Metabolism is one of the vital functions of cells and living organisms, and the systems to sense and respond to the metabolic alterations play pivotal roles in a plethora of biological processes, including cell proliferative activities, immune cell functions, aging processes, and neuronal functions. Recently, we have reported that a transcriptional cofactor, C-terminal binding protein 2 (CtBP2), serves as a critical metabolite sensor in this context. CtBP2 has a structural pocket called Rossmann fold to accommodate metabolites, and it has been reported to be activated upon binding to NADH/NAD^＋. Owing to its preferential binding affinity for NADH compared with NAD^＋, increased glycolysis activates CtBP2 by regenerating NADH from NAD^＋. Furthermore, we recently reported that fatty acyl-CoAs, metabolites accumulated under the condition of lipid overload, as represented by obesity, can inactivate CtBP2. These observations suggest that CtBP2 monitors not only redox state but also energy substrate preference in the maintenance of metabolic homeostasis. In line with these metabolite-sensing capabilities, CtBP2 is activated in healthy subjects to protect against metabolic disturbances, whereas inactivation of CtBP2 in obesity contributes to the pathogeneses of obesity.

This metabolic system orchestrated by CtBP2 can provide a novel framework for understanding how cells maintain their homeostasis through coordination of metabolism, and CtBP2 incapacitation can be a critical point of the obesogenic cascade.

Aim: Omega-3 fatty acids have emerged as a new option for controlling the residual risk for coronary artery disease (CAD) in the statin era. Eicosapentaenoic acid (EPA) is associated with reduced CAD risk in the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention trial, whereas the Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia trial that used the combination EPA/docosahexaenoic acid (DHA) has failed to derive any clinical benefit. These contradictory results raise important questions about whether investigating the antiatherosclerotic effect of omega-3 fatty acids could help to understand their significance for CAD-risk reduction.

Methods: The Attempts at Plaque Vulnerability Quantification with Magnetic Resonance Imaging Using Noncontrast T1-weighted Technic EPA/DHA study is a single-center, triple-arm, randomized, controlled, open-label trial used to investigate the effect of EPA/DHA on high-risk coronary plaques after 12 months of treatment, detected using cardiac magnetic resonance (CMR) in patients with CAD receiving statin therapy. Eligible patients were randomly assigned to no-treatment, 2-g/day, and 4-g/day EPA/DHA groups. The primary endpoint was the change in the plaque-to-myocardium signal intensity ratio (PMR) of coronary high-intensity plaques detected by CMR. Coronary plaque assessment using computed tomography angiography (CTA) was also investigated.

Results: Overall, 84 patients (mean age: 68.2 years, male: 85%) who achieved low-density lipoprotein cholesterol levels of ＜100 mg/dL were enrolled. The PMR was reduced in each group over 12 months. There were no significant differences in PMR changes among the three groups in the primary analysis or analysis including total lesions. The changes in CTA parameters, including indexes for detecting high-risk features, also did not differ.

Conclusion: The EPA/DHA therapy of 2 or 4 g/day did not significantly improve the high-risk features of coronary atherosclerotic plaques evaluated using CMR under statin therapy.

Aims: It remains inconclusive regarding alcohol intake and stroke risk because determining risk factors depends on the specific pathogenesis of stroke. We used the variant rs671 in the aldehyde dehydrogenase 2 gene (ALDH2) as an instrument to investigate the causal role of alcohol intake in cerebral small- and large-vessel diseases.

Methods: We studied 682 men (mean age, 70.0 years), without stroke, in a cross-sectional Mendelian randomization analysis. We assessed small-vessel diseases (SVDs), which comprised lacunar infarcts, white matter hyperintensities (WMHs), and cerebral microbleeds, and large intracranial artery stenosis (ICAS) on brain magnetic resonance imaging.

Results: The median (25%tiles, 75%tiles) alcohol consumption by ALDH2-rs671 inactive A allele (n=313 [45.9%]) and non-A allele (n=369 [54.1%]) carriers was 3.5 (0.0, 16.0) and 32.0 (12.9, 50.0) g/day, respectively. Non-A allele carriers had higher prevalent hypertension and lower low-density lipoprotein cholesterol concentrations than A allele carriers. In age-adjusted ordinal logistic regression for graded burden, odds ratios (95% confidence intervals) for total SVDs, lacunar infarcts, WMHs, cerebral microbleeds, and ICAS in non-Aallele carriers were 1.46 (1.09-1.94), 1.41 (0.95-2.08), 1.39 (1.05-1.85), 1.69 (1.06-2.69), and 0.70 (0.50-0.98), respectively, compared with A allele carriers. These associations attenuated to statistical non-significance after considering covariates and amount of alcohol intake.

Conclusions: Our findings suggest a positive association of alcohol consumption with risk of cerebral SVDs and its inverse association with risk of large-vessel disease through intermediaries, such as hypertension or low-density lipoprotein cholesterol. These findings provide insight into potential causal mechanisms linking alcohol consumption with stroke risk.

Aim: The accuracy of the DISFORM (diameter reduction, spiral shape, flow impairment, or adverse morphology) classification system has not been validated.

Methods: This retrospective multicenter observational study enrolled 288 consecutive patients with lower extremity artery disease who underwent endovascular therapy with drug-coated balloons for femoropopliteal lesions between January 2018 and December 2021. Patients were classified into DISFORM I–IV groups. Primary patency (PP) and freedom from clinically driven target lesion revascularization (CD-TLR) at 12 months, and recurrence predictors at 12 months were investigated.

Results: In total, 183, 66, 11, and 28 patients were classified into DISFORM I, II, III, and IV groups, respectively. In the DISFORM I, II, III, and IV groups, the PP rates were 75.3%, 91.1%, 87.5%, and 50.0%, respectively, and freedom from CD-TLR rates were 86.0%, 91.6%, 88.9%, and 76.7%, respectively, at 12 months. In the DISFORM I–III and IV groups, the PP rates were 79.4% and 50.0%, respectively, and freedom from CD-TLR rates were 87.5% and 76.7%, respectively, at 12 months. Multivariate analysis showed that chronic limb-threatening ischemia, DISFORM IV, and Lutonix™ use were independent predictors of PP loss at 12 months.

Conclusion: DISFORM IV had a lower PP rate than DISFORM I–III in midterm phase.

Aim: Both recurrent myocardial infarction (ReMI) and bleeding events after acute myocardial infarction (AMI) were reportedly associated with increased mortality. To date, the prognostic impact of these events on subsequent outcomes in East Asians is still unclear. In this study, we aimed to investigate the impact of bleeding or thrombotic events during acute phase on subsequent mortality and time-dependent change of the impact in patients with AMI undergoing percutaneous coronary intervention (PCI).

Method: We conducted a prospective, multicenter, observational study of patients with AMI (n=12,093). The patients who did not undergo emergent PCI were excluded. In addition, the patients registered before 2003 were excluded because the data of bleeding severity was not obtained. Eligible patients were divided into two groups based on the occurrence of major bleeding within 7 days of PCI, and the same approach was performed for ReMI within 7 days of PCI. The endpoint of this study was all-cause death. We assessed the impact of major bleeding and ReMI, which occurred within 7 days of index PCI, on the subsequent clinical outcomes up to 5 years.

Results: A total of 6,769 patients were found to be eligible. All-cause death occurred in 898 (13.3%) patients during a median follow-up period of 1,726 [511–1,840] days. After adjustment for multiple confounders, major bleeding in 7 days from index PCI was independently associated with higher 30-day and 30-day to 1-year mortality (odds ratio [OR]: 2.06 [1.45–2.92] p＜0.001, OR: 2.03 [1.28–3.15] p=0.002), whereas ReMI was not (OR: 1.93 [0.92–3.80] p=0.07, OR: 0.81 [0.24–2.03] p=0.68). Major bleeding and ReMI did not affect mortality between 1 and 5 years (hazard ratio [HR]: 1.32 [0.77–2.26] p=0.31, HR: 0.48 [0.12–1.94] p=0.30).

Conclusion: Major bleeding in 7 days from admission was independently associated with higher 30-day and 1-year mortality but not during 1–5 years. ReMI did not affect mortality in all phases. We should be more concerned about bleeding event during acute phase after PCI.

Aims: Several studies have revealed an association between moderate-to-vigorous physical activity (MVPA) and arterial stiffness, which is a known risk factor for cardiovascular disease. However, a few studies have considered the difference in the longitudinal effect of its intensity in a large general population. Therefore, we examined the effect of MVPA intensity on longitudinal changes in arterial stiffness.

Methods: We conducted a prospective cohort study involving 1,982 Japanese men and women. Arterial stiffness was measured using the cardio–ankle vascular index (CAVI) at baseline and 5-year follow-up. Physical activity was quantified using the Japan Arteriosclerosis Longitudinal Study Physical Activity Questionnaire and categorized into quartiles as MVPA levels. Linear mixed models were used to examine the differences at baseline and the rate of changes in CAVI associated with MVPA levels for over 5 years.

Results: The multivariable-adjusted mean differences in CAVI at baseline were significantly lower in the third (β=−0.019 [95% confidence interval {CI}=−0.033 to −0.005]) and fourth (β=−0.018 [95% CI=−0.035 to −0.001]) quartiles of the MVPA group compared with those in the lowest quartile of MVPA, and the significant effect persisted 5 years later.

Conclusions: In summary, this study provides evidence to support the existence of a threshold for beneficial levels of MVPA in the prevention of arterial stiffness. Furthermore, this study suggests that exceeding this threshold may exert similar effects on arterial stiffness. These findings suggest that an optimal level of MVPA exists for preventing arterial stiffness, and exceeding this threshold may not engender additional benefits.

Aims: In the arterial tree, a pressure gradient of the systolic blood pressure (SBP) is observed from the center to the periphery, with the pressure being higher in the periphery because of pressure wave reflection. However, this gradient is attenuated, with elevation of the central SBP (cSBP), in cases with abnormal pressure wave reflection in the arterial tree. It remains unclear if increase of the cSBP might be an independent risk factor for accelerated progression of arterial stiffness. We conducted this prospective observational study using latent growth curve model (LGCM) analyses to examine if elevated cSBP might be an independent risk factor for accelerated progression of the arterial stiffness in middle-aged Japanese men.

Methods: In this 9-year prospective observational study, we analyzed the data of 3862 middle-aged Japanese men (43±10years old) without cerebrocardiovascular disease at the study baseline who had undergone repeated annual measurements of the brachial-ankle pulse wave velocity (baPWV) and cSBP, as represented by the second peak of the radial pressure waveform (SBP2) in radial pressure waveform analysis.

Results: During the follow-up period (6.3±2.5years), significant increases of both the baPWV and SBP2 were observed in all the subjects. Analysis using the LGCM confirmed that the SBP2, a marker of the cSBP (B=0.260, P＜0.001), was a significant determinant of the slope of the annual changes of the baPWV during the study period.

Conclusions: Our finding may appear to confirm elevated cSBP as an independent risk factor for accelerated progression of the arterial stiffness in middle-aged Japanese men.