Improvements induced in lipid metabolism in the liver by D-47, a newly developed compound, were examined herein. WHHLMI rabbits, an animal model of hypercholesterolemia and coronary atherosclerosis, was fed D-47-supplemented chow for 5 weeks at a dose of 30mg/kg. Lipid concentration were assayed using enzymatic methods. Plasma lipoproteins were fractionated with an ultracentrifuge. mRNA expression was analyzed with real-time PCR. Lipidome analyses of lipoproteins were performed using supercritical fluid chromatography mass spectrometry. In the D-47-treated group, serum lipid levels decreased by 23% for total cholesterol and by 40% for triglycerides. These reductions were mainly attributed to decreases in the VLDL fraction. Compared with the control, in the D-47 group, lipid contents in the liver were decreased by 22% in cholesterol and by 69% in triglycerides, and fat accumulation was decreased by 57% in pericardial fat and by 17% in mesenteric fat. In lipidome analyses of VLDL fraction, lysophosphatidylcholine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylethanolamine plasmalogen, sphingomyelin, and ceramide were decreased by the D-47 treatment. mRNA expression in the liver was 51% lower for FAS and 24% lower for MTP, but 5.9- and 5.1-fold higher for CYP7A1 and CPT-1, respectively, in the D-47 group than in the control. mRNA expression was 72%, 64%, and 36% higher for LPL, CTP-1, and PPARγ, respectively, in mesenteric fat in the D-47 group. D-47 is a potent lipid-lowering compound that uses a different mechanism of action from that of statins. It has potential as a compound in the treatment of steatohepatitis and metabolic syndrome.

Aims: The relationship between the coronary artery running pattern and development of coronary lesions was re-examined herein using WHHLMI rabbits, an animal model of spontaneous coronary atherosclerosis.Methods: The coronary artery running pattern was analyzed using an X-ray computed tomography (CT) apparatus after perfusion. Pathological sections were prepared (Victoria blue-HE staining) at 100 µm intervals from the origin of the left circumflex artery (LCX). The severity of coronary lesions was evaluated based on cross-sectional narrowing (lesion area/inner area of the internal elastic lamina).Results: In the CT analysis, the angle of the main curvature of the LCX negatively correlated with the percentage of sections with lesions and cross-sectional narrowing. The percentage of sections with lesions was significantly higher in acute angle-type LCX than in obtuse angle-type LCX. Cross-sectional narrowing was also significantly greater in acute angle-type LCX than in obtuse angle-type LCX. The percentage of fibrous lesions was high at the proximal region of LCX, whereas that of lipid-rich lesions was high at the curvature. In 24 months age group, the percentage of sections with calcification in acute angle-type LCX was about twice that in obtuse angle-type LCX.Conclusions: Individual differences were observed in the angle of the main curvature of the LCX, which affected the occurrence and extension of atherosclerotic lesions.

Background There is increasing evidence to use direct oral anticoagulants (DOACs) in atrial fibrillation (AF) ablation. Uninterrupted use of DOACs is recommended for peri-procedural anticoagulation; the ways of choosing and/or using DOACs depend on physicians' decisions and preferences. Uninterrupted dabigatran (DAB), a direct thrombin inhibitor, reportedly decreased the risk of major bleeding (MB) in AF ablation, compared to uninterrupted warfarin (NEJM 2017; 376:1627). Among DOACs, only regular-dose of DAB (150 mg b.i.d.), showed superiority to warfarin for preventing ischemic thromboembolism (TE) in patients with non-valvular AF, implicating the powerful anti-thrombotic agent. DAB may decrease the potential risk of procedure-related TE. Purpose To evaluate whether use of DAB on the day of AF ablation decreases the prevalence of silent cerebral ischemia (SCI) detected by magnetic resonance imaging (MRI). Methods 414 AF patients on DOACs were enrolled and admitted on the day before AF ablation. Among 354 patients on factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban), the original DOACs were switched to DAB (150 mg b.i.d.) on the day of the procedure in 172 patients (Group D); the treatment remained unchanged in 182 patients (Group non-D). In both groups, DOACs were continuously used throughout the procedure. After propensity-score matching, procedure-related parameters/events and the incidence of MRI-detected SCI were compared between Group D (n=134) and Group non-D (n=134). These parameters in patients originally taking DAB, used without interruption during the procedure (uninterrupted DAB, n=55), were also compared to Group D (n=55) after propensity-score matching. Results Baseline activated clotting time (ACT) before initial heparin injection was increased in Group D vs. Group-non-D (179±25* vs. 146±23 sec, *p<0.05 vs. Group non-D). The time to achieve optimal ACT (>300 sec) was shorter in Group D (34±29* vs. 43±32 min). The amounts of heparin needed to achieve optimal ACT and the total amount of heparin used during the procedure were unchanged between Group D and Group non-D. The incidence of SCI decreased in Group D (13.1%* vs. 21.9%), suggesting the potential anti-thrombotic efficacy of DAB. No MB or symptomatic TE events were observed in either group. Baseline ACT, the time to achieve ACT >300 sec, and the incidence of SCI in Group D were comparable to those in uninterrupted DAB (183±38 vs. 181±32 sec, 39±31 vs. 42±28 min, and 14.5% vs. 16.4%, respectively). No MB or symptomatic TE events were observed either in Group D or uninterrupted DAB. Conclusions Temporarily switching to DAB from the other DOACs and using it on the day of procedure enable us to achieve optimal ACT quickly and decrease the incidence of SCI, showing similar potential anti-thrombotic efficacy to uninterrupted DAB. Use of DAB on the day of AF ablation also benefits from the availability of its antidote in the case of MB during the procedure.

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