Lipid-lowering therapy plays a central role in reducing cardiovascular events. Over the past few decades, clinical trials utilizing several imaging techniques have consistently shown that lipid-lowering therapy can reduce the coronary plaque burden and improve plaque composition. Although intravascular ultrasound has been the most extensively used modality to assess plaque burden, other invasive modalities, such as optical coherence tomography and near-infrared spectroscopy, provide relevant data on plaque vulnerability, and computed tomography angiography detects both plaque volume and characteristics non-invasively. A large body of evidence supports the notion that reducing low-density lipoprotein cholesterol using statins combined with ezetimibe and proprotein convertase subtillisin/kexin type 9 inhibitors consistently shows improvements in plaque burden and favorable morphological changes. This review summarizes previously obtained data on the impact of lipid-lowering treatment strategies on atherosclerotic plaque regression, as assessed using several imaging modalities.

Despite advancements in managing traditional cardiovascular risk factors, many cardiovascular diseases (CVDs) persist. Fibroblast growth factors (FGFs) have emerged as potential diagnostic markers and therapeutic targets for CVDs. FGF1, FGF2, and FGF4 are primarily used for therapeutic angiogenesis. Clinical applications are being explored based on animal studies using approaches such as recombinant protein administration and adenovirus-mediated gene delivery, targeting patients with coronary artery disease and lower extremity arterial disease. Although promising results have been observed in animal models and early-stage clinical trials, further studies are required to assess their therapeutic potential. The FGF19 subfamily, consisting of FGF19, FGF21, and FGF23, act via endocrine signaling in various organs. FGF19, primarily expressed in the small intestine, plays important roles in glucose, lipid, and bile acid metabolism and has therapeutic potential for metabolic disorders. FGF21, found in various tissues, improves glucose metabolism and insulin sensitivity, suggesting potential for treating obesity and diabetes. FGF23, primarily secreted by osteocytes, regulates vitamin D and phosphate metabolism and serves as an important biomarker for chronic kidney disease and CVDs. Thus, FGFs holds promise for both therapeutic and diagnostic applications in metabolic and cardiovascular diseases. Understanding the mechanisms of FGF may pave the way for novel strategies to prevent and manage CVDs, potentially addressing the limitations of current treatments. This review explores the roles of FGF1, FGF2, FGF4, and the FGF19 subfamily in maintaining cardiovascular health. Further research and clinical trials are crucial to fully understand the therapeutic potential of FGFs in managing cardiovascular health.

Aims: Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator that lowers serum triglyceride levels and increases high-density lipoprotein cholesterol levels, is approved for treating dyslipidemia as twice-daily immediate-release (IR) tablets. A once-daily extended-release (XR) tablet has also been developed. We aimed to confirm the non-inferiority of XR (0.2 or 0.4 mg/day; once daily) to IR (0.2 mg/day; twice daily) in lowering triglyceride levels in patients with hypertriglyceridemia.

Methods: This phase 3, multicenter, randomized, double-blind study included patients with fasting triglycerides ≥ 200 mg/dL who received IR (0.2 mg/day) or XR (0.2 or 0.4 mg/day). The primary efficacy endpoint was the percentage change in fasting triglyceride levels from baseline to 4, 8, and 12 weeks. Common treatment effects at weeks 4 through 12 were compared between groups using repeated analysis of covariance.

Results: In 356 randomized patients, fasting triglyceride levels decreased by 48.0%, 43.8%, and 48.0% with IR 0.2, XR 0.2, and XR 0.4 mg/day, respectively, confirming the non-inferiority of both XR regimens to IR. The proportion of patients who achieved fasting triglycerides ＜150 mg/dL was 45.7%, 37.4%, and 51.7%, while the percentage change of triglycerides in the subgroup with baseline triglycerides ≥ 500 mg/dL was -59.3%, -52.2%, and -66.3% with IR 0.2, XR 0.2, and XR 0.4 mg/day, respectively.

Conclusions: XR (0.2 and 0.4 mg/day) was non-inferior to IR (0.2 mg/day). XR 0.4 mg/day demonstrated a more potent triglyceride-lowering effect than XR 0.2 mg/day and should be considered for patients with high triglyceride levels.

Aim: A twin study is a valuable tool for elucidating the acquired factors against lifestyle diseases such as dyslipidemia, diabetes mellitus, and obesity. We aimed 1. to investigate the factors that affect low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) in monozygotic (MZ) twins, and 2. to identify genes which expression levels changed in pairs with large differences in LDL-C or HDL-C levels.

Methods: The registered database at the Center for Twin Research, Osaka University, containing 263 pairs of MZ twins, was analyzed. 1. The effects of smoking, exercise, nutritional factors, and anthropometric and biochemical parameters on LDL-C or HDL-C levels were examined in MZ twins. 2. RNA sequencing in the peripheral blood mononuclear cells of 59 pairs was analyzed for large differences of LDL-C or HDL-C groups.

Results: 1. The ΔLDL-C levels were significantly associated with an older age, the ΔTG levels, and ΔBMI. ΔHDL-C levels were associated with the ΔBMI, ΔTG, ΔTP, and ΔLDL-C levels. The HDL-C levels were affected by smoking and exercise habits. The intakes of cholesterol and saturated fatty acids were not associated with the LDL-C or HDL-C levels. 2. An RNA sequencing analysis revealed that the expression of genes related to the TLR4 and IFNG pathways was suppressed in accordance with the HDL-C levels in the larger ΔHDL-C group among the 59 pairs.

Conclusion: We identified the factors affecting the LDL-C or HDL-C levels in monozygotic twins. In addition, some types of inflammatory gene expression in peripheral blood mononuclear cells were suppressed in accordance with the HDL-C levels, thus suggesting the importance of weight management and exercise habits in addition to dietary instructions to control the LDL-C or HDL-C levels.

Aims: Hypertriglyceridemia is a risk factor for chronic kidney disease (CKD). However, whether or not it predicts the risk of CKD progression is unknown. This study evaluated the association between serum triglyceride (TG) levels and kidney disease progression in patients with non-dialysis-dependent CKD.

Methods: The Fukuoka Kidney disease Registry (FKR) study was a multicenter, prospective longitudinal cohort study. In total, 4,100 patients with CKD were followed up for 5 years. The primary outcome was the incidence of CKD progression, defined as a ≥ 1.5-fold increase in serum creatinine level or the development of end-stage kidney disease. The patients were divided into quartiles according to baseline serum TG levels under non-fasting conditions: Q1 ＜87 mg/dL; Q2, 87–120 mg/dL; Q3, 121–170 mg/dL, and Q4 ＞170 mg/dL.

Results: During the 5-year observation period, 1,410 patients met the criteria for CKD progression. The multivariable-adjusted Cox proportional hazards model showed a significant association between high serum TG level and the risk of CKD progression in the model without macroalbuminuria as a covariate (multivariable hazard ratio[HR] for Q4 versus Q1, 1.20; 95% CI, 1.03–1.41; P=0.022), but the significance disappeared after adjusting for macroalbuminuria (HR for Q4 versus Q1, 1.06; 95% CI, 0.90–1.24; P=0.507).

Conclusions: The present findings suggest that individuals with high serum TG levels are more likely to develop CKD progression than those without; however, whether or not higher serum TG levels reflect elevated macroalbuminuria or lead to CKD progression via elevated macroalbuminuria is unclear.

Aim: This study investigated the impact of rurality on acute ischemic stroke (AIS) outcomes, emphasizing the hyperacute phase, in which immediate care is crucial.

Methods: This retrospective cohort study analyzed data from a large Japanese hospital network covering AIS patients from 2013-2021, was analyzed. The focus was on patients admitted within 4.5 h of the onset, using the Rurality Index for Japan (RIJ) to categorize patients into rural or urban groups. This study examined treatment methods (intravenous thrombolysis [IVT] and mechanical thrombectomy [MT]) and functional outcomes measured using the modified Rankin Scale (mRS), where scores of 3-6 indicated poor outcomes. Multilevel logistic regression was used to calculate the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for poor outcomes based on rurality. The study also evaluated the population-attributable fraction (PAF) to estimate potential outcome improvements in urban settings.

Results: Of 27,691 patients, 17,516 were included in the total cohort and 4,954 in the hyperacute cohort. Urban patients constituted 73.7% (12,902), with higher IVT (5.2%) and MT (3.6%) rates than rural patients (4.1% IVT, 2.0% MT). Poor mRS outcomes were more common in rural areas than in urban areas, with adjusted ORs of 1.30 (1.18-1.43) in the total cohort and 1.43 (1.19-1.70) in the hyperacute cohort. The PAF for poor outcomes due to rural residency was 14.8% (0.5%-31.0%).

Conclusion: This study demonstrated a notable association between rurality and poorer AIS outcomes in Japan, particularly in the hyperacute phase.

Aim: Oral anticoagulants (OACs) reduce the risk of ischemic stroke but may increase the risk of major bleeding in patients with non-valvular atrial fibrillation (NVAF). Various risk scores, such as HAS-BLED, ATRIA, ORBIT, and DOAC, have been proposed to assess the risk of major bleeding in patients with NVAF receiving OACs. However, limited data are available regarding bleeding risk stratification in Japanese patients with NVAF.

Methods: Of the 16,098 NVAF patients from the J-RISK AF study, the combined data of the five major AF registries in Japan (J-RHYTHM Registry, Fushimi AF Registry, Shinken Database, Keio interhospital Cardiovascular Studies, and Hokuriku-Plus AF Registry), we analyzed 11,539 patients receiving OACs (median age, 71 years old; women, 29.6%; median CHA₂DS₂-VASc score, 3).

Results: During the 2-year follow-up period, major bleeding occurred in 274 patients (1.3% per patient-year). In a multivariate Cox proportional hazards analysis, an advanced age, hypertension (systolic blood pressure ≥ 150 mmHg), bleeding history, anemia, thrombocytopenia, and concomitant antiplatelet agents were significantly associated with a higher incidence of major bleeding. We developed a novel risk stratification system, HED-[EPA]₂-B₃ score, which had a better predictive performance for major bleeding (C-statistics 0.67, [95% confidence interval, 0.63-0.70]) than the HAS-BLED (0.64, [0.60-0.67], P for difference 0.02) and ATRIA (0.63, [0.60-0.66], P for difference ＜0.01) scores. Furthermore, it was non-significantly higher than the ORBIT (0.65, [0.62-0.68], P for difference 0.07) and DOAC (0.65, [0.62-0.68], P for difference 0.17) scores.

Conclusion: Our novel risk stratification system, the HED-[EPA]₂-B₃ score, may be useful for identifying Japanese patients receiving OACs at a risk of major bleeding.

Aims: This was a retrospective cohort study that aimed to determine cutoff values for major adverse cardiovascular events (MACEs) in patients with heterozygous FH (HeFH) for Achilles tendon (AT) thickness (ATT) measured by ultrasonography (US-ATT) and radiography (Xp-ATT), AT softness, and intima-media thickness of carotid artery (C-IMT), and to examine the effectiveness of these values as well as AT calcification as indexes in assessing risk for MACEs.

Methods: The subjects were 391 clinically diagnosed HeFH patients. Kaplan-Meier curves were drawn based on the threshold values for the individual indexes calculated from ROC curves, and multivariate analysis was used to examine whether they were predictors of the development of MACEs.

Results: The median observation period was 1,239 days (700-1,827 days). Twenty-one subjects (5%) had MACEs during the observation period. The cutoff values for MACEs for US-ATT were 9.9 mm in males and 7.1 mm in females, and those for C-IMT were 1.6 mm in males and 1.5 mm in females. Subjects were classified into two groups according to whether they were above or below the cutoff values and presence of calcification, and we compared MACE rates between them. MACE rates were significantly increased in groups with AT thickening determined by ultrasonography (P＜0.001), AT softening (P＜0.001), presence of calcification in AT (P=0.016) and greater C-IMT (P＜0.001). However, classification according to Xp-ATT revealed no significant difference in MACE rate (P=0.112).

Conclusions: These thresholds and examination for AT calcification will help in risk assessment for patients in Japanese FH practice and encourage stricter and more comprehensive management for patients who exceed the thresholds.

Aim: No pharmacotherapeutic treatment has been established for metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). This trial compared the effects of pemafibrate and omega-3-acid ethyl ester on hepatic function in patients with hypertriglyceridemia complicated by MASLD.

Methods: Patients with hypertriglyceridemia complicated by MASLD were enrolled, randomly assigned to the pemafibrate or omega-3-acid ethyl ester group, and followed for 24 weeks. The primary endpoint was the change in alanine aminotransferase (ALT) from baseline to week 24. The secondary endpoints included other hepatic enzymes, lipid profiles, and hepatic fibrosis biomarkers.

Results: A total of 80 patients were enrolled and randomized. The adjusted mean change in ALT from baseline to week 24 was significantly lower in the pemafibrate group (-19.7±5.9 U/L) than in the omega-3-acid ethyl ester group (6.8±5.5 U/L) (intergroup difference, -26.5 U/L; 95% confidence interval, -42.3 to -10.7 U/L; p=0.001). Pemafibrate significantly improved the levels of other hepatic enzymes (aspartate aminotransferase and gamma-glutamyl transpeptidase), lipid profiles (triglycerides, total cholesterol, high-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol), and hepatic fibrosis biomarkers (Mac-2 binding protein glycan isomer and Fibrosis-4 index). No cases of discontinuation due to adverse drug reactions were identified in either group, and there were no safety concerns.

Conclusions: Pemafibrate is recommended over omega-3-acid ethyl ester for lipid management and MASLD treatment in patients with hypertriglyceridemia complicated by MASLD. The study results may contribute to the development of future treatment strategies for patients with MASLD/MASH.

Abetalipoproteinemia (ABL) is a rare disease characterized by extremely low apolipoprotein B (apoB)-containing lipoprotein levels, dietary fat, and fat-soluble vitamin malabsorption, leading to gastrointestinal, neuromuscular, and ophthalmological symptoms. We herein report a case of ABL with novel compound heterozygous mutations in the microsomal triglyceride transfer protein gene (c.1686_1687del [p.Ser563TyrfsTer10] and c.1862T>C [p.Ile621Thr]), identified via panel sequencing. Although the patient had extremely reduced low-density lipoprotein cholesterol levels and a fatty liver, he did not exhibit other typical complications. Furthermore, unlike typical ABL, this patient had a preserved apoB-48 secretion and increased concentrations of high-density lipoprotein cholesterol, which may account for the normal serum fat-soluble vitamin levels.