Metabolomics has developed as a powerful tool for investigating the complex pathophysiology underlying atherosclerosis and cardiovascular disease. Many epidemiological studies have applied this technique to accurately and comprehensively assess the effects of environmental factors on health outcomes, which used to be a perpetual challenge. Metabolites are defined as small molecules which are intermediate products of metabolic reactions catalyzed by numerous enzymes occurring within cells. Consequent to both genetic variation and environment, they allow us to explore the gene–environment interactions and to gain a better understanding of multifactorial diseases like cardiovascular disease. This review article highlights the findings of well-known prospective cohort studies around the world that have utilized metabolomics for a wide range of purposes, including biomarker discovery, improving cardiovascular risk prediction and early disease diagnosis, and exploring detailed mechanisms of disease onset and progression. However, technical challenges still exist in applying them clinically. One limitation is due to various analytical platforms that are used based on the judgment of each study; comparative assessments among different platforms need to be conducted in order to correctly interpret and validate each data externally. Secondly, metabolite levels obtained in most high-throughput metabolomics profiling studies are often semiquantitative rather than fully quantitative concentrations, which makes it difficult to compare and combine results among different studies and to determine the levels for practical use. In 2014, the Consortium of Metabolomics Studies was developed, which is expected to take the lead in overcoming these issues.

Aim: Endothelial lipase (EL), hepatic lipase (HL), and lipoprotein lipase (LPL) are all triglyceride lipases and are associated with coronary artery disease (CAD). However, whether they can be simultaneous independent risk factors for CAD is unknown. In the present study, we investigated whether the three lipases can be independent risk factors simultaneously for CAD and whether combining these lipases could provide greater predictive power than high-density lipoprotein cholesterol (HDL-c) for the development of CAD.

Methods: Eighty-six patients with CAD and 65 healthy controls were enrolled in the study. Additionally, 38 patients who underwent one-year follow-up angiography after percutaneous coronary intervention with stent implantation were collected to investigate in-stent restenosis. Serum EL, HL, and LPL concentrations were measured and compared with other coronary risk factors.

Results: Serum EL and HL concentrations were both significantly increased in patients with CAD or in-stent restenosis, whereas serum LPL concentration was reduced significantly in patients with CAD. Multivariate logistic regression analysis indicated that the three lipases were simultaneous independent risk factors for CAD. However, only serum EL concentration was considered an independent risk factor for in-stent restenosis. Importantly, the receiver operating characteristic curve showed that the combined measurement of the three lipases displayed better predictive power than HDL-c or any one of the three lipases for CAD.

Conclusions: Serum EL concentration was an independent risk factor for both CAD and in-stent restenosis. Moreover, the combined assessment of serum EL, HL, and LPL concentrations as multiple risk factors provided potent predictive power for CAD.

Aim: Previous studies suggested a positive association between eczema and cardiovascular disease (CVD), probably through enhanced systemic inflammation. However, several studies reported null findings about eczema and CVD, so the evidence is still controversial.

Methods: We asked 85,099 participants (35,489 men and 49,610 women), aged 40 to 79 years, without a history of CVD or cancer at baseline between 1988 and 1990, to complete a lifestyle questionnaire, including information eczema frequency (seldom, sometimes or often).

Results: During the 6,389,818 person-years of follow-up, there were 1,174 deaths from coronary heart disease (CHD), 979 from heart failure, 366 from cardiac arrhythmia, 2,454 from total stroke, 1,357 from ischemic stroke, 1,013 from hemorrhagic stroke, and 201 from aortic aneurysm or dissection. The multivariable-adjusted model showed that individuals who “sometimes” or “often” had eczema had 0.82 (95%confidence interval (CI): 0.69–0.97) or 1.26 (95%CI: 1.01–1.56) times the risk of mortality from CHD, respectively, compared to those who “seldom” did. Individuals who “often” had 1.30 (95%CI: 1.05–1.61) times the risk of mortality from CHD, compared to those who “seldom or sometimes” did. There was no association of eczema with mortality from other CVD, or no interaction between eczema and sex or age, in relation to any CVD mortality risk.

Conclusions: Self-reported frequent eczema was associated with increased risk of mortality from CHD, but not other major CVD, in a Japanese general population. Since steroid usage was not considered, future studies should include it as a potential confounding factor.

Aim: Carotid–cerebral pulse wave velocity (ccPWV) reflects the segment (C-M segment) stiffness between the common carotid artery and ipsilateral middle cerebral artery. C-M segment atherosclerosis (CMSA) is regarded the most frequent cause of anterior circulation ischemic stroke. We aimed to evaluate the association of ccPWV with early stage CMSA in this study.

Methods: Eighty-one acute ischemic stroke (AIS) patients with 154 C-M segments who were successfully evaluated with digital subtraction angiography, ccPWV, carotid intima–media thickness (cIMT), and brachial–ankle pulse wave velocity were enrolled into this study. Patient demographics and clinical data were retrieved from our AIS databases.

Results: Multivariate analyses showed that CMSA was independently associated with higher systolic BP, ccPWV, and cIMT. ccPWV and cIMT presented good diagnostic values for evaluating early stage CMSA in the receiver operating characteristic curve analyses. The areas under the curve (AUCs) of ccPWV were significantly higher than that of cIMT (Z=2.204, P=0.007). The AUC, sensitivity, specificity, Youden index, and cutoff of ccPWV for detecting early stage CMSA were 0.815 (P＜0.001), 86%, 70.7%, 0.567, and 5.4 m/s, respectively. Furthermore, ccPWV was significantly correlated with the stenosis of CMSA at the early stage in Spearman’s correlation analyses (r=0.877, P＜0.001) and fractional polynomial plot with 95% confidence intervals.

Conclusions: Cerebral arterial stiffness has the potential to be a new marker of early stage atherosclerosis of the cerebral large artery. This finding may help us prevent the occurrence of stroke and decrease the burden of society from stroke patients.

Aim: Coronary artery stenosis (CAS) ≥ 50% frequently coexists in patients with acute ischemic cerebrovascular disease (AICVD), which portends unfavorable outcomes. We sought to examine whether patients with AICVD with CAS had more severe and more diffused cervicocephalic atherosclerosis (CA).

Methods: Patients with AICVD were consecutively enrolled and underwent simultaneous computed tomography angiography (CTA) of the coronary and cervicocephalic arteries. A total of 140 patients were divided into “AICVD＋CAS” and “AICVD only” groups according to whether CTA showed stenosis of ≥ 50% in at least one coronary arterial segment. The relationship of the presence of CAS with the severity and extent of CA were examined.

Results: The CA severity characteristics, including the presence of stenosis ≥ 50% and the grade of the most severe stenotic segment, were not significantly different between the two groups. Regarding the extent of CA, the presence of stenosis ≥ 50% in both sides (adjusted odds ratio [OR]: 4.29, 95% confidence interval [CI]: 1.67–10.98), both extracranial and intracranial (adjusted OR: 5.26, 95% CI: 2.24–12.35), both anterior and posterior circulation (adjusted OR: 5.29, 95% CI: 2.22–12.64), and the number of stenotic segments ≥ 50% in cervicocephalic arteries (adjusted OR: 1.58, 95% CI: 1.28–1.96) were associated with CAS in patients with AICVD, independently of clinical demographics and CA severity characteristics.

Conclusion: CA was similarly severe in patients with AICVD with and without CAS, but those with CAS had significantly more diffused CA. The extent of CA and CAS were mutual indicators in patients with AICVD, irrespective of CA severity.

Aims: The proper management of atherosclerotic risk factors (ARFs) and attainment of target levels (TLs) for ARFs are crucial in preventing atherosclerotic cardiovascular disease (ASCVD). In this study, utilizing data from the “Specific Health Check and Guidance in Japan,” which was conducted from 2008 to 2011, we examined TL attainment status of low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP) and prescription status of dyslipidemia and hypertension in patients with diabetes undergoing medical treatment, and analyzed the factors that affected prescription status.

Methods: Subjects receiving medical treatment for diabetes were selected from the database. Subjects were classified by prescription status for dyslipidemia and hypertension, and TL attainment status was assessed for each ARF.

Results: The percentage of subjects who did not attain TLs and were not under medication was higher for LDL-C than for BP. The un-prescribed rates among non-TL-attained subjects were 60%–75% for LDL-C, and around 30%–40% for BP. The un-prescribed rates to those who were qualified for prescription therapy were also higher for LDL-C than for BP. Logistic regression analyses revealed that the subjects who were prescribed for dyslipidemia had the following characteristics compared with the un-prescribed non-TL-attained subjects: older age, higher body mass index, lower estimated glomerular filtration rate, previous heart or cerebrovascular disease, and higher medication rate for other ARFs.

Conclusions: The present study revealed that, in Japan, the adequate prescription rate for dyslipidemia was lower than that for hypertension in patients with diabetes, suggesting the proper prescription therapy for dyslipidemia should be pursued to further prevent ASCVD.

Aim: The visceral adiposity index (VAI) has been proposed as an estimate of visceral adipose tissue (VAT) mass and as an indicator of VAT dysfunction. Both parameters are associated with cardiometabolic risk, including insulin resistance. In this study, we investigated whether VAI is associated with subclinical atherosclerosis in subjects who were free of cardiovascular disease but were at risk of developing diabetes mellitus.

Methods: A total of 731 adults with a median age of 47 years old without diabetes mellitus were included in this cross-sectional study. The anthropometric data, blood pressure, and lipid profiles of 398 women and 333 men were measured. All subjects underwent an oral glucose tolerance test, and carotid intima–media thickness (cIMT) was evaluated by ultrasound. Insulin resistance was estimated using the homeostatic model assessment of insulin resistance (HOMA-IR).

Results: VAI and HOMA-IR (ß_st=0.44, p＜0.0001), VAI and cIMT (ß_st=0.17, p＜0.0001), and HOMA-IR and cIMT (ß_st=0.09, p=0.0127) were correlated with each other. After adjusting for cofounding variables, VAI is still correlated with HOMA-IR (ß_st=0.42, p＜0.0001). Furthermore, VAI (ß_st=0.07, p=0.0392) but not HOMA-IR (ß_st=0.03, p=0.37) was correlated with cIMT independently of other established cardiovascular risk factors.

Conclusion: The calculation of VAI may provide a better estimation of subclinical atherosclerosis than the calculation of HOMA-IR.

Aim: ATP-binding cassette A1 (ABCA1) plays an important role in reducing the risk of stroke. Egg is the major source of dietary cholesterol and is known to be associated with the risk of stroke and atherosclerosis. We aimed to assess the effects of interaction between an ABCA1 variant (rs2066715) and egg consumption on the risk of ischemic stroke (IS), carotid plaque, and carotid-intima media thickness (CIMT) in the Chinese population.

Methods: In total, 5869 subjects (including 1213 IS cases) across 1128 families were enrolled and divided into two groups based on the median egg consumption (4 eggs per week). In the analyses for the presence of carotid plaque and CIMT, 3171 out of 4656 IS-free controls without self-reported history of coronary heart disease and lipid-lowering medications were included. Multilevel logistic regression models were used to model the genetic association of rs2066715 with the risk of IS, and mixed-effect linear regression for the genetic association of rs2066715 with carotid plaque, and CIMT. The gene-by-egg cross-product term was included in the regression model for interaction analysis.

Results: We found that rs2066715 was associated with the increased risk of carotid plaque among those who consumed ＜4 eggs per week after adjustment (odds ratio [95% confidence interval]: 1.61 [1.08, 2.39], P =0.019). A significant effect of interaction between rs2066715 and egg consumption on the risk of carotid plaque was identified (P =0.011).

Conclusion: rs2066715 was found to interact with egg consumption in modifying the risk of carotid plaque in the Chinese population.