Aims: Small arteries can be visualized in the ocular fundus, and findings of retinopathy based on Scheie classification are often applied to evaluate the impact of hypertension and atherosclerosis. However, the relationship between damage in the large and small arteries has not been investigated sufficiently, especially in the early stages. The present study investigated possible associations between large artery atherosclerosis and small artery retinopathy in untreated middle-aged individuals.

Methods: Untreated middle-aged workers undergoing periodic health check-ups (n=7,730, 45±8 years) were enrolled in this study. The absence or presence and extent of retinopathy were characterized by ophthalmologists as hypertensive (H0-4) and atherosclerotic grades (S0-4) based on Scheie classification. Large artery atherosclerosis was examined based on functional assessment of the cardio-ankle vascular index (CAVI) and morphological assessment of the carotid intima-media thickness (IMT) by ultrasound.

Results: We found significant differences in CAVI and carotid IMT between individuals with and without hypertensive or atherosclerotic retinopathy. Multivariable regression analysis showed that the presence of hypertensive and atherosclerotic retinopathy was significantly associated with CAVI and carotid IMT. Logistic regression analysis with the endpoint of a hypertensive or atherosclerotic lesion revealed that CAVI and carotid IMT are independent determinants of retinopathy.

Conclusions: CAVI and carotid IMT were significantly associated with the presence of retinopathy based on Scheie classification in untreated middle-aged subjects, implying that atherosclerotic examination in large arteries could reveal early-stage small artery retinopathy.

Aim: Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades the low-density lipoprotein (LDL) receptor, leading to hypercholesterolemia and cardiovascular risk. Treatment with a statin leads to a compensatory increase in circulating PCSK9 level. Anagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to decrease LDL cholesterol (LDL-C) levels to a greater extent than that by sitagliptin, another DPP-4 inhibitor, in the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. We investigated PCSK9 concentration in type 2 diabetes mellitus (T2DM) and the impact of treatment with anagliptin or sitagliptin on PCSK9 level as a sub-analysis of the REASON trial.

Methods: PCSK9 concentration was measured at baseline and after 52 weeks of treatment with anagliptin (n=122) or sitagliptin (n=128) in patients with T2DM who were receiving statin therapy. All of the included patients had been treated with a DPP-4 inhibitor prior to randomization.

Results: Baseline PCSK9 level was positively, but not significantly, correlated with LDL-C and was independently associated with platelet count and level of triglycerides. Concomitant with reduction of LDL-C, but not hemoglobin A1c (HbA1c), by anagliptin, PCSK9 level was significantly increased by treatment with sitagliptin (218±98 vs. 242±115 ng/mL, P=0.01), but not anagliptin (233±97 vs. 250±106 ng/mL, P=0.07).

Conclusions: PCSK9 level is independently associated with platelet count and level of triglycerides, but not LDL-C, in patients with T2DM. Anagliptin reduces LDL-C level independent of HbA1c control in patients with T2DM who are on statin therapy possibly by suppressing excess statin-mediated PCSK9 induction and subsequent degradation of the LDL receptor.

Aims: This study aimed to evaluate the tracking pattern of serum total cholesterol (TC) levels among Japanese children using data collected continuously for 9 years and examine the relationship between childhood and adulthood TC levels.

Methods: TC levels of 2,608 first grade primary school children enrolled during 1981-2014 from two Japanese towns were measured during annual health check-ups. Nine-year trajectories of estimated TC levels stratified by TC quartiles in the first grade were analyzed using a mixed effects model. Adulthood TC levels were measured in participants who underwent health check-ups in the same area.

Results: Overall, 1,322 boys and 1,286 girls in the first grade of a primary school were followed for 9 years. Trajectories of TC levels during the period stratified by TC quartiles in the first grade differed significantly and did not cross each other for both sexes. Childhood data of 242 adult participants were linked with their adulthood data; the mean of age was late 20s for both sexes. The average TC levels in adulthood increased from the first to the fourth quartile in the first grade. Additionally, trajectories of TC levels differed between boys and girls. The later the admission year, the more elevated the TC levels in girls.

Conclusion: Among Japanese children, TC levels were strongly tracked from childhood to adolescence for 9 years, and elevated TC levels in childhood were related to elevated TC levels in adulthood. Maintaining appropriate TC levels during childhood may be important to prevent future coronary artery diseases.

Aim: The association between high-density lipoprotein cholesterol (HDL-C) level after statin therapy and cardiovascular events in patients with stable coronary artery disease (CAD) remains unclear. Thus, in this study, we sought to determine how HDL-C level after statin therapy is associated with cardiovascular events in stable CAD patients.

Methods: From the REAL-CAD study which had shown the favorable prognostic effect of high-dose pitavastatin in stable CAD patients with low-density lipoprotein cholesterol (LDL-C) ＜120 mg/dL, 9,221 patients with HDL-C data at baseline and 6 months, no occurrence of primary outcome at 6 months, and reported non-adherence for pitavastatin, were examined. The primary outcome was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina requiring emergent admission after 6 months of randomization. Absolute difference and ratio of HDL-C levels were defined as (those at 6 months–at baseline) and (absolute difference/baseline)×100, respectively.

Results: During a median follow-up period of 4.0 (IQR 3.2–4.7) years, the primary outcome occurred in 417 (4.5%) patients. The adjusted risk of all HDL-C-related variables (baseline value, 6-month value, absolute, and relative changes) for the primary outcome was not significant (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.91–1.08, HR 1.03, 95% CI 0.94–1.12, HR 1.05, 95% CI 0.98–1.12, and HR 1.08, 95% CI 0.94–1.24, respectively). Furthermore, adjusted HRs of all HDL-C-related variables remained non-significant for the primary outcome regardless of on-treatment LDL-C level at 6 months.

Conclusions: After statin therapy with modestly controlled LDL-C, HDL-C level has little prognostic value in patients with stable CAD.

Aim: According to recent clinical trials, a combination of direct oral anticoagulants with antiplatelet drugs is often recommended for atrial fibrillation patients who receive drug-eluting stents (DESs). Although the optimal combination comprises direct factor Xa inhibitors and a P2Y₁₂ receptor antagonist (or aspirin), their influence on vascular responses to DESs remains unclear.

Methods: Pigs were given either aspirin and clopidogrel (dual antiplatelet therapy [DAPT] group), aspirin and rivaroxaban (AR group), or clopidogrel and rivaroxaban (CR group), followed by everolimus-eluting stent (Promus Element) implantation into the coronary artery. Stented coronary arteries were evaluated via intravascular optical coherence tomography (OCT) and histological analysis at 1 and 3 months.

Results: OCT revealed lower neointimal thickness in the DAPT group and comparable thickness among all groups at 1 and 3 months, respectively. Histological analyses revealed comparable neointimal area among all groups and the smallest neointimal area in the CR group at 1 and 3 months, respectively. In the DAPT and AR groups, the neointima continued to grow from 1 to 3 months. A shortened time course for neointima growth was observed in the CR group, with rapid growth within a month (maintained for 3 months). A higher incidence of in-stent thrombi was observed in the AR group at 1 month; no thrombi were found in either group at 3 months. More smooth muscle cells with contractile features were found in the CR group at both 1 and 3 months.

Conclusions: Our results proved the noninferiority of the combination of rivaroxaban with an antiplatelet drug, particularly the dual therapy using rivaroxaban and clopidogrel, compared to DAPT after DES implantation.

Aim: Feedback activation of factor XI (FXI) by thrombin is believed to play a critical role in the amplification phase of thrombin generation and to contribute to thrombosis development and hemostasis. However, the activation of FXI by thrombin has been shown in vitro to require a cofactor. In this study, the role of thrombin in activated FXI (FXIa) formation in vivo is investigated.

Methods: The study population comprised probands in whom coagulation activation was triggered by low-dose (15 µg/kg) recombinant activated factor VII (rFVIIa, n=89), of whom 34 with (VTE+) and 45 without a history of venous thromboembolism (VTE−), and patients undergoing major orthopedic surgeries (n=45). FXIa was quantified via an enzyme capture assay using a monoclonal FXI-specific antibody. Thrombin formation was monitored using an oligonucleotide-based enzyme capture assay and the thrombin activation markers prothrombin fragment 1＋2 (F1＋2) and thrombin–antithrombin complex (TAT).

Results: In the rFVIIa cohort, FXIa and thrombin remained below their lower limit of quantification of 3.48 and 1.06 pmol/L, respectively. By contrast, during the surgeries, median FXIa levels increased from 3.69 pmol/L pre-operatively to 9.41 pmol/L mid-operatively (P=4·10⁻⁴) and remained significantly elevated 24 h thereafter, with 9.38 pmol/L (P=0.001). Peak levels of F1+2 were comparable in the VTE+, VTE−, and surgery cohort (235, 268, and 253 pmol/L), whereas peak TAT levels were higher in the surgery cohort (53.1, 33.9, and 147.6 pmol/L).

Conclusions: Under in vivo conditions, the activation of FXI requires specific local features that are present at the wounded site including potential cofactors of thrombin.

Aim:The prediction of functional outcome is essential in the management of acute ischemic stroke patients. We aimed to explore the various prognostic factors with multivariate linear discriminant analysis or neural network analysis and evaluate the associations between candidate factors, baseline characteristics, and outcome.

Methods: Acute ischemic stroke patients (n=1,916) with premorbid modified Rankin Scale (mRS) scores of 0–2 were analyzed. The prediction models with multivariate linear discriminant analysis (quantification theory type II) and neural network analysis (log-linearized Gaussian mixture network) were used to predict poor functional outcome (mRS 3–6 at 3 months) with various prognostic factors added to age, sex, and initial neurological severity at admission.

Results: Both models revealed that several nutritional statuses and serum alkaline phosphatase (ALP) levels at admission improved the predictive ability. Of the 1,484 patients without missing data, 560 patients (37.7%) had poor outcomes. The patients with poor outcomes had higher ALP levels than those without (294.3±259.5 vs. 246.3±92.5 U/l, P＜0.001). Multivariable logistic analyses revealed that higher ALP levels (1-SD increase) were independently associated with poor stroke outcomes after adjusting for several confounding factors, including the neurological severity, malnutrition status, and inflammation (odds ratio 1.21, 95% confidence interval 1.02–1.49). Several nutritional indicators extracted from prediction models were also associated with poor outcome.

Conclusion: Both the multivariate linear discriminant and neural network analyses identified the same indicators, such as nutritional status and serum ALP levels. These indicators were independently associated with functional stroke outcome.

Aim: Abdominal aortic aneurysm (AAA) is a lethal and multifactorial disease. To prevent a rupture and dissection of enlarged AAA, prophylactic surgery and stenting are currently available. There are, however, no medical therapies preventing these complications of AAA. Statin is one of the candidates, but its efficacy on AAA formation/progression remains controversial. We have previously demonstrated that nanoparticles (NPs) incorporating pitavastatin (Pitava-NPs)—clinical trials using these nanoparticles have been already conducted—suppressed progression of atherosclerosis in apolipoprotein E-deficient ( Apoe^−/−) mice. Therefore, we have tested a hypothesis that monocytes/macrophages-targeting delivery of pitavastatin prevents the progression of AAA.

Methods: Angiotensin II was intraperitoneally injected by osmotic mini-pumps to induce AAA formation in Apoe^−/− mice. NPs consisting of poly(lactic-co-glycolic acid) were used for in vivo delivery of pitavastatin to monocytes/macrophages.

Results: Intravenously administered Pitava-NPs (containing 0.012 mg/kg/week pitavastatin) inhibited AAA formation accompanied with reduction of macrophage accumulation and monocyte chemoattractant protein-1 (MCP-1) expression. Ex vivo molecular imaging revealed that Pitava-NPs not only reduced macrophage accumulation but also attenuated matrix metalloproteinase activity in the abdominal aorta, which was underpinned by attenuated elastin degradation.

Conclusion: These results suggest that Pitava-NPs inhibit AAA formation associated with reduced macrophage accumulation and MCP-1 expression. This clinically feasible nanomedicine could be an innovative therapeutic strategy that prevents devastating complications of AAA.

Aims: Recent studies suggested plaque erosion with noncritical stenosis could be treated distinctly from that with critical stenosis, but their morphological features remained largely unknown. The present study aimed to investigate morphological features of eroded plaques with different lumen stenosis using optical coherence tomography (OCT).

Methods: A total of 348 ST-segment elevated myocardial infarction patients with culprit OCT-defined plaque erosion (OCT-erosion) were analyzed. Based on the severity of lumen area stenosis, all patients with OCT-erosions were divided into the following three groups: Group A (area stenosis ＜50%, n=50); Group B (50% ≤ area stenosis ＜75%, n=146); Group C (area stenosis ≥ 75%, n=152).

Results: Compared with patients in Groups A and B, patients in Group C were older (p=0.008) and had higher prevalence of hypertension (p=0.029). Angiographic analysis showed that 72.0% of the eroded plaques in Group A were located in the left anterior descending artery, followed by 67.8% in Group B, and 53.9% in Group C (p=0.039). OCT analysis showed that Group A had the highest prevalence of fibrous plaques (p＜0.001) and nearby bifurcation (p=0.036), but the lowest prevalence of lipid-rich plaques (p＜0.001), macrophage accumulation (p＜0.001), microvessels (p=0.009), cholesterol crystals (p＜0.001), and calcification (p=0.023). Multivariable regression analysis showed fibrous plaque (odds ratio [OR]: 3.014, 95% confidence interval [CI]: 1.932–4.702, p＜0.001) and nearby bifurcation (OR: 1.750, 95% CI: 1.109–2.761, p=0.016) were independently associated with OCT-erosion with an area stenosis of ＜75%.

Conclusions: More than half of OCT-erosions presented with ＜75% area stenosis, having distinct morphological features from those of OCT-erosions with critical stenosis. Fibrous plaque and nearby bifurcation were independently associated with noncritically stenotic OCT-erosion, suggesting that eroded plaques might need individualized treatment.