Journal of atherosclerosis and thrombosis最新文献

Aims: Pemafibrate effectively reduces the triglyceride levels in patients with coronary artery disease (CAD). However, its effect on the fibrinogen levels in these patients remains unclear. This study aimed to investigate the effects of pemafibrate on thrombogenicity and the plasma fibrinogen levels in patients complicated by hypertriglyceridemia.

Methods: This multicenter, randomized, controlled trial enrolled 101 patients with hypertriglyceridemia (fasting triglycerides ≥ 150 mg/dL) and CAD who received antiplatelet monotherapy and statin therapy. After exclusion, 98 participants were randomly assigned to receive either pemafibrate 0.1 mg twice daily (intervention group) or standard care without any additional lipid-lowering therapy (control group), and 96 patients were analyzed. The fibrinogen levels were assessed at the baseline and after 12 weeks of treatment. The primary endpoint was the change in the fibrinogen level from baseline to week 12. The secondary endpoints included thrombogenicity measured using the Total Thrombus-formation Analysis System (T-TAS).

Results: Among the 96 patients, the median baseline fasting triglyceride, HDL cholesterol, LDL cholesterol, and fibrinogen levels were 175 mg/dL, 45 mg/dL, 72 mg/dL, and 299 mg/dL, respectively. The median decrease in triglycerides from baseline to 12 weeks was greater in the pemafibrate group than in the control group (-62 mg/dL vs. -5 mg/dL, p＜0.001), as was the median decrease in fibrinogen (-58 mg/dL vs. 9 mg/dL, p＜0.001).

Conclusions: Pemafibrate significantly reduced fibrinogen levels in patients with CAD and hypertriglyceridemia, thus highlighting its primary benefit in lowering thrombotic risk.

Aim: Chronic kidney disease (CKD) is linked to accelerated vascular remodeling, characterized by medial thickening and fibrosis; however, the molecular mechanisms driving this process remain unclear.

Methods: We investigated the role of toll-like receptor 4 (TLR4) in CKD-associated vascular remodeling using a 5/6 nephrectomy mouse model. TLR4 signaling was selectively inhibited by the long-term administration of TAK-242, a small-molecule-specific inhibitor of TLR4.

Results: TLR4 blockade decreased aortic medial thickening and perivascular fibrosis independent of blood pressure. Immunostaining revealed that blockade of TLR4 decreased Mac-3-positive macrophage accumulation and Ki-67-positive proliferating cells in the aorta. The mRNA expression of IL-6 was suppressed in aortas treated with TAK-242. Disulfide HMGB1 induced the expression of IL-6 in macrophages. Serum from CKD mice induced the expression of IL-6 in RAW264.7 cells and promoted in vitro vascular smooth muscle cell growth, both of which were attenuated with serum from TAK-242-treated CKD mice.

Conclusion: These findings suggest that TLR4-mediated sterile inflammation may contribute to vascular remodeling in CKD and that modulation of TLR4 signaling could be explored as a potential therapeutic strategy to mitigate cardiovascular complications in CKD patients.

Aim: Apolipoprotein CIII (ApoC-III) is a lipid-associated protein crucial for the lipid metabolism. Recent studies have shown that ApoC-III also plays a role in vascular dysfunction and the development of coronary heart disease (CHD). This study examined the hypothesis that the serum ApoC-III concentration is associated with the future risk of CHD in a general Japanese population.

Methods: We prospectively studied 1,676 individuals (1,005 women, 671 men; mean age 57.1 years) in a rural community in Japan. In the 1993 baseline survey, anthropometric examinations, current smoking status, blood pressure, and serum concentrations of lipids and apolipoproteins were assessed. During the follow-up period of 10.9 years (interquartile range 10.8 - 11.1), 48 participants developed CHD, including 18 fatal and non-fatal myocardial infarction patients and 30 sudden death cases.

Results: In the age- and sex-adjusted analysis, we did not find any association between the baseline serum ApoC-III concentration and the risk of CHD and sudden death (HR 2.11, CI 0.88 - 5.03, P = 0.094). However, in a multivariable analysis adjusted for age, sex, the presence of hypertension, presence of diabetes mellitus, current smoking status, total cholesterol, high-density lipoprotein cholesterol, and triglycerides, serum ApoC-III concentration was significantly associated with the risk of CHD and sudden death (HR 3.59, CI 1.05 - 12.3, P = 0.041).

Conclusion: Serum ApoC-III concentration was independently associated with the risk of CHD and sudden death in a general Japanese population.

A 79-year-old Chinese man was referred for nephrotic syndrome (proteinuria 4.4 g/day). In blood tests, serum high-density lipoprotein (HDL) cholesterol was undetectable, and the esterified cholesterol to total cholesterol ratio was very low. Lecithin: cholesterol acyltransferase (LCAT) activity was also undetectable. Since he had neither corneal opacity nor pathological mutations in the LCAT gene and anti-LCAT antibodies were detected in serum, a diagnosis of acquired LCAT deficiency was made. Renal biopsy revealed glomerulopathy associated with LCAT deficiency and membranous nephropathy (MN). Since the patient's proteinuria did not improve despite prescribing an angiotensin II receptor blocker (ARB), we suggested the prescription of prednisolone, but he returned to China due to the expiration of his residence visa for Japan. One year after the initial visit, his proteinuria had improved to 0.9 g/day without immunosuppressive therapy. However, his HDL cholesterol level was still low at around 3 mg/dL, indicating a discrepancy between remission of nephrotic syndrome and lack of improvement in lipid levels.Of the 11 patients with acquired LCAT deficiency reported to date, 4 with undetectable LCAT activity and MN on renal biopsy required immunosuppressive therapy to alleviate proteinuria. The present patient was prescribed only an ARB according to his preference, which happened to be consistent with the MN treatment guideline that states, "Wait 6 months for spontaneous remission while using maximal antiproteinuric therapy." The clinical course of acquired LCAT deficiency varies, and further case reports are needed to determine the necessity of immunosuppressive therapy.

Aims: Despite strong recommendations for medical consultation, the treatment status and low-density lipoprotein cholesterol (LDL-C) levels at 1-year follow-up of individuals with referral-level LDL-C identified in health checkups remain unclear. We evaluated the treatment status and 1-year LDL-C control among individuals identified in health checkups as requiring early medical consultation due to LDL-C levels of ≥ 180 mg/dL.

Methods: We conducted a nationwide cohort study including health checkup data for individuals aged 20-74 years. We identified 102,049 individuals (median age: 48 years; male: 66.8%) with uncontrolled LDL-C (≥ 180 mg/dL) at baseline, who had no prior lipid-lowering therapy. Poisson regression with robust error variance was used to assess factors associated with uncontrolled LDL-C at 1 year.

Results: Among individuals with LDL-C ≥ 180 mg/dL at baseline, 56,147 (55.0%) visited a medical institution within 3 months of the checkup, and 13,124 (12.9%) were prescribed lipid-lowering medications at 1 year. At 1 year follow-up, 49,260 (48.3%) still had LDL-C ≥ 180 mg/dL. Factors associated with persistent LDL-C ≥ 180 mg/dL at 1 year included obesity (RR: 1.07, [95% CI: 1.06-1.09]), 10 mg/dL increase in LDL-C at baseline (1.11 [1.10-1.11]), smoking (1.05 [1.04-1.07]), alcohol consumption (0.95 [0.94-0.97]), poor sleep quality (1.02 [1.01-1.03]), and skipping breakfast ≥ 3 times per week (1.07 [1.05-1.08]).

Conclusions: Despite being classified as requiring early medical intervention, only half of individuals with LDL-C ≥ 180 mg/dL visited a physician within 3 months, and nearly half continued to have uncontrolled LDL-C at 1 year. Strategies to facilitate timely medical visits and appropriate lipid management in health checkup-identified cases are warranted.

Aim: This study addressed the alteration and related factors of cholesterol efflux capacity (CEC) and anti-oxidative activity in patients with chronic kidney disease (CKD).

Methods: This retrospective cross-sectional observational study included 333 patients (median age: 50 [20, 81] years old, male: 46.5%) who underwent a kidney biopsy at Kitano Hospital. CEC and oxygen radical adsorption capacity (ORAC) were measured using serum obtained at the time of the kidney biopsy. Changes in CEC and ORAC in relation to the clinical and kidney injury parameters were evaluated.

Results: Mean CEC and ORAC were 0.83±0.15 and 0.86±0.14, respectively. High-density lipoprotein-cholesterol (HDL-C) levels were significantly associated with CEC (r = 0.673, p＜0.001) and ORAC (r = 0.164, p = 0.003). CEC showed a weak association with ORAC (r = 0.333, p＜0.001). Both HDL-C and CEC were negatively associated with the body mass index (r = -0.407, p＜0.001 and r = -0.248, p＜0.001, respectively) and were significantly higher in women than in men (p＜0.001). The ORAC was positively associated with the serum albumin level (r = 0.330, p＜0.001) and negatively associated with the urinary protein creatinine ratio (UPCR) (r = -0.236, p＜0.001). A multiple regression analysis showed that CEC was associated with the estimated glomerular filtration rate (eGFR), serum albumin, and ORAC. There was no significant correlation between global sclerosis and either CEC or ORAC.

Conclusions: The HDL-C level did not represent HDL functionalities in CKD patients. The decreased eGFR and reduced serum albumin levels induced by an increased UPCR might therefore be associated with impaired HDL functionalities.

Aims: This study examined whether or not the coexistence of smoking and metabolic syndrome synergistically increases the risk of cardiovascular disease (CVD) beyond their individual effects.

Methods: This prospective cohort study included 68,743 workers from the Japan Epidemiology Collaboration on Occupational Health Study. The participants were categorized into four groups based on their smoking status and metabolic syndrome. Biological interactions were evaluated using relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (S).

Results: During a mean follow-up of 7.2 (range: 0.1-10.9) years, 346 participants developed CVD. Current smokers with metabolic syndrome had the highest CVD risk (hazard ratio: 6.45, 95% confidence interval [CI]: 4.73-8.80). Approximately 35% of CVD cases among individuals exposed to both factors were attributed to their biological interactions (RERI: 2.27, 95% CI: 0.56-3.98; AP: 0.35, 95% CI: 0.15-0.55; S: 1.71, 95% CI: 1.16-2.52). An analysis of CVD subtypes revealed a significant biological interaction for myocardial infarction (RERI: 5.14, 95% CI: 0.65-9.62; AP: 0.52, 95% CI: 0.26-0.78; S: 2.38, 95% CI: 1.22-4.62) but not for stroke (RERI: 1.34, 95% CI: -0.46-3.13; AP: 0.25, 95% CI: -0.03-0.53; S: 1.44, 95% CI: 0.89-2.34).

Conclusion: Smoking and metabolic syndrome interact synergistically to elevate CVD risk, particularly for myocardial infarction. Targeting both factors is essential for CVD prevention.

Aims: Interleukin-6 (IL-6) is a cytokine involved in the development of atherosclerosis and ischemic stroke. Herein, we investigated the association between serum IL-6 levels at stroke onset and long-term outcomes in patients with ischemic stroke.

Methods: This prospective observational study enrolled 655 consecutive patients (mean age, 70 years; male, 62.1%) with ischemic stroke within one week of onset followed-up for one year. Patients were divided into 3 groups according to baseline serum IL-6 tertiles: tertile 1, ＜2.6 pg/mL (n = 216); tertile 2, 2.6-6.1 pg/mL (n = 217); and tertile 3, ＞= 6.2 pg/mL (n = 222). We evaluated the association of serum IL-6 levels with a composite of major adverse cardiovascular events (MACE; nonfatal stroke, nonfatal acute coronary syndrome, major peripheral artery disease, and vascular death) and the poor functional outcome defined as modified Rankin Scale score of ≥ 3 at one year.

Results: Higher serum IL-6 levels were associated with increased prevalence of chronic kidney disease, atrial fibrillation, chronic heart disease, active cancer, and post-stroke pneumonia. The three groups showed significant differences in the one-year MACE risk (annual rate, 11.2%, 10.8%, and 19.1% in the tertiles 1, tertile 2, and tertile 3 groups, respectively). Higher serum IL-6 levels were significantly associated with poor functional outcomes at one year after stroke (14.4%, 29.5%, and 56.8% in the tertile 1, tertile 2, and tertile 3 groups, respectively; P＜0.001), even when adjusting for baseline covariates and MACE during follow-up.

Conclusions: Higher serum IL-6 level at ischemic stroke onset was an independent predictor of poor functional prognosis at one year.

Aim: The preoperative to early remote postoperative von Willebrand factor (VWF) large multimer index (LMI) in patients with aortic stenosis (AS) remains unclear. Assessment of LMI changes may be better understood if other valvular diseases are integrated. However, this association requires further investigation.

Methods: A quantitative time-course assessment of the VWF, including LMI, was performed in 23 patients with AS who underwent aortic valve replacement. The proposed total valve score was used to study the correlation between the LMI and valvular diseases, including diseases other than AS.

Results: The postoperative VWF LMI was significantly higher; this increase was sustained across nine measurements up to one year postoperatively. The total valve score showed a moderate negative correlation with the VWF LMI (Spearman correlation coefficient r_s = -0.5483, p = 0.0068), demonstrating a stronger negative correlation and a lower p-value than the peak flow velocity and mean pressure gradient.

Conclusions: Improved VWF LMI was maintained one year after AS surgery and correlated better with echocardiographic severity when considering other valvular diseases than AS severity alone. VWF LMI may indicate overall cardiac shear stress and treatment effectiveness in early remote stages.