Lecithin:cholesterol acyltransferase (LCAT) is the only enzyme capable of esterifying cholesterol in plasma, thus determining the maturation of high-density lipoproteins. Because it maintains an unesterified cholesterol gradient between peripheral cells and extracellular acceptors, for a long time, LCAT has been considered as a key enzyme in reverse cholesterol transport. However, despite the fact that it has been more than 50 years since the identification of LCAT, the role of this enzyme in the pathogenesis of atherosclerosis is still debated. A number of studies have been conducted in different animal models, with contradictory results. Studies in humans, in particular in the general population, in subjects at high cardiovascular risk, and in carriers of genetic LCAT deficiency in an excellent model to evaluate the correlation between the reduction of LCAT activity and atherosclerosis also gave conflicting results. This review provides a comprehensive overview of the controversial findings obtained in animals and humans, strengthening the necessity of further investigation to establish how LCAT could be regulated in a promising therapeutic strategy to reduce cardiovascular risk.
Since 2001, brachial-ankle pulse wave velocity (brachial-ankle PWV) measurement has been applied for risk stratification of patients with atherosclerotic cardiovascular disease and/or its risk factors in Japan. Measurement of the brachial-ankle PWV is simple and well standardized, and its reproducibility and accuracy are acceptable. Several cross-sectional studies have demonstrated a significant correlation between the brachial-ankle PWV and known risk factors for cardiovascular disease; the correlation is stronger in subjects with cardiovascular disease than in those without cardiovascular disease. We conducted a meta-analysis, which demonstrated that the brachial-ankle PWV is an independent predictor of future cardiovascular events. Furthermore, the treatment of cardiovascular risk factors and lifestyle modifications have been shown to improve the brachial-ankle PWV. Thus, at present, brachial-ankle PWV is close to being considered as a useful marker in the management of atherosclerotic cardiovascular disease and/or its risk factors.
Heart failure is a primary cause of death worldwide, and it is notable that heart failure patients exhibit a high incidence of diabetes. On the other hand, comorbid diabetes significantly worsens the prognosis of heart failure, even independently of complicated coronary artery disease. To date, heart failure caused by diabetes has been designated as “diabetic cardiomyopathy (DMC),” and a recent cohort study of the large-scale (1.9 million people) research platform of linked electronic medical records in UK (CALIBER registry) demonstrated that heart failure and peripheral arterial disease are the most common initial manifestations of cardiovascular disease in type 2 diabetes. The underlying pathophysiology has been characterized as microvasculopathy, myocardial hypertrophy, and cardiac fibrosis; however, these evidences are mostly obtained under a preclinical setting, and its clinical application on DMC in terms of its diagnosis and therapeutic intervention yet has reached practical. Our group has focused on and clarified the molecular mechanisms underlying DMC both in preclinical and clinical settings and has found the primary role of “dipeptidyl peptidase-4 (DPP4)” in the pathogenesis of diabetic microvasculopathy in the heart. Moreover, there are evidences implicating the potent role of circulating DPP4 activity in the diagnosis of diastolic heart failure. The present review aimed to review the current comprehension regarding diabetes and heart failure and discuss the therapeutic and diagnostic roles of DPP4.
Measurement of arterial stiffness in routine medical practice is important to assess the progression of arteriosclerosis. So far, many parameters have been proposed to quantitatively represent arterial stiffness. Among these, pulse wave velocity (PWV) has been most frequently applied to clinical medicine because those could be measured simply and non-invasively. PWV had established the usefulness of measuring arterial wall stiffness. However, PWV essentially depends on blood pressure at the time of measurement. Therefore, PWV is not appropriate as a parameter for the evaluation of arterial stiffness, particularly for the studies involving blood pressure changes. On the other hand, stiffness parameter β is an index reflecting arterial stiffness without the influence of blood pressure. Recently, this parameter has been applied to develop a new arterial stiffness index called cardio-ankle vascular index (CAVI). Therefore, CAVI does not depend on blood pressure changes during the measurements; CAVI could represent the stiffness of the arterial tree from the origin of the aorta to the ankle. Many clinical studies obtained from CAVI are being accumulated. CAVI showed high value in arteriosclerotic diseases, such as coronary artery diseases, cerebral infarction, and chronic kidney diseases, and also in majority of people with various coronary risk factors. The improvement of those risk factors decreased CAVI. Furthermore, the role of CAVI as a predictor of cardio-vascular events was reported recently. We review the clinical studies on CAVI and discuss the clinical usefulness of CAVI as a candidate surrogate end-point marker for cardiovascular disease.
Aim: In Japan Atherosclerosis Society guidelines for the prevention of atherosclerotic cardiovascular diseases 2012 (JAS2012), NIPPON DATA80 risk assessment chart (ND80RAC) was adopted to estimate the 10-year probability of coronary artery disease (CAD) mortality. However, there was no comparison between the estimated mortality calculated by ND80RAC and actual mortality in external populations. Accordingly, we used the large pooled database of cohorts in Japan, EPOCH-JAPAN, as an external population. Methods: The participants of EPOCH-JAPAN without a history of cardiovascular disease (15,091 men and 18,589 women aged 40–74 years) were analyzed based on sex. The probability of a 10-year risk of CAD/stroke mortality was estimated by ND80RAC. The participants were divided into both decile of their estimated mortality and three categories according to JAS2012. The calibration between the mean estimated mortality and the actual mortality was performed by the Hosmer and Lemeshow (H-L) test. Results: In both sexes, the estimated CAD mortality was higher than the actual mortality, particularly in higher deciles of estimated mortality, and the estimated stroke mortality was almost concordant with the actual mortality in low/moderate deciles of estimated mortality. As for the categories according to JAS2012, the estimated CAD mortality was higher than the actual mortality in both sexes; actual mortality in Category III was lower than that in Category II in women. However, it increased in the ascending order of category when we excluded the presence of diabetes from Category III. Conclusions: The estimated CAD mortality by ND80RAC tended to be higher than the actual mortality in the population in which the baseline survey was more recently performed.
Aim: Arteriosclerosis obliterans (ASO) of the lower extremities is a major cause of adult limb loss worldwide. A timely diagnosis in the early stages of the disease determines the clinical outcomes, however lacking of palpable symptoms remains the biggest obstacle. This study aimed to screen a cluster of microRNAs (miRNAs) that can be used as biomarker for the ASO in the earlier stages. Methods: Plasma from 3 patients with ASO and 3 healthy controls were profiled to screen altered miRNAs by microarray, then Real time PCR was further used to confirm the changes in 55 ASO patients and 54 controls.We also analyzed the correlation of miRNAs level with Fontaine stages and the influence of T2DM which is a common complication with ASO on the level of miRNAs. Result: Twenty-four aberrantly expressed miRNAs were screened in the plasma of ASO patients. Real time PCR verified that the level of miR-4284 was significantly increased, while levels of miR-4463, miR-4306 and miR-221-3p were significantly decreased both in the plasma and in the sclerotic samples compared with the controls. Interestingly, we revealed a time and stage specific expression manner, as shown that expression of miR-4284 increased at the stage I of ASO and maintained the tendency to stage IV, while miR-4463 expression decreased at every stage of ASO; however, the expression of miR-4463 showed opposite changes in ASO patients with or without T2DM. Conclusion: Altered expressions of miR-4284 and miR-4463 are novel characteristics and may serve as potential biomarkers for the early diagnosis of ASO.
Aim: The association between aging and insulin resistance has been unclear. We evaluated the effects of aging on visceral fat area (VFA) and subcutaneous fat area (SFA) measured by computed tomography, homeostasis model assessment of insulin resistance (HOMA-IR), and homeostasis model assessment of β-cell function (HOMA-β) among participants in a comprehensive health checkup. Methods: This study included 1,050 male and 700 female Japanese participants aged 35-84 years in our comprehensive health checkup program during a 2-year period. Participants who were on medication for diabetes mellitus or those who met the pre-determined exclusion criteria were excluded. The participants were divided into five groups according to age. Results: As age increased from Group 1 to Group 5, both VFA and VFA/SFA ratio significantly increased in both male and female participants, whereas log[HOMA-IR] linearly and significantly decreased (p＜0.0001 for each). Body mass index (BMI), waist circumference (WC), and SFA increased with age in female participants but decreased in male participants. Although age was not or only weakly correlated with log[glucose] and log[HbA1c] in both male and female participants, age showed significant negative correlations with log[insulin], log[HOMA-IR], and log[HOMA-β] even after adjusting for BMI and WC (p＜0.0001 for each). Serum high-molecular-weight adiponectin (HMW-ADPN) levels were measured in 114 male and 87 female participants, and log[HMW-ADPN] was negatively correlated with log[HOMA-IR] and positively correlated with age in both male and female participants. Conclusions: In the present study, both male and female participants showed increases in VFA and VFA/SFA ratio and decreases in insulin, HOMA-IR, and HOMA-β with age.
Aim: Increased carotid artery intima media thickness (C-IMT) is an early feature of atherosclerosis. It has been reported to be altered in patients with thyroid dysfunction, and the evidence is still controversial. The present study aimed to explore the relationship between C-IMT and possible variations in thyroid function in Chinese adults aged 40 years and above.
Methods: A community-based cross-sectional study was conducted among 2276 non-diabetic participants. Serum free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH) were determined by chemiluminescent microparticle immunoassay.
Results: The prevalence of elevated C-IMT decreased according to FT3 quartiles (29.8%, 24.3%, 24.2%, and 22.2%, P for trend=0.005). In both univariate and multivariate linear regression analyses, FT3 levels were inversely associated with C-IMT (both P values ≤ 0.002). Multivariate-adjusted logistic regression analysis showed that high FT3 levels were associated with low prevalent elevated C-IMT. The adjusted odds ratio for elevated C-IMT was 0.71 (95% confidence interval, 0.52-0.99, P=0.04) when comparing the highest with the lowest quartile of FT3.
Conclusions: Serum FT3 levels were inversely associated with elevated C-IMT in middle-aged and elderly Chinese adults without diabetes, independent of traditional risk factors for atherosclerosis.
Aim: Postprandial lipid level increases induce oxidative stress, which is involved in atherogenesis. The antioxidant properties of paraoxonase 1 (PON1) have attracted attention. However, changes in postprandial PON1 levels differ across prior studies, and changes in PON1 lactonase activity, potentially relevant to PON1 physiology, after the consumption of ordinary meals are unknown. Herein we evaluated postprandial serum lipid levels and PON1 changes following mixed-meal consumption of the amounts recommended for ordinary meals. Methods: Nine healthy male volunteers consumed three different meals in a randomized cross-over design. The test meals were as follows: S, white rice; SMF, S with fat-containing protein-rich main dishes; and SMFV: SMF with vegetable dishes. The serum lipid concentrations and PON1 lactonase and arylesterase activities were determined during a three-hour period after the consumption of these meals. Results: The postprandial triglyceride levels were higher after consuming the SMF and SMFV meals than after consuming the S meal. Despite postprandial high-density lipoprotein cholesterol being unchanged, PON1 lactonase activity was decreased, while PON1 arylesterase activity was increased in the postprandial state after all test meals. Postprandial changes in lactonase and arylesterase activities did not differ among the test meals. Conclusions: Inverse changes in PON1 lactonase and arylesterase activities were observed after consuming recommended ordinary meals. This observation provides useful information for choosing PON1 species as postprandial markers.
Aim: The amount of contrast media and renal atheroemboli are risk factors for acute kidney injury after percutaneous coronary intervention (PCI). However, the chronic kidney injury after PCI has not been fully characterized. The purpose of this study was to investigate factors affecting renal function in the late phase after PCI by measuring serum Cystatin C (CysC). Methods: In 143 consecutive patients who underwent elective PCI, CysC was evaluated at baseline and at 9 months after PCI, and the percent change in CysC (%CysC) was calculated. The association between %CysC and baseline characteristics, including medication use, was assessed. Results: Of 143 patients, 86 had worsening renal function (WRF; %CysC ≥0), and 57 did not (non-WRF; %CysC ＜0). Only the use of angiotensin-converting enzyme inhibitor (ACEI) and baseline CysC were significantly different between WRF and non-WRF patients (15 vs. 40%, p=0.001 and 1.02±0.26 vs. 1.13±0.26 mg/L, p=0.015). In univariate analysis, the use of ACEI and CysC were negatively associated with WRF [Odds ratio (OR)=0.26, 95% confidence interval (CI)=0.12–0.57, p＜0.001 and OR=0.20, 95% CI=0.05–0.73, p=0.015]. Furthermore, multivariate analysis revealed that the use of ACEI and CysC significantly correlated with WRF (OR=0.26, 95% CI=0.11–0.57, p＜0.001 and OR=0.20, 95% CI=0.05–0.74, p=0.016). The %CysC in 36 patients with ACEI was significantly lower than that in 107 patients without ACEI [median: －3.8%; interquartile range (IQR), －11.0 to 4.2%; vs. median: 3.3%; IQR －2.9 to 11.0%, p=0.001]. Conclusion: The use of ACEI was associated with lower CysC after PCI, suggesting that ACEI prevents worsening of renal function in late phase after PCI.