High-density lipoprotein (HDL) levels have long been inversely associated with cardiovascular disease (CVD) and are traditionally evaluated by serum HDL-cholesterol (HDL-C) levels. However, recent studies have raised doubts regarding the causal role of HDL quantity (HDL-C), drawing attention to HDL functionality. Reverse cholesterol transport (RCT) is a major anti-atherosclerotic mechanism involving ATP-binding cassette A1 (ABCA1), ATP-binding cassette G1 (ABCG1), scavenger receptor class B type I (SRB1), and regulatory factors, such as liver X receptor (LXR) and peroxisome proliferator-activated receptor gamma (PPARγ). Notably, HDL-C levels do not necessarily reflect RCT efficiency, and novel regulatory factors, such as microRNAs, endothelial lipase, and ANGPTL3, have been implicated. HDL also exhibits vasoprotective functions by enhancing nitric oxide (NO) production and modulating sphingosine-1-phosphate (S1P) signaling. Furthermore, it exerts anti-inflammatory effects by suppressing adhesion molecules, proinflammatory cytokines, and innate immune activation while modulating adaptive immune responses and attenuating tissue fibrosis. In addition, HDL influences megakaryopoiesis and platelet activation, thereby contributing to its antithrombotic properties. Despite these broad functional spectra, clinical assessments remain largely limited to cholesterol efflux capacity, and other key functional aspects have not been adequately explored. A more comprehensive understanding of HDL’s pleiotropic roles, spanning lipid metabolism, vascular biology, inflammation, and hemostasis, is necessary from both the basic and clinical perspectives. Recent studies have further suggested potential roles of HDL in the central nervous system, expanding its relevance beyond cardiovascular prevention and toward broader therapeutic applications.

Aims: To investigate the predictors associated with inadequate adherence in patients receiving proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs) in China and to assess the mean LDL-C levels and the percentage reduction of LDL-C.

Methods: Patients with at least one PCSK9-mAbs prescription filled between January 2021 and December 2022 were included in this study. The LDL-C levels before and after treatment initiation were assessed using medical records. Adherence to PCSK9-mAbs was assessed for up to 12 months after treatment initiation using the proportion of days covered.

Results: A total of 415 patients were enrolled. The medication adherence to PCSK9-mAbs after 12 months was 31.8%. A multivariate analysis revealed that better education (junior or high school adjusted OR 2.7 and college or higher adjusted OR 5.2) and LDL-C ＜1.4 mmol/L at 3 months after starting PCSK9-mAbs (adjusted OR 3.0) were consistent predictors of adherence. At 12 months, LDL-C was 1.5mmol/L in the adherence group (mean [SD] decrease, 44.5% [26.5%]) and 1.9 mmol/L in the poor adherence group (mean [SD] decrease, 31.0% [32.7%]), with a group difference of 0.42 mmol/L (group difference in decrease, 13.48%).

Conclusions: A better education and LDL-C ＜1.4 mmol/L at 3 months after starting treatment with PCSK9-mAbs were consistent predictors of adherence. In addition, the treatment effect declined more significantly in the poor adherence group over time.

Aims: The blood inflammatory marker interleukin 6 (IL-6) has been shown to predict future stroke, major adverse cardiovascular events (MACEs), and dementia. However, no study has yet examined this relationship in the same population. The present study compared the predictive utility of IL-6 levels in stroke, MACEs, and Alzheimer’s disease (AD) dementia.

Methods: In this post-hoc analysis, we derived data from a Japanese observational registry in which 1011 patients with evidence of cerebral vessel disease were enrolled. After excluding patients who required assistance with daily tasks, were suspected of having dementia, and lacked IL-6 measurement, 471 patients were included. The patients were followed up until March 2023. The outcomes were incident stroke, MACEs, and AD dementia.

Results: During a median follow-up period of 4.6 years, stroke, MACEs, and AD dementia occurred in 24, 36, and 21 patients, respectively. Serum IL-6 levels are associated with age, sex, and vascular factors. A Cox proportional hazard analysis revealed that the highest IL-6 tertile (≥ 2.5 pg/mL) was associated with a significantly higher risk of stroke and MACEs than the lowest IL-6 tertile after adjusting for confounding factors (stroke, adjusted hazard ratio 4.84 [95% confidence interval, 1.02-23.05], P = 0.048; MACEs, adjusted hazard ratio 3.68 [95% confidence interval, 1.01-13.51], P = 0.049). However, no association was found between IL-6 tertile groups and AD dementia.

Conclusion: Serum IL-6 levels predicted stroke and cardiovascular events but not AD dementia in patients with vascular risk factors. The involvement of low-grade systemic inflammation appears to be significantly greater in atherothrombotic events than that in AD dementia.

Aim: Recently, we reported that a pemafibrate extended-release (XR) formulation lowered low-density lipoprotein cholesterol (LDL-C) and cholesterol synthesis and absorption markers in a phase 2 clinical pharmacology study. Here we describe our post-hoc analysis of that study, discuss the mechanism by which pemafibrate lowers LDL-C, and suggest which patients may respond favorably to pemafibrate treatment.

Methods: In the phase 2 study, patients with hypertriglyceridemia received treatment with pemafibrate immediate-release (IR) 0.2 mg/day or XR 0.4 mg/day or 0.8 mg/day. This post-hoc subgroup analysis examined the percentage change in LDL-C, apolipoprotein B (ApoB), non-HDL-C, and cholesterol synthesis and absorption markers, in subgroups by baseline LDL-C, and then determined the correlation between the percentage change in LDL-C and the percentage change in cholesterol synthesis and absorption markers.

Results: Our analysis included 60 patients who received two of three formulations of the drug. A total of 78.3% (47/60) were male, 16.7% (10/60) had type 2 diabetes mellitus, and 10% (6/60) received concomitant statins. The percentage of LDL-C lowering was greater in the population with high baseline LDL-C, and similar trends were noted for the ApoB, non-HDL-C, and cholesterol synthesis and absorption markers. The percentage change in LDL-C was positively correlated with the percentage change in lathosterol, β-sitosterol, and campesterol.

Conclusions: In patients with hypertriglyceridemia, results suggested that pemafibrate lowered LDL-C by inhibiting cholesterol synthesis in the liver and cholesterol absorption from the intestinal tract. This lowering effect was greater in populations with higher baseline LDL-C.

Aims: Branch atheromatous disease (BAD)-related stroke, caused by atherosclerotic occlusion at the origin of a deep penetrating artery, are prone to early neurological deterioration (END). This study aimed to assess the association between hemostatic activation markers and occurrence of END in patients with BAD-related stroke.

Methods: This prospective observational study included 88 patients with BAD-related stroke within 7 days of onset. On admission, plasma beta-thromboglobulin (beta-TG), platelet factor 4 (PF4), and D-dimer levels were measured. END was defined as an increase of ≥ 2 points in the total National Institutes of Health Stroke Scale (NIHSS) score or ≥ 1 point in the motor items of the NIHSS within 7 days of admission.

Results: Of the 88 patients, 34 (38.6%) experienced END. Mean beta-TG (158 ng/mL vs. 102 ng/mL; P = 0.021), PF4 (61 ng/mL vs. 35 ng/mL; P = 0.024), and D-dimer (2.0 µg/mL vs. 1.2 µg/mL; P = 0.037) levels were significantly higher in patients with END than in those without END. Multivariate analysis revealed that beta-TG and PF4 levels were independently associated with the occurrence of END, with an adjusted odds ratio per 10 ng/mL increase (95% confidence interval) of 1.09 (1.01-1.20) and 1.21 (1.02-1.49), respectively. In contrast, D-dimer levels were not independent predictors. The optimal cutoff values for predicting END were 130 and 55 ng/mL for beta-TG and PF4, respectively.

Conclusions: Elevated beta-TG and PF4 levels were independent predictors of END in patients with BAD-related stroke. Hence, the measurement of these platelet activation markers helps improve the risk assessment of BAD-related stroke and may provide management implications.

Aim: The aim of this study was to clarify the association between serum total cholesterol and fatal subarachnoid hemorrhage in Japanese men and women.

Methods: The study involved a pooled analysis of individual data from 12 well-qualified cohort studies conducted in Japan. The participants were classified according to their serum total cholesterol levels: ＜4.14 mmol/L (＜160 mg/dL), 4.14–4.64 mmol/L (160–180 mg/dL), 4.65–5.16 mmol/L (180–199 mg/dL), 5.17–5.68 mmol/L (200–219 mg/dL), 5.69–6.20 mmol/L (220–239 mg/dL), and ≥ 6.21 mmol/L (≥ 240 mg/dL). The outcome of the analysis was death from subarachnoid hemorrhage.

Results: A total of 120,973 participants (70,947 women and 50,026 men) aged 18–96 years at baseline underwent follow-up for a median of 12.7 years, and 261 participants died from subarachnoid hemorrhage during this period. In women, both low (＜5.69 mmol/L [＜220 mg/dL]) and high (≥ 6.21 mmol/L [≥ 240 mg/dL]) serum total cholesterol levels were significantly associated with a higher risk of fatal subarachnoid hemorrhage compared with the reference group (5.69–6.20 mmol/L [220–239 mg/dL]). These associations remained significant after adjustment for confounding factors. In contrast, no associations were observed in men.

Conclusion: Both low and high serum total cholesterol levels were associated with a higher risk of fatal subarachnoid hemorrhage in 70,947 female participants from 12 cohort studies throughout Japan.

Aims: Intensive lipid-lowering therapy is recommended for secondary prevention of cardiovascular events after acute myocardial infarction (AMI). However, the prescription rate of PCSK9 inhibitors (PCSK9is) remains low among patients not achieving low-density lipoprotein (LDL) cholesterol target levels.

Methods: A retrospective analysis was conducted on 194 patients with AMI who were discharged alive and followed up as outpatients at our institution between October 2022 and October 2024. In October 2023, we implemented the Physician-led Strike Early–Strike Strong Lipid-Lowering Protocol (Physician-led Protocol) to enhance lipid management. Patients were divided into two groups: pre-protocol (October 2022–September 2023) and post-protocol (October 2023–October 2024). Patient background characteristics, lipid-lowering therapies, and LDL cholesterol levels in the chronic phase were compared between the two groups. The outcomes included post-discharge PCSK9i initiation rates and chronic-phase LDL levels.

Results: While the prescription rates of strong statins and ezetimibe were similar between the groups, PCSK9i use was significantly higher in the post-protocol group than in the pre-protocol group (15.3% vs. 2.8%, p = 0.002). Furthermore, the chronic LDL levels were significantly lower in the post-protocol group than in the pre-protocol group (51.0 vs. 58.0 mg/dL, p = 0.007). Multivariate logistic regression showed that initial LDL levels and PCSK9i use were associated with achieving chronic LDL levels ＜55 mg/dL. Among eligible patients in the post-protocol group, 36.4% received PCSK9is.

Conclusions: The physician-led protocol increased PCSK9i prescriptions, achieving a median chronic LDL level of 51 mg/dL.

Aim: Arteriosclerosis is a condition that leads to coronary artery disease (CAD) and stroke. Basic and clinical studies have suggested a link between the gut microbiota and various diseases, including atherosclerosis. Therefore, we focused on gut microbiota and aimed to develop a probiotic-based treatment for atherosclerosis.

Method: From 6 to 14 weeks of age, apoE-deficient mice, a mouse model of atherosclerosis, were orally administered with Phocaeicola dorei and Phocaeicola vulgatus or saline five times/week. The diet was changed to a western diet at eight weeks of age. Finally, the mice were sacrificed at 14 weeks of age, and the atherosclerotic lesion area was evaluated.

Result: Previous studies have shown that atherosclerosis is suppressed by the administration of live type strains (TS) of P. dorei and P. vulgatus in apoE-deficient mice. In this study, we isolated P. vulgatus AF299, which highly expresses commensal colonization factors. Oral administration of P. dorei TS and AF299 to model mice further suppressed atherosclerosis compared to the administration of P. dorei TS and P. vulgatus TS. Genetic analysis of lesion tissues showed that the expression levels of genes associated with inflammatory responses were significantly reduced in mice treated with P. dorei TS and AF299. Moreover, gene expression related to immune response and IgA secretion was increased in the ileum.

Conclusion: Our results suggest that the bacteria-induced immune response in the gut leads to the suppression of the inflammatory response in atherosclerotic lesions. These results indicate the potential for the development of prophylactic drugs for atherosclerosis.

Although the risk of acute coronary syndrome increases during pregnancy and the postpartum period compared to the non-pregnant state, dyslipidemia–one of the key risk factors for atherosclerotic cardiovascular disease–is often undertreated in this population. Several lipid-lowering medications, including statin, have not been used due to concerns about their impact on the fetus. Herein, we report a pregnant woman with possible familial hypercholesterolemia (FH) and coronary artery stenosis, whose low-density lipoprotein cholesterol (LDL-C) level was managed by a combination of statin and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor for the secondary prevention of coronary artery disease.

A 37-year-old pregnant woman with dyslipidemia was found to have severe coronary artery stenosis. She was suspected of having FH, and her lipid control was initiated with the goal of lowering LDL-C levels to ＜100 mg/dL. Althoug ezetimibe and colestimide were administered at 14 weeks, the target LDL-C level was not achieved. Thus, treatment with pravastatin was started at 23 weeks and evolocumab at 32 weeks of gestation. With the combination of pravastatin and evolocumab, her LDL-C levels decreased to 67 mg/dL after 35 weeks of gestation. The patient delivered vaginally at 37 weeks of gestation without any cardiac events, and her baby did not present with any abnormalities. In conclusion, the combined use of statin and PCSK9 inhibitor could effectively manage LDL-C levels, and it might be a safe option during pregnancy. Nevertheless, further research is required to assess the safety and efficacy of this combination therapy during pregnancy.