smoking status, whereas Model 2 also included incidence of stroke prior to disabling dementia for further analysis.

Results: The proportion of cases (controls) with retinal vascular changes was 23.1 (15.7)% for generalized arteriolar narrowing, 7.7 (7.5)% for focal arteriolar narrowing, 15.7 (11.8)% for arteriovenous nicking, 10.5 (9.3)% for increased arteriolar wall reflex, and 11.4 (9.8)% for any other retinopathy. Generalized arteriolar narrowing was associated with an increased risk of disabling dementia: crude OR, 1.66 (95% confidence interval, 1.19–2.31); Model 1: OR, 1.58 (1.12–2.23); Model 2: OR, 1.48 (1.04–2.10). The number of retinal abnormalities was associated in a dose–response manner with the risk.

Conclusion: Generalized arteriolar narrowing and total number of retinal abnormalities may be useful markers for identifying persons at higher risks of disabling dementia.

Aim: The prognostic value of homocysteine (HCY) in patients with coronary artery diseases (CAD) is still controversial. The objective of this study was to investigate whether elevated HCY level at admission predict long-term outcomes in patients after percutaneous coronary interventions (PCI) with coronary artery stenting.

Methods: From the institutional registry of Cardiovascular Atherosclerosis and Percutaneous TrAnsluminal INterventions (CAPTAIN), we enrolled a total of 1,307 patients with documented CAD undergone PCI with bare metal stents from July 2003 to December 2014. They were divided into two groups according to the fasting plasma HCY levels before catheterization: group Ⅰ (883 patients, ＜12 µmol/L) and group II (424 patients, ≥12 µmol/L). The primary endpoint was occurrence of major adverse cardiac events (MACE), including cardiac death, nonfatal myocardial infarction, stroke, target lesion revascularization, new lesion stenting, and requiring bypass surgery.

Results: After a mean follow-up period of 58±41 months, the group II patients had a higher MACE rate (33.3% vs. 25.6%, p=0.005). The main differences between two groups were cardiac death (8.0% vs. 3.4%, p=0.001) and new lesion stenting (13.6% vs. 9.5%, p=0.034). The risks of long-term MACE remained significantly higher in patients with elevated HCY level (≥12 µmol/L) after adjusting for clinical variables, with a hazard ratio of 1.29 (95% CI, 1.02–1.64, p=0.036).

Conclusions: Elevated HCY level (≥12 µmol/L) was independently associated with increased risk of long-term cardiovascular events in patients after coronary artery bare metal stents implantations. Thus, hyperhomocysteinemia may remain a useful prognostic marker for the risk assessment in clinical care of CAD patients.

Aim: It is not clear whether elevated serum non-high-density lipoprotein cholesterol (non-HDL-C) levels are a risk factor for cardiovascular disease (CVD) in subjects with chronic kidney disease (CKD) in the general population.

Methods: A total of 2,630 community-dwelling Japanese subjects (1,107 men and 1,523 women) without history of CVD and aged ≥40 years were prospectively followed up for an average of 19 years, and the association between serum non-HDL-C levels and the incidence of type-specific CVD was estimated using a Cox proportional hazards model. CKD was defined as estimated glomerular filtration rate ＜60 mL/min/1.73 m² or proteinuria (≥1＋ on dipstick).

Results: At baseline, 357 subjects had CKD. During the follow up, 186 coronary heart disease (CHD) and 277 stroke events occurred. The age- and sex-adjusted incidence of CHD was significantly higher in subjects with higher non-HDL-C levels, both in those with and without CKD. In the CKD group, the risk of CHD was significantly higher in those with non-HDL-C levels of 150– 189 mg/dL [adjusted hazard ratio (HR), 2.23; 95% confidence interval (CI), 1.04–4.77] and those with levels ≥190 mg/dL (adjusted HR, 3.20; 95% CI, 1.46–7.03) than in those with levels ＜150 mg/dL. In the non-CKD group, the risk of CHD was significantly higher only in those with nonHDL-C levels ≥190 mg/dL (adjusted HR, 2.12; 95% CI, 1.33–3.38). However, no such association was observed for the risk of stroke.

Conclusions: Our findings suggest that higher serum non-HDL-C levels are associated with greater risk of CHD in subjects with and without CKD and that this association is greater in subjects with CKD than in those without CKD.

Aim: Vascular calcification (VC) is a risk factor of cardiovascular and all-cause mortality in patients with chronic kidney disease (CKD). CKD–mineral and bone metabolism disorder is an important problem in patients with renal failure. Abnormal levels of serum phosphate and calcium affect CKD–mineral and bone metabolism disorder and contribute to bone disease, VC, and cardiovascular disease. Hypercalcemia is a contributing factor in progression of VC in patients with CKD. However, the mechanisms of how calcium promotes intracellular calcification are still unclear. This study aimed to examine the mechanisms underlying calcium-induced calcification in a rat aortic tissue culture model.

Methods: Aortic segments from 7-week-old male Sprague–Dawley rats were cultured in serum-supplemented medium for 10 days. We added high calcium (HiCa; calcium 3.0 mM) to high phosphate (HPi; phosphate 3.8 mM) medium to accelerate phosphate and calcium-induced VC. We used phosphonoformic acid and the calcimimetic R-568 to determine whether the mechanism of calcification involves Pit-1 or the calcium-sensing receptor.

Results: Medial VC was significantly augmented by HPi+HiCa medium compared with HPi alone (300%, p＜0.05), and was associated with upregulation of Pit-1 protein. Pit-1 protein concentrations in HPi+HiCa medium were greater than those in HPi medium. Phosphonoformic acid completely negated the augmentation of medial VC induced by HPi+HiCa. R-568 had no additive direct effect on medial VC.

Conclusion: These results indicated that exposure to HPi+HiCa accelerates medial VC, and this is mediated through Pit-1, not the calcium-sensing receptor.

Aim: We investigated the relationships of serum uric acid levels with the progression of atherosclerosis in patients with peripheral arterial disease (PAD) after treatment.

Methods: Subjects were male patients diagnosed with PAD. Atherosclerosis at the common carotid artery was evaluated based on its intima–media thickness (IMT). Leg arterial flow was evaluated by measuring ankle–brachial index (ABI) and exercise-induced decrease in ABI.

Results: Among various risk factors including age, blood pressure, adiposity, estimated glomerular filtration rate, and blood lipid, blood glucose, uric acid, fibrinogen and C-reactive protein levels, only uric acid levels showed significant correlations with ABI [Pearson's correlation coefficient, −0.292 (p＜0.01)] and leg exercise-induced decrease in ABI [Pearson's correlation coefficient, 0.236 (p＜ 0.05)]. However, there was no significant correlation between uric acid levels and maximum or mean IMT. Odds ratios of subjects with the 3rd tertile versus subjects with the 1st tertile for uric acid levels were significantly higher than the reference level of 1.00 for low ABI [4.44 (95% confidence interval, 1.45–13.65, p＜0.01)] and for high % decrease in ABI after exercise [4.31 (95% confidence interval, 1.34–13.82, p＜0.05)]. The associations of uric acid levels with the indicators of leg ischemia were also found after adjustment for age, history of revascularization therapy, diabetes, smoking, alcohol consumption, body mass index, triglyceride levels, and renal function.

Conclusion: Uric acid levels are associated with the degree of leg ischemia in patients with PAD. Further interventional studies are needed to determine whether the correction of uric acid levels is effective in preventing the progression of PAD.

Aim: Elevated level of serum triglyceride (TG) is a characteristic of type 2 diabetes. We evaluated the clinical significance of intervention for the serum TG levels in the fasting and postprandial states in patients with type 2 diabetes.

Methods: Fifty patients with type 2 diabetes, treated with statins, were selected and divided into two groups. One group was treated with a combination of fenofibrate and ezetimibe (F/E group) and the other group with statins (statin group) for 12 weeks. The lipoprotein profile of both groups was compared using high-performance liquid chromatography, and the vascular function was assessed using flow-mediated dilation (FMD) at the forearm.

Results: The levels of very low-density lipoprotein (VLDL) cholesterol, malondialdehyde low-density lipoprotein (MDA-LDL), total TG, chylomicron-TG, VLDL-TG, and HDL-TG decreased in the F/E group, whereas those of HDL cholesterol increased. Furthermore, the peak particle size of LDL increased, but that of HDL decreased in the F/E group. The combination treatment significantly improved the FMD. The change in the cholesterol level in a very small fraction of HDL was a significant independent predictor for determining the improvement of FMD (p＜0.01).

Conclusions: Compared with the treatment with statins, the treatment with the combination of fenofibrate and ezetimibe effectively controlled the LDL cholesterol and TG levels, increased the HDL cholesterol level, especially in its small fraction, and improved vascular function of patients with type 2 diabetes.