Inflammation plays a crucial role in the initiation, progression, and destabilization of atherosclerotic plaques and it contributes to recurrent cardiovascular events in patients with coronary artery disease (CAD). High-sensitivity C-reactive protein (hsCRP) is a well-established biomarker of systemic inflammation and it is a predictor of adverse outcomes, independent of low-density lipoprotein cholesterol (LDL-C) levels. Elevated hsCRP levels are consistently associated with higher event rates in both chronic and acute coronary syndromes, thus reflecting the residual inflammatory risk not addressed by lipid-lowering therapy or revascularization. Imaging studies have revealed that higher hsCRP levels correlate with a greater plaque burden and vulnerability. Recent trials have shown that anti-inflammatory therapies, including low-dose colchicine and interleukin-6 inhibition, can reduce this residual risk, while agents such as glucagon-like peptide-1 receptor agonists, sodium–glucose cotransporter 2 inhibitors, and bempedoic acid offer additional anti-inflammatory effects. The integration of anti-inflammatory strategies with intensive lipid management may thus provide additional cardiovascular benefits.

MicroRNAs (miRNAs) serve as fundamental post-transcriptional regulators of gene expression, among which the miR-33 family, consisting of miR-33a and miR-33b, has emerged as a critical modulator in the pathogenesis of cardiovascular and metabolic diseases. These miRNAs are embedded within the intronic regions of SREBF genes and play pivotal roles in cholesterol homeostasis, fatty acid metabolism, and inflammatory regulation. Notably, miR-33a is highly conserved across various species, whereas miR-33b is found primarily in primates and some other mammals, complicating the development of relevant animal models. These miRNAs inhibit their target genes involved in cholesterol metabolism, fatty acid oxidation, and insulin signaling, consequently influencing the development and progression of cardiovascular and metabolic diseases. Inhibition or genetic ablation of miR-33 has shown therapeutic potential, improving dyslipidemia, atherosclerosis, and metabolic dysfunction-associated steatotic liver disease, through altered cholesterol metabolism, attenuation of inflammation, and increased fatty acid utilization. In addition, miR-33 suppression has been shown to promote skeletal muscle regeneration. However, systemic inhibition of miR-33 requires caution due to the role of miR-33 in hunger signaling and sympathetic nerve activity in the central nervous system, which may lead to obesity. Therefore, the development of tissue-specific strategies is essential for the safe and effective therapeutic targeting of miR-33.

Aim: Desmosterol, a cholesterol precursor, is converted by Δ24-dehydrocholesterol reductase. Hence, desmosterol levels are considered to reflect cholesterol metabolism. This study aimed to evaluate sterols as novel biomarkers of liver condition in Asian moderate obese patients with metabolic dysfunction-associated steatotic liver disease (MASLD).

Methods: In total, 218 patients with MASLD who underwent liver biopsy were prospectively enrolled. Liver biopsy samples were evaluated by a well-versed pathologist according to the criteria. The serum sterols of biopsy-proven patients’, such as desmosterol, sitosterol, and campesterol, of the patients with biopsy-proven MASLD were analyzed using liquid chromatography-mass spectrometry.

Results: Inflammation grade 0/1/2/3 was observed in 8/107/90/12 patients, and fibrosis stage 0/1/2/3/4 was observed in 25/48/64/63/17 patients, respectively. Serum desmosterol levels were significantly different by inflammation grade 0-3 (one-way analysis of variance [ANOVA], p = 0.004), with a beta coefficient of 0.219 (95% confidence interval [CI]: 0.088-0.350, p＜0.01). Ordinal logistic regression analysis data on inflammation grade, adjusted for other parameters, showed that desmosterol had an odds ratio of 3.727 (95% CI 1.422-9.901, p＜0.005). Although desmosterol levels are influenced by statin treatment, in non-statin-treated patients, serum desmosterol levels remained significantly different by inflammation grade (one-way ANOVA, p = 0.041), and the beta coefficient was 0.233 (95% CI: 0.066-0.400, p＜0.01).

Conclusions: Serum desmosterol levels indicated the degree of hepatic inflammatory activity in patients with MASLD. Since desmosterol, a ligand of nuclear receptor LXR, reflects hepatic cholesterol metabolism, we hope that our findings will contribute to establishing a novel biomarker to screen the high-risk patients for cardiovascular diseases in MASLD.

Aim: Mounting evidence suggests apolipoprotein E-containing high-density lipoprotein cholesterol (APOE-HDLC) as an indicator of the anti-atherogenic function of HDLC, but data are lacking on whether or not APOE-HDLC is involved in the development of atherosclerosis in humans. This study was performed to explore whether or not APOE-HDLC is associated with atherosclerotic plaque progression in humans.

Methods: Among 823 participants 45 to 74 years old who were free of cardiovascular disease, we assessed nuclear magnetic resonance spectroscopy-measured HDL particle concentrations, APOE-HDLC levels and HDLC levels at baseline, and performed carotid ultrasound measurements in surveys conducted in 2002 and again in 2007 after a 5-year interval. The ratio of APOE-HDLC to total HDLC (APOE-HDLC/HDLC ratio) was calculated to assess the relative proportion of APOE-HDLC in total HDLC, given the strong correlation between them.

Results: The baseline APOE-HDLC/HDLC ratio was significantly associated with the risk of 5-year plaque progression (relative risk [RR] = 0.71; 95% confidence interval [CI] = 0.53-0.95), which is independent of the ratio of HDLC to the HDL particle number (HDLC/P ratio). In particular, participants with an HDLC/P ratio ≥ 44.8 (denoted very high level of cholesterol content per HDLP, a marker of dysfunctional HDL) had a 36% reduced 5-year plaque progression risk (RR = 0.64; 95% CI = 0.43-0.97) if combined with the highest APOE-HDLC/HDLC ratio, as compared with the lowest APOE-HDLC/HDLC ratio.

Conclusions: These results highlight the potential utility of APOE-containing HDL as a candidate emerging biomarker for the anti-atherosclerotic function of HDL particles.

Aims: MN-001 (tipelukast), a compound with lipid-modulating and anti-inflammatory properties, and its active metabolite MN-002, have been suggested to influence cholesterol metabolism. This study aimed to investigate whether MN-001 and MN-002 enhance cholesterol efflux via ABCA1 and ABCG1, thereby reducing foam cell formation. We also evaluated cholesterol efflux capacity in patients with diabetes before and after MN-001 administration.

Methods: Cholesterol efflux was assessed in THP-1 macrophages treated with MN-001 and MN-002 in the presence of ApoA-I or HDL. ABCA1 and ABCG1 expression were evaluated using western blot and qPCR analyses. A 12-week observational study in patients with diabetes evaluated the cholesterol efflux capacity using ApoB-depleted serum and radiolabeled J774.1 macrophages. Molecular docking simulations were conducted to explore MN-002 binding affinities, aiming to identify potential target proteins and elucidate the molecular mechanisms underlying their effects on cholesterol metabolism.

Results: MN-002 enhanced ABCA1-mediated cholesterol efflux and upregulated ABCA1 expression independently of PKA. It also increased ABCG1 expression; however, neither MN-001 nor MN-002 influenced HDL-mediated efflux. MN-001 showed no significant improvement in cholesterol efflux capacity (p = 0.6507) in patients with diabetes. Molecular docking simulations indicated that MN-002 may bind to PPAR-alpha, suggesting a potential mechanism for its effects.

Conclusion: MN-002 offers a novel therapeutic approach for atherosclerosis by upregulating ABCA1 and ABCG1 expression and enhancing ApoA-I-mediated cholesterol efflux. Further studies are required to clarify the underlying mechanisms and assess their clinical potential in atherosclerosis and metabolic disorders.

Aims: The phase angle (PhA) derived from a bioelectrical impedance analysis (BIA) is a risk factor for cardiovascular disease (CVD). The present study explored the relationship between PhA and the progression of subclinical atherosclerosis in asymptomatic adults.

Methods: Two cross-sectional studies were performed on 15579 participants who underwent carotid ultrasound testing and a BIA as well as 8228 participants who underwent brachial ankle pulse wave velocity (baPWV) testing and a BIA. We also conducted a longitudinal study in participants without CVD and carotid atherosclerosis (CAS) at baseline who underwent carotid ultrasound ≥ 2 times (n = 2680) or baPWV testing [≥ 2 times] (n = 1775). CAS and the brachial ankle pulse wave velocity (baPWV) were selected as the subclinical atherosclerosis markers.

Results: In the cross-sectional studies, participants with CAS (5.43±0.60° vs. 5.73±0.61°, P＜0.001) or elevated baPWV (5.38±0.62° vs. 5.74±0.59°, P＜0.001) had lower PhA values than controls. Furthermore, the PhA value was independently and inversely correlated with CAS (adjusted odds ratio [OR] = 0.41, 95% confidence interval [CI] 0.37-0.46, P＜0.001) and elevated baPWV (adjusted OR = 0.45, 95% CI 0.39-0.52, P＜0.001). Restricted cubic spline curve analyses indicated dose-response associations of PhA values with subclinical atherosclerosis. In the longitudinal study, high PhA values at baseline decreased the risk of incident CAS (adjusted hazard ratio = 0.44, 95% CI 0.36-0.54, P＜0.001). Multivariate linear regression analyses showed that the PhA was negatively associated with absolute or relative annual changes in baPWV.

Conclusion: The PhA value is significantly associated with the progression of subclinical atherosclerosis, indicating that PhA may serve as a noninvasive marker for monitoring subclinical atherosclerosis in a primary prevention setting.

Aim: The long-term clinical outcomes of endovascular therapy (EVT) for aortoiliac (AI) artery lesions remain unclear. This study aimed to investigate 10-year patency and mortality after AI stent implantation.

Methods: This multicenter retrospective study included 1919 patients (2375 limbs) who underwent AI stent implantation to treat symptomatic peripheral artery disease (PAD) between January 2005 and December 2010. The study outcome was primary patency, which was defined as a treated vessel without restenosis, mortality, and associated factors.

Results: The mean age of the study cohort was 71±9 years. Chronic limb-threatening ischemia (CLTI) accounted for 17.2% of cases, and chronic total occlusion (CTO) was found in 24.6% of cases. During a median follow-up period of 2.9 years (interquartile range: 1.0–6.0 years), 412 patients lost patency, whereas 467 patients died without experiencing loss of patency. At 1, 6, and 10 years post-EVT, respectively, the primary patency rates were estimated to be 92.8%, 79.3%, and 77.2%, and the survival rates were 94.9%, 77.0%, and 63.1%. Female sex, CTO, and the presence of outflow lesions were significantly associated with an increased risk of patency loss after stent implantation (all P＜0.05), whereas age, dialysis-dependent renal failure, heart failure, and CLTI were significantly associated with an increased risk of mortality.

Conclusion: Stent implantation for AI lesions achieved favorable 10-year patency, with patency loss plateauing after six years. No AI lesion characteristic was associated with mortality. These results support the long-term efficacy of EVT in the clinical practice.

Aims: We aimed to evaluate the effect of serum lipoprotein(a) (Lp(a)) levels on carotid artery ulceration using digital subtraction angiography (DSA), which is the gold standard for assessing atherosclerotic plaque surface morphology.

Methods: Of the consecutive cerebrovascular patients prospectively collected serum Lp(a) levels from June 2021 to October 2024 admitted to our institution, patients with carotid artery stenosis were enrolled in this study. Blood samples were collected within three months of admission. Based on common carotid angiography and 3D rotational angiography to confirm the morphology of stenotic lesions, patients were dichotomized according to the presence or absence of carotid artery ulceration.

Results: Of the 439 cerebrovascular patients, 94 with carotid artery stenosis were analyzed (18 females, median 75 [interquartile range, 71–81] years) and carotid artery ulceration was confirmed in 38 (40.0 %) patients. Patients with carotid artery ulceration showed a higher proportion of dyslipidemia (94.7% versus 75.0%; p = 0.013), and higher L(a) levels (28 [11–56] vs 10 [5–25] mg/dL, p = 0.007) than those without. Multivariable logistic analysis adjusted for other atherosclerotic risk factors showed a significant association between higher Lp(a) levels and carotid artery ulceration (odds ratio per 10 mg/dL increase, 1.21; 95%CI, 1.02–1.43; p = 0.026). Receiver operating characteristic curve analysis showed that Lp(a) ≥ 26 mg/dL was the threshold to predict the presence of carotid artery ulceration (area under the curve = 0.67; sensitivity, 52.6%; specificity, 78.6%).

Conclusions: In patients with carotid artery stenosis who may be considered candidates for surgical treatment, elevated Lp(a) levels were associated with carotid artery ulceration.

Familial hypercholesterolemia (FH) is an inherited disorder characterized by elevated LDL cholesterol levels and an increased risk of early-onset atherosclerotic cardiovascular disease. In pregnant female with FH, apheresis is the preferred treatment because standard therapeutic agents such as statins are contraindicated during pregnancy. LDL adsorption therapy is commonly used; however, after 27 weeks of gestation, it is often switched to dual filtration plasma exchange (DFPP) due to the significant drop in blood pressure caused by bradykinin production. However, DFPP has limited ability to adapt to the increase in circulating plasma volume associated with pregnancy. Here we discuss the case of a 32-year-old female with homozygous FH who underwent different apheresis strategies during her pregnancies. In her first pregnancy, she continued LDL adsorption therapy using DFPP but ultimately delivered a small-for-gestational-age infant via cesarean section. For her second pregnancy, double-filtration plasmapheresis thermo mode, DF-thermo, was introduced to mitigate the limitations of DFPP and LDL adsorption therapies, such as hypotension during apheresis and albumin loss. By minimizing these complications, DF-thermo allowed for a successful delivery without compromising fetal growth.