Journal of atherosclerosis and thrombosis最新文献

Aim: Adiponectin is an anti-diabetic and anti-atherogenic protein secreted primarily from adipose tissue. Adiponectin and modified LDL (mLDL) form a complex to modulate their biological activity. To elucidate the significance of the complex formation, we analyzed its effects on vascular tissue and developed and verified novel quantifying methods for adiponectin.

Methods: To study the significance of the mLDL-adiponectin complex (MAC) formation, we used the wire-myography method on rat mesenteric artery. We developed a method to measure MAC by using LOX-1 as the capture protein and anti-adiponectin antibody for detection. We compared serum MAC levels between hemodialysis patients and control subjects.

Results: Administering mLDL alone to rat mesenteric artery impaired endothelium-dependent vasorelaxation, whereas simultaneously administering adiponectin with mLDL protected rat mesenteric artery from the mLDL-induced impairment of vasorelaxation. This finding indicates MAC formation prevents endothelium from mLDL-induced dysfunction in tissue. Using our novel ELISA for MAC, we found that MAC was increasingly detectable depending on the doses of mLDL and adiponectin in vitro. In serum, hemodialysis patients showed a significantly higher ratio of MAC-high patients (higher than the median level of MAC) than did healthy controls. Furthermore, the MAC-high hemodialysis group had lower mLDL activity measured as LOX-1 ligand containing apoB.

Conclusion: Using our ELISA, we detected MAC in human serum that protected blood vessels from the deleterious effects of oxidized LDL.

Aim: The accumulation of metabolic risk factors, namely high blood pressure, hyperlipidemia, and hyperglycemia, has been associated with cardiovascular diseases. However, little evidence is available on the prognostic significance of metabolic risk factor accumulation in nonobese individuals. This study investigated this issue by analyzing prefecture-wide health checkup and health insurance data in Japan.

Methods: We analyzed data from 366,881 adults aged 40-74 years who were enrolled in the National Health Insurance, excluding those who experienced a stroke or coronary artery diseases or required long-term care. Baseline clinical information was obtained from annual health checkup data. Incidences of stroke and coronary artery diseases were obtained from insurance data.

Results: In the nonobese population, the hazard ratio for stroke increased linearly with the number of accumulated metabolic risk factors, particularly among those aged ＜65 years men (one factor: 2.21, two factors: 2.60; three factors: 3.93) and women (one factor: 1.49, two factors: 1.57; three factors: 2.27). Similar results were observed in the analysis for coronary artery diseases. After excluding participants receiving medications, the association of metabolic risk factor with stroke remained significant, although its association with coronary artery disease became less significant. In the analysis for each metabolic risk factors, high blood pressure (men: hazard ratio = 2.85; women: hazard ratio = 2.17; P＜0.001), but not hyperlipidemia and hyperglycemia, was associated with stroke in the nonobese population.

Conclusion: The accumulation of metabolic risk factors needs to be considered a risk factor for cardiovascular diseases even in individuals without obesity.

Aim: Screening for familial hypercholesterolemia (FH) is important for reducing the incidence of cardiovascular diseases (CVDs). Cost-effectiveness was evaluated using the Kagawa FH screening model, which is a combination of universal screening (US) in the universal health examination for children 9-10 years old conducted in Kagawa Prefecture, and reverse cascade screening (RCS) of the probands' relatives.

Methods: A lifetime simulation was conducted using mathematical models (decision tree and Markov model) to determine the cost-effectiveness of introducing a series of FH screenings (US in children + RCS in adult relatives). Only screening-related costs and direct medical costs were included, using quality-adjusted life years (QALYs) as an outcome. The costs of statins were estimated using the public health insurance claims database DeSC Healthcare, Inc. The risk of each CVD event was estimated using the same claims data and adjusted for age. We hypothesized that standard statin treatment decreases CVD risk by reducing plasma low-density lipoprotein cholesterol levels.

Results: A series of FH screenings (US in children + RCS in adult relatives) was cost-effective compared to no screening, with an incremental cost-effectiveness ratio (ICER) of approximately JPY 150,000 (USD 1,042)/QALY, which was below the willingness-to-pay threshold of JPY 5,000,000 (USD 34,722)/QALY for medical technology in Japan (USD 1 = JPY 144). The ICER for the US without RCS was also acceptable at approximately JPY 2,720,000 (USD 18,889)/QALY.

Conclusion: The cost-effectiveness analysis revealed that a series of FH screenings (US in children + RCS in adult relatives) based on the Kagawa model was cost-effective.

Aims: Intermittent claudication is a major barrier to establishing an exercise routine in patients with peripheral artery disease (PAD). This study investigated the preconditioning effects of neuromuscular electrical stimulation (NMES) on walking capacity in patients with PAD and intermittent claudication. Additionally, it aimed to determine the optimal NMES settings and the underlying mechanisms of its effects.

Methods: A total of 15 patients with PAD (Fontaine II) participated in a crossover study. Each patient underwent 10-min sessions of NMES at two frequencies (4 and 20 Hz) and two intensities (moderate and high), plus a sham condition, before treadmill walking tests using the modified Gardner protocol.

Results: Pain-free walking distance significantly increased after a single session of 20 Hz high-intensity NMES (259.2±27.5 m; p＜0.05) relative to the sham group (201.9±23.6 m). The maximum walking distance also improved significantly after 4 and 20 Hz high-intensity NMES. The vascular endothelial function, assessed by flow-mediated dilation, was significantly enhanced following 20 Hz moderate- and high-intensity NMES, as well as 4 Hz high-intensity NMES, relative to the sham group. Additionally, lower extremity blood flow, as measured via transcutaneous partial pressure of oxygen, improved significantly in all NMES conditions. However, serum markers such as myeloperoxidase, hepatocyte growth factor, vascular endothelial growth factor, and CD34^＋/CD133^＋ progenitor cell counts did not differ significantly between the NMES and sham groups.

Conclusion: High-intensity 20 Hz NMES is an effective preconditioning strategy for instantaneously enhancing the walking capacity in patients with PAD, likely due to nitric oxide-mediated vasodilation. These findings suggest that NMES is a promising therapeutic approach for PAD rehabilitation.

Aims: Long-term safety and efficacy of pemafibrate once-daily extended-release (XR) tablets, taken in morning or evening, were evaluated in dyslipidemic patients with high triglycerides (TG).

Methods: In this multicenter, randomized, open-label, parallel-group, phase 3 long-term study, dyslipidemic patients with high TG were randomly assigned to morning or evening administration of XR for 52 weeks. The dose was started at 0.2 mg/day and increased to 0.4 mg/day for patients having fasting serum TG ≥ 150mg/dL during treatment. The primary efficacy endpoint was percent change in fasting serum TG.

Results: The study enrolled 121 patients, assigning 61 to morning and 60 to evening administration. The study population included 71.1% males. Mean age was 58.5±11.1 (mean±SD) years, body mass index 27.7±4.3 kg/m², and fasting TG 264.0±109.2 mg/dL. Fasting serum TG decreased significantly from baseline to 52 weeks among patients overall and in the morning and evening groups (-45.7%, -44.8%, and -46.6%, respectively, p＜0.001 vs. baseline). The difference in least-squares mean between the morning and evening groups was 3.0%, not statistically significant. The dose was increased in 82 patients (44 morning and 38 evening), with 57.3% (95%CI 45.9, 68.2) achieving fasting serum TG ＜150 mg/dL. Adverse events occurred in 83.5% and adverse drug reactions in 19.0% but with no notable safety problems.

Conclusions: Long-term, once-daily administration of XR was effective and safe in dyslipidemic patients with high TG. XR provided favorable TG-lowering effects regardless of morning or evening administration, and the XR dose increase proved effective in patients having initially inadequate response.

Aims: Previous studies have linked platelet-derived growth factors (PDGFs) and their receptor beta (PDGFRB) genetic variants to coronary artery disease (CAD), but their impact on major adverse cardiovascular events (MACEs) remains unclear.

Methods: A cohort study of 3139 patients with CAD followed up until December 1, 2022 (median 5.42 years), genotyped 13 tagSNPs in PDGFs/PDGFRB pathway genes to establish weighted genetic risk scores (wGRS). Multiple Cox regression models analyzed the association of SNPs and wGRS with MACE outcomes using hazard ratios (HRs) and 95% confidence intervals (CIs). The wGRS improvement on traditional risk factors (TRFs) and the Global Registry of Acute Coronary Events (GRACE) score for MACEs were assessed using the C-statistic, net reclassification improvement (NRI), and integrated discrimination improvement (IDI).

Results: Compared to low MACE-GRS (Q1 of quintile), high MACE-GRS (Q5 of quintile) had an increased risk of MACEs, with an adjusted HRs of 1.441 (P = 0.006). Compared to the TRF prediction model, the addition of MACE-GRS showed an improved discrimination with an NRI of 5.1% (95% CI, 0.7%-9.5%, P＜0.001) and IDI of 0.3% (95% CI, 0.0%-0.6%, P＜0.001). In addition, compared to the TRFs and GRACE score model, the addition of MACE-GRS showed an improved discrimination with an NRI of 5.1% (95% CI, 0.7%-9.6%, P＜0.001) and IDI of 0.3% (95% CI, 0.0%-0.5%, P＜0.001).

Conclusions: Variants in the PDGF-PDGFRB pathway genes contribute to the risk of MACEs after CAD, and the wGRS might be able to serve as a risk predictor of MACEs in addition to TRFs.

Aims: To investigate the association between metabolic health status, defined by the combination of metabolic syndrome (MetS) and obesity, and cardiovascular disease (CVD) in a Japanese community.

Methods: A total of 2,842 participants without prior CVD, aged 40 years or older, were followed up from 2007 until 2017. Participants were classified into 4 metabolic health statuses based on the presence of obesity (body mass index ≥ 25 kg/m²) and MetS: metabolically healthy normal weight (MHN) (obesity [-] and MetS [-]), metabolically unhealthy normal weight (MUN) (obesity [-] and MetS [+]), metabolically healthy obesity (MHO) (obesity [+] and MetS [-]), and metabolically unhealthy obesity (MUO) (obesity [+] and MetS [+]). The risk estimates were computed by using a Cox hazard regression analysis.

Results: During the follow-up period, 190 participants developed CVD. The MUO group had a 1.94-times greater risk of developing CVD than the MHN group after adjusting for confounders, but no excess risk was observed in the MHO group. Moreover, in 1,595 participants who had undergone a health checkup in 2002, 5 years before baseline, the risk of developing CVD was 2.18-times greater in the group that transitioned from MHO to MUO and 1.75-times higher in the stable MUO group than in the stable MHN group, but was not higher in the stable MHO group.

Conclusions: The present findings suggest that cardiovascular risk increases when metabolic abnormalities are present simultaneously with obesity. In individuals with obesity, it may be important to maintain metabolic health and/or lose weight to prevent CVD.

Aim: Postprandial hypertriglyceridemia (PHTG) is an independent risk factor for coronary heart diseases. PHTG exhibits accumulation of apoB-48 containing chylomicron remnants (CM-Rs) and apoB-100 containing VLDL remnants (VLDL-Rs), which are both known to be atherogenic. However, unlike VLDL-Rs, structural and functional characterization of CM-Rs remains to be elucidated due to challenges in separating CM-Rs from VLDL-Rs. Recently, we successfully isolated CM-Rs and VLDL-Rs utilizing anti-apoB-48 or apoB-100 specific antibodies. This study aimed to characterize the proteome of CM-Rs along with that of VLDL-Rs.

Methods: Eight healthy subjects were enrolled. Venous blood was drawn 3 hours after high-fat-containing meals. We isolated CM-Rs and VLDL-Rs from sera through combination of ultracentrifugation and immunoprecipitation using apoB-48 or apoB-100 specific antibodies, followed by shotgun proteomic analysis.

Results: We identified 42 CM-Rs or VLDL-Rs-associated proteins, including 11 potential newly identified proteins such as platelet basic protein (PPBP) and platelet factor 4, which are chemokines secreted from platelets. ApoA-I, apoA-IV, and clusterin, which are also known as HDL-associated proteins, were significantly more abundant in CM-Rs. Interestingly, apoC-I, which reduces the activity of lipoprotein lipase and eventually inhibits catabolism of remnant proteins, was also more abundant in CM-Rs. Moreover, we identified proteins involved in complement regulation such as complement C3 and vitronectin, and those involved in acute-phase response such as PPBP, serum amyloid A protein 2, and protein S100-A8, in both CM-Rs and VLDL-Rs.

Conclusions: We have firstly characterized the proteome of CM-Rs. These findings may provide an explanation for the atherogenic properties of CM-Rs.

Aim: We aimed to assess the association between non-high-density lipoprotein cholesterol (non-HDL-C) and symptomatic intracranial artery stenosis (sICAS), as well as the impact of non-HDL-C on recurrent vascular events in patients with mild ischemic stroke ( NIHSS score ≤ 5).

Methods: This prospective study was based on data from patients presenting within 72 hours of stroke occurrence. We included patients admitted to 8 Chinese hospitals between September 2019 and November 2021. The associations of non-HDL-C with sICAS and recurrent vascular risk were assessed using multivariate regression models and a restricted cubic spline analysis.

Results: Among the 2,544 patients analyzed at 12 months, 652 (25.6%) were diagnosed with sICAS. Elevated non-HDL-C was linked to a higher incidence of sICAS, and the adjusted odd ratios for quintile variables and continuous variables were 1.36 ([95% CI, 1.01-1.81]) and 1.14 ([95% CI, 1.04-1.24). In comparison to those in the first quintile, the adjusted hazard ratio of the fifth quintile of non-HDL-C was 1.19 ([95% CI 0.78-1.80]) for recurrent ischemic stroke and was 0.39 ([95% CI, 0.17-0.91]) for intracranialhemorrhage.

Conclusions: The non-HDL-C level may be a useful predictor of sICAS. Higher non-HDL-C levels may be associated with a lower risk of intracranial hemorrhage in mild, noncardiogenic stroke, but not a higher risk of recurrent ischemic stroke.