Patients with chronic kidney disease (CKD) have a high incidence of atherosclerotic diseases, such as ischemic heart disease, cerebrovascular disease, and peripheral arterial disease. To prevent the incidence of atherosclerotic cardiovascular disease in patients with CKD, the pathology of arteriosclerosis should be determined. Vascular calcification is a characteristic of arteriosclerosis in patients with CKD. Recent studies have reported that coronary artery calcification is associated with acute coronary syndromes. CKD is frequently associated with heart failure. Furthermore, recent evidence suggests that coronary artery calcification affects asymptomatic myocardial ischemia. Hyperphosphatemia and calciprotein particles may be involved in the pathology of vascular calcification. Controlling the progression of vascular calcification and classical atherosclerotic risk factors is important to prevent the occurrence of atherosclerotic diseases in CKD.

Aims: Pemafibrate substantially lowers serum triglyceride (TG) levels and increases high-density lipoprotein cholesterol (HDL-C) levels primarily in Japan, but it has not been evaluated in China. We aimed to confirm the efficacy and safety of pemafibrate in Chinese patients with hypertriglyceridemia and low HDL-C levels by comparing placebo and fenofibrate.

Methods: A multicenter, double-masked trial was conducted in China involving 344 patients with high TG and low HDL-C levels randomly assigned to one of four groups: pemafibrate 0.2 mg/d, pemafibrate 0.4 mg/d, fenofibrate 200 mg/d, or placebo for 12 weeks. The primary endpoint was the percentage change in fasting TG levels.

Results: The percentage change in TG levels from baseline was -34.1%, -44.0%, -30.5%, and 6.5% in the pemafibrate 0.2 mg/d, pemafibrate 0.4 mg/d, fenofibrate 200 mg/d, and placebo groups, respectively. Pemafibrate 0.4 mg/d significantly reduced TG levels compared with that in both placebo (p＜0.0001) and fenofibrate groups (p=0.0083). Significant improvements in HDL-C, remnant cholesterol, and apolipoprotein A1 levels were also observed with both doses of pemafibrate than with the placebo. Pemafibrate showed significantly smaller changes in alanine aminotransferase, aspartate aminotransferase, and serum creatinine levels than those with fenofibrate.

Conclusions: In Chinese patients, pemafibrate exhibited superior efficacy in improving TG levels and enhanced hepatic and renal safety compared to fenofibrate. Thus, pemafibrate may represent a promising therapeutic option for dyslipidemia in Chinese patients.

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.

Aim: To investigate medication adherence and treatment persistence in patients receiving proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs) in Japan.

Methods: Using an anonymized claims database from January 2015 to December 2021, data on adult patients at high risk for atherosclerotic cardiovascular disease or with a history of coronary artery disease (CAD) who had at least 1 prescription for PCSK9-mAbs were retrieved.

Results: In total, 276 patients were analyzed. The cumulative treatment persistence rate after 1 year was 67.0%. A multivariate analysis revealed that better adherence to oral low-density lipoprotein cholesterol (LDL-C)-lowering therapy in the year before starting PCSK9-mAbs (adjusted odds ratio [OR] 2.16) and a history of CAD for secondary prevention (adjusted OR 2.44) were associated with better adherence to PCSK9-mAbs in the first year. Better adherence to oral LDL-C-lowering therapy in the year before starting PCSK9-mAbs (adjusted OR 2.32) and a history of CAD for secondary prevention (adjusted OR 3.03) were also associated with a lower rate of discontinuation of PCSK9-mAbs. Age, sex, comorbidity, number of tablets taken daily (all medications), and number of hospital or clinic visits in the year prior to starting PCSK9-mAbs did not affect the persistence rate or adherence to PCSK9-mAbs in the multivariate analyses.

Conclusion: Better adherence to oral LDL-C-lowering therapy and secondary prevention were identified as factors associated with better medication adherence and treatment persistence in patients receiving PCSK9-mAbs within the first year.

Aim: In this subanalysis of the EXPAND study, we evaluated the risks and benefits of rivaroxaban plus antiplatelet therapy (APT) for patients with non-valvular atrial fibrillation (NVAF) complicated by stable coronary artery disease (CAD), ischemic stroke, or peripheral artery disease (PAD).

Methods: From the EXPAND study population (n=7,141), patients with NVAF complicated by stable CAD (n=886), ischemic stroke (n=1,231), or PAD (n=160) were included. Patients complicated by any of them were set as ALL (n=2,030). Patients were all treated with rivaroxaban (10 or 15 mg/day) with (+) or without (−) APT. Efficacy outcomes were symptomatic stroke＋systemic embolism (SE), symptomatic stroke＋SE＋myocardial infarction＋cardiovascular death, and all-cause death. Safety outcomes included major and any bleeding. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for differences between the APT(+) and APT(−) groups.

Results: There were no significant differences in the efficacy outcomes between the APT(+) and APT(−) groups in the ALL cohort or in the CAD and STROKE sub-cohorts. In the PAD subcohort, the HR [95% CI] for all-cause death in the APT(+) group increased (4.43 [1.05–18.71]; p=0.043). In the APT(+) group, the HR [95% CI] for any bleeding increased in the ALL cohort (1.28 [1.01–1.62]; p=0.044) and STROKE subcohort (1.42 [1.01–2.01]; p=0.047), and for major bleeding in the CAD subcohort (2.00 [1.01–3.93]; p=0.046).

Conclusions: Rivaroxaban with APT did not reduce ischemic outcomes in patients with stable CAD or ischemic stroke; however, it did increase the risk of bleeding in patients with stable CAD or ischemic stroke.

Aim: Increased arterial stiffness impairs the functional and structural properties of arteries, which in turn elevates blood pressure (BP). The aim of this study was to test whether indices obtained from the second derivative of the finger photoplethysmogram (SDPTG), a marker of arterial stiffness, predict future development of hypertension in middle-aged men.

Methods: The SDPTG was measured in 902 men without hypertension (mean age 44±6 years) at an annual medical checkup. The development of hypertension was monitored for a maximum of 4 years. Two indices of arterial stiffness were calculated from the SDPTG waveforms: b/a, an index of large elastic arterial stiffness, and d/a, an index of systemic arterial stiffness, including the structural and functional properties of small and muscular arteries and peripheral circulation. A Cox proportional hazards model was used to examine whether the b/a and d/a ratios were independent predictors of future development of hypertension.

Results: During the follow-up period, 124 individuals developed hypertension, defined as a systolic/diastolic BP ≥ 140/90 mm Hg or the use of antihypertensive medications. The hazard ratio for the development of hypertension significantly increased in the lowest quartile of the d/a ratio (2.84, 95% confidence interval: 1.58–5.13, p＜0.001) compared with the highest quartile, after adjusting for multiple potential confounders. In contrast, the b/a ratio did not show significant hazard ratios for the development of hypertension.

Conclusions: The d/a ratio, calculated from the SDPTG waveforms, predicted the risk of future development of hypertension in this study population.

Aim: To determine whether the severity of cerebral small vessel disease (SVD) is associated with prehospital delay in acute ischemic stroke.

Methods: Consecutive patients with ischemic stroke were included in this study. We evaluated the SVD burden using the total SVD score. Patients were divided into 2 groups: onset-to-door time within 4.5 hours (early arrival group) and onset-to-door time over 4.5 hours (delayed arrival group). First, we assessed whether the total SVD score was related to prehospital delay using a logistic regression analysis. Second, we assessed which item of the score was independently associated with delays. Finally, we determined whether the item had a linear association with the delay.

Results: Of the 2,112 screened patients, 1,754 were enrolled in the study (1,253 males [71%]; median age, 69 years). There were 1,105 patients (63%) in the delayed arrival group. The total SVD score was independently associated with delay (OR 1.11, 95% CI 1.01–1.21, p=0.025). Among the 4 items of the score, only enlarged perivascular spaces (EPVS) in the basal ganglia was independently associated with delay (OR 1.37, 95% CI 1.05–1.80, p=0.022). A linear trend was observed between EPVS grade and delay with reference to EPVS grade 0–1 (EPVS grade 2: OR 1.22, 95% CI 0.92–1.62, p=0.170, EPVS grade 3: OR 1.69, 95% CI 1.20–2.38, p=0.002, EPVS grade 4: OR 2.17, 95% CI 1.37–3.44, p=0.001).

Conclusions: Prehospital delay in acute ischemic stroke could be associated with the severity of SVD, particularly EPVS in the basal ganglia.

Aims: Per the package insert, pemafibrate was contraindicated for use in patients with severe renal impairment despite its biliary excretion. To validate this, we evaluated the pharmacokinetics and safety of pemafibrate for 12 weeks in patients with hypertriglyceridemia and renal impairment.

Methods: In this phase 4, multicenter, placebo-controlled, double-blind, parallel-group, comparative study, 21 patients were randomly assigned to pemafibrate 0.2 mg/day or placebo within Groups A (estimated glomerular filtration rate [eGFR] ＜30 mL/min/1.73m² without hemodialysis; pemafibrate n=4; placebo, n=2), B (hemodialysis; pemafibrate, n=4; placebo, n=1), and C (eGFR ≥ 30 and ＜60 mL/min/1.73m² without hemodialysis; pemafibrate, n=8; placebo, n=2) for 12 weeks. Area under the concentration vs time curve within the dosing interval (τ) (AUC_τ) of pemafibrate was measured after 12-week administration.

Results: The AUC_τ (geometric mean) of pemafibrate was 7.333 and 7.991 ng·h/mL in Groups A+B and C, respectively; in Groups A+B to C at 12 weeks, the geometric mean ratio of pemafibrate AUC_τ was 0.92 (90% confidence interval [CI]: 0.62, 1.36). The upper limit of the 90% CI was ≤ 2.0 (predetermined criterion). There was no consistent trend in the AUC_τ and maximum plasma concentration of pemafibrate with/without statin use. Renal impairment degree did not affect the incidence of adverse events. No safety concerns were observed.

Conclusion: Pemafibrate repeated administration in patients with severe renal impairment did not increase pemafibrate exposure.

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.

Aims: Cardiovascular disease (CVD) is a common cause of death in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Therefore, CVD surveillance is important, but it is not well established. We evaluated the association between liver fibrosis, carotid artery atherosclerosis, and coronary artery stenosis in patients with MASLD.

Methods: Overall, 153 patients with MASLD who underwent carotid artery ultrasound were enrolled. Maximum intima–media thickness including plaques (Max-IMT) was measured by ultrasound. To predict liver fibrosis, liver stiffness was measured by vibration-controlled transient elastography and the fibrosis 4 (FIB-4) index was calculated. Coronary computed tomography angiography was performed to detect coronary artery stenosis based on a Max-IMT of ≥ 1.1 mm.

Results: The median Max-IMT was 1.3 mm, and 63 patients (41.2%) had a Max-IMT of ≥ 1.5 mm. FIB-4 index and liver stiffness was significantly correlated with Max-IMT, respectively (ρ=0.356, p＜0.001, ρ=0.25, p=0.002). Liver stiffness was significantly associated with a Max-IMT of ≥1.5 mm, independent of age. Individuals with higher FIB-4 index had moderate or severe coronary artery stenosis more frequently. Individuals with higher LSM level also had moderate or severe coronary artery stenosis more frequently, especially severe stenosis.

Conclusions: Liver fibrosis parameters were associated with carotid artery atherosclerosis and coronary artery stenosis. Evaluation of liver fibrosis may be useful to identify significant atherosclerosis and coronary artery stenosis in patients with MASLD.

Aims: We report that small dense low-density lipoprotein cholesterol (sdLDL-C) levels are sensitive biomarkers of metabolic dysfunction-associated steatotic liver disease (MASLD). Since triglyceride (TG)-rich very low-density lipoprotein (VLDL) is a precursor of sdLDL and is overproduced by MASLD, the composition of VLDL may be more directly associated with MAFLD than sdLDL-C or plasma TG. To identify TG-rich VLDL, this author proposed “Excess TG” and examined its association with MASLD.

Methods: Patients with type 2 diabetes (n=1295), excluding fasting hypertriglyceridemia (TG ≥ 400 mg/dL) and heavy drinkers were examined. Liver steatosis and visceral fat area (VFA) were evaluated using CT. VLDL-C was calculated as the total C minus direct LDL-C minus HDL-C. The average VLDL-TG level can be estimated using VLDL-C×5, according to the principle of the Friedewald equation for LDL-C. Thus, VLDL-TG was estimated as VLDL-C×5, and Excess TG was calculated as plasma TG minus VLDL-C×5.

Results: Patients with MASLD were younger, more likely to be men and drinkers, and had higher VFA, TG, sdLDL-C, and excess TG, while VLDL-C was comparable. Excess TG was found to be the most sensitive lipid parameter for identifying MASLD, independent of sdLDL-C, TG, TG/VLDL-C, and VFA. The odds ratios for MASLD were 2.4-, 3.7-, and 3.9-fold higher for Excess TG ranges of 0–24, 25–49, and ≥ 50 mg/dL, respectively, relative to ＜0 mg, and a close relationship remained significant after adjustment for lipid- and adiposity-related parameters.

Conclusions: Excess TG in VLDL was strongly associated with MASLD beyond TG and sdLDL-C levels, which may reflect the presence of TG-rich VLDL.