Dual antiplatelet therapy (DAPT) is a therapeutic cornerstone to prevent stent thrombosis following percutaneous coronary intervention (PCI) for coronary artery disease (CAD). However, the longer the DAPT duration, the higher the incidence of bleeding and mortality. Since the advent of second-generation drug-eluting stents (DES), the continuous evolution of DES has reduced the thrombotic risk and allowed for a shorter DAPT duration. On the other hand, concerns on the elevated risk of bleeding during antithrombotic therapy have been further raised due to the growing number of elderly CAD patients with multiple comorbidities. The consequent debate topic over post-PCI antithrombotic therapy has shifted from simply reducing thrombotic risk to safely minimizing bleeding risk. Due to the significant impact of bleeding on clinical outcomes, including prognosis, current guidelines on antithrombotic therapy for CAD prioritize stratification of patients at a high bleeding risk (HBR) as the top consideration in determining post-PCI antithrombotic therapy. Achieving optimal antithrombotic therapy for each patient undergoing PCI requires a better understanding of the clinical variables constituting the balance of bleeding and thrombotic risk. This review highlights relevant evidence required to optimize antithrombotic therapy for HBR patients undergoing PCI.

Aim: Manganese (Mn) is an essential element in the human body, and it has a significant impact on cardiovascular risk factors such as diabetes, blood pressure, and cholesterol levels. However, no research has been conducted on the association between Mn and cardiovascular disease (CVD), to the best of our knowledge. This study thus examined the association between dietary Mn intake and CVD mortality in the general Japanese population.

Methods: The CVD mortality among 58,782 participants from the Japan Collaborative Cohort Study (JACC) aged 40–79 years was determined during a median follow-up period of 16.5 years. The Mn intake was estimated using a food frequency questionnaire at the baseline (1989–1990), and multivariate-adjusted hazard ratios (HRs) for mortality were computed according to quintiles of energy-adjusted Mn intake.

Results: During the follow-up period, a total of 3408 CVD deaths were recorded. Participants in the highest quintile of Mn intake had a lower risk of mortality from total stroke (HR:95% CI, 0.76: 0.64–0.90), ischemic stroke (HR: 0.77, 0.61–0.97), ischemic heart disease (HR: 0.76, 0.58–0.98), and total CVD (HR: 0.86, 0.76–0.96) compared with those in the lowest quintile. The reduced risk of mortality from intraparenchymal hemorrhage with high Mn intake was observed among women (HR: 0.60, 0.37–0.96) but not men (HR: 0.93, 0.59–1.47). The observed associations were more robust in postmenopausal than in premenopausal women.

Conclusions: Our study is the first to show the prospective association between dietary Mn intake and reduced risk of mortality from CVD in the Japanese population.

Aim: More than 5-year clinical outcomes after femoropopliteal (FP) stenting with bare-nitinol stent (BNS) have not yet been unclear. We investigate the long-term patency and mortality following FP stenting with BNS.

Methods: This study was a multicenter retrospective study of a prospectively maintained database. From April 2004 to December 2011, 1824 consecutive patients (2211 limbs) who underwent FP stenting with BNS for de novo lesions were selected and analyzed. Primary endpoint was primary patency which was defined as treated vessel without restenosis and reintervention and its associated factors.

Results: The prevalence of diabetes mellitus and dialysis was 60.5% and 23.8%, respectively. Chronic limb-threatening ischemia (CLTI) accounted for 30.8%. Chronic total occlusion (CTO) was found in 52.7%, and lesion length was more than 20 cm in 22.6%. During the median follow-up of 3.8 years (interquartile range, 1.4 to 7.4 years), 1049 cases lost patency, whereas 355 cases were dead without experiencing loss of patency. The primary patency (95% CI) was estimated to be 74.8%, 47.3% and 29.1% at 1-, 5- and 10-year. On multivariate analysis, female sex, age ≥ 80 years, diabetes, dialysis, CLTI, CTO, arterial calcification, long lesion (＞20 cm), and small vessel (≤ 4 mm) were the independent predictors of primary patency after FP stenting. In addition, the prognostic impact of age ≥ 80 years, CLTI, and arterial calcification was significantly attenuated afterwards (P＜0.05).

Conclusions: Ten-year patency after BNS implantation for FP disease has been continuously reducing up to 10 years and the prognostic impact of risk factors was changed over time.

Aim: We investigated the relationship between small dense low-density cholesterol (sdLDL-C) and risk of major adverse cardiovascular events (MACE) in patients treated with high- or low-dose statin therapy.

Methods: This was a prospective case-cohort study within the Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study, a randomized trial of high- or low-dose (4 or 1 mg/d pitavastatin, respectively) statin therapy, in patients with stable coronary artery disease (CAD). Serum sdLDL-C was determined using an automated homogenous assay at baseline (randomization after a rule-in period, ＞1 month with 1 mg/d pitavastatin) and 6 months after randomization, in 497 MACE cases, and 1543 participants randomly selected from the REAL-CAD study population.

Results: High-dose pitavastatin reduced sdLDL-C by 20% than low-dose pitavastatin (p for interaction ＜0.001). Among patients receiving low-dose pitavastatin, baseline sdLDL-C demonstrated higher MACE risk independent of LDL-C (hazard ratio [95% confidence interval], 4th versus 1st quartile, 1.67 [1.04–2.68]; p for trend=0.034). High-dose (versus low-dose) pitavastatin reduced MACE risk by 46% in patients in the highest baseline sdLDL-C quartile (＞34.3 mg/dL; 0.54 [0.36–0.81]; p=0.003), but increased relative risk by 40% in patients with 1st quartile (≤ 19.5 mg/dL; 1.40 [0.94–2.09]; p=0.099) and did not alter risk in those in 2nd and 3rd quartiles (p for interaction=0.002).

Conclusions: These findings associate sdLDL-C and cardiovascular risk, independent of LDL-C, in statin-treated CAD patients. Notably, high-dose statin therapy reduces this risk in those with the highest baseline sdLDL-C.

Aim: Using a nationwide epidemiological database, we sought to examine whether there was a sex difference in the association between lipid profiles and subsequent cardiovascular disease (CVD) in young adults.

Methods: Medical records of 1,909,362 young adults (20–49 years old) without a prior history of CVD and not taking lipid-lowering medications were extracted. We conducted multivariable Cox regression analyses to identify the association between the number of abnormal lipid profiles and incident CVD.

Results: After a mean follow-up of 3.4±2.6 years, myocardial infarction (MI), angina pectoris (AP), stroke, and heart failure (HF) developed in 2,575 (0.1%), 26,006 (1.4%), 10,748 (0.6%), and 24,875 (1.3%) subjects, respectively. The incidence of MI, AP, and HF increased with the number of abnormal lipid profiles in both men and women, whereas the incidence of stroke increased with the number of abnormal lipid profiles only in men but not in women. Multivariable adjusted hazard ratios (HRs) for MI per 1-point higher abnormal lipid profile were 1.57 (95% confidence interval [CI] 1.49–1.65) in men and 1.25 (95% CI 1.07–1.47) in women. HRs for AP, stroke, and HF per 1-point higher abnormal lipid profile were 1.14 (95% CI 1.12–1.16), 1.06 (95% CI 1.02–1.09), and 1.10 (95% CI 1.08–1.12) in men and 1.18 (95% CI 1.13–1.23), 1.09 (95% CI 1.03–1.16), and 1.10 (95% CI 1.05–1.14) in women.

Conclusion: Our analysis demonstrated an association between the number of abnormal lipid profiles and incident CVD in both men and women. The association between the number of abnormal lipid profiles and incident MI was pronounced in men.

Aim: We investigated whether retinal arteriolosclerosis (RA) could be used for cardiovascular disease (CVD) risk stratification of individuals categorized according to the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) Blood Pressure (BP) guideline.

Methods: We studied 291,522 participants without a history of CVD and not taking any BP-lowering medications from the JMDC Claims Database. RA was defined as Keith–Wagener–Barker system grade ≥ 1. Each participant was classified into one of the six groups: (1) normal or elevated BP without RA, (2) normal or elevated BP with RA, (3) stage 1 hypertension without RA, (4) stage 1 hypertension with RA, (5) stage 2 hypertension without RA, and (6) stage 2 hypertension with RA.

Results: Median (interquartile range) age was 46 (40–53) years, and 141,397 (48.5%) of the participants were men. During a mean follow-up of 1,223±830 days, 527 myocardial infarction (MI), 5,718 angina pectoris, 2,890 stroke, and 5,375 heart failure (HF) events occurred. Multivariable Cox regression analyses revealed that the risk of CVD increased with BP category, and this association was pronounced by the presence of RA. Compared with normal or elevated BP without RA, the hazard ratios (HRs) for MI (HR 1.17, 95% CI 0.93–1.47) were higher in stage 1 hypertension without RA. The HRs for MI further increased in stage 1 hypertension with RA (1.86 [1.17–2.95]). This association was present in stroke and HF.

Conclusion: Incorporation of the assessment for RA may facilitate the CVD risk stratification of people classified based on the 2017 ACC/AHA BP guideline, particularly for those categorized in stage 1 hypertension.

Aims: We previously associated acute ST-elevation myocardial infarction (STEMI) with decreased plasma LL-37 levels. Therefore, this study investigated whether plasma LL-37 levels could predict ischemic cardiovascular events in patients after STEMI.

Methods: We prospectively collected peripheral plasma samples and clinical and laboratory data from consecutive patients who presented with STEMI and underwent primary percutaneous coronary intervention at Fuwai Hospital between April and November 2017. Enzyme-linked immunosorbent assay measured plasma LL-37 levels, and we followed the patients for 3 years. Major adverse cardiovascular events (MACEs) were a composite of all-cause mortality, reinfarction, unscheduled revascularization, or ischemic stroke.

Results: The study included 302 patients divided into high (≥ median) and low LL-37 level (＜median) groups. The cumulative incidence of MACE (29.1% vs. 12.6%, p=0.0003), all-cause death (12.6% vs. 3.3%, p=0.003), reinfarction (7.1% vs. 2.0%, p=0.04), and unscheduled revascularization (13.0% vs. 5.4%, p=0.04) were higher in the low than those in the high LL-37 level group. Multivariable Cox regression analysis showed that higher LL-37 level independently predicted lower risks of MACE (hazard ratio [HR] 0.390; 95% confidence interval [CI] 0.227–0.669; p＜0.001), all-cause death (HR 0.324; 95%CI 0.119–0.879; p=0.027), and unscheduled revascularization (HR 0.391; 95%CI 0.171–0.907; p=0.027).

Conclusions: High basal plasma level of human LL-37 may predict lower 3-year risks of ischemic cardiovascular events in patients after STEMI.

Aim: Weight change could have many health outcomes. This study aimed to investigate the association between weight change and mortality risk due to total cardiovascular disease (CVD), ischemic heart disease (IHD), and stroke among Japanese.

Methods: We used Suita Study data from 4,746 people aged 30-79 years in this prospective cohort study. Weight change was defined as the difference between baseline weight and weight at age 20. We used Cox proportional hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of total CVD, IHD, and stroke mortality for 1) participants with a weight change (＞10, 5 to 10, -5 to -10, and ＜-10 kg) compared to those with stable weight (-4.9 to 4.9 kg) and 2) participants who moved from one body mass index category (underweight, normal weight, or overweight) to another compared to those with normal weight at age 20 and baseline.

Results: Within a median follow-up period of 19.9 years, the numbers of total CVD, IHD, and stroke mortality were 268, 132, and 79, respectively. Weight loss of ＞10 kg was associated with the increased risk of total CVD mortality 2.07 (1.29, 3.32) and stroke mortality 3.02 (1.40, 6.52). Moving from normal weight at age 20 to underweight at baseline was associated with the increased risk of total CVD, IHD, and stroke mortality: 1.76 (1.12, 2.77), 2.10 (1.13, 3.92), and 2.25 (1.05, 4.83), respectively.

Conclusion: Weight loss, especially when moving from normal to underweight, was associated with the increased risk of CVD mortality.

Aim: Cervicocephalic atherosclerosis (AS) of patients with large-artery atherosclerotic (LAA) stroke might be more closely correlated to the functional outcome than patients with stroke of other etiologies. We aimed to investigate whether a whole-scope evaluation of cervicocephalic AS condition was better at predicting the 90-day functional outcome of LAA stroke than evaluation of intracranial or cervical AS condition alone.

Methods: Patients with LAA stroke were consecutively enrolled in this study. Computed tomography angiography was performed to evaluate AS condition of various cervicocephalic arterial segments. AS conditions ranging from no AS plaque to complete arterial occlusion scored 0–4 points. Intracranial atherosclerotic burden (IAB) and cervical atherosclerotic burden (CAB) were in respective the sums of AS scores of all intracranial arterial segments and all cervical arterial segments. And the sum of them was intracranial and cervical atherosclerotic burden (ICAB). Relationships of these three scores with the 90-day unfavorable functional outcome (modified Rankin Scale[mRS] score ＞2 points) were compared.

Results: Of 172 patients who finished 90-day follow-up, only ICAB (adjusted odds ratio[OR]=1.10, 95% confidence interval[CI]:1.00–1.21, p=0.044) predicted 90-day unfavorable functional outcome independently of clinical factors, National Institutes of Health Stroke Scale (NIHSS) and mRS scores at admission. ICAB (adjusted hazard ratio[HR]=1.16, 95%CI:1.02–1.32, p=0.029) was related to 90-day recurrent ischemic stroke/death independently of clinical factors and was independently, positively correlated with NIHSS score at admission (r=0.16, p=0.047), whereas IAB and CAB were not.

Conclusion: A whole-scope evaluation of cervicocephalic AS condition using ICAB outperformed evaluation of intracranial or cervical AS condition alone in predicting 90-day functional outcome of patients with LAA stroke.

Aims: Higher serum uric acid (UA) may impair endothelial function. However, population-based evidence examining the association between serum UA levels and endothelial function remains to be limited. Thus, in this study, we aimed to investigate this in the general population.

Methods: In this cross-sectional study, 1000 participants (496 males and 504 females), aged 30–79 years, free from a history of gout, have undergone both serum UA and brachial artery flow-mediated dilation (FMD) measurements. Participants were divided into four groups based on serum UA quartiles. Logistic regression models were used to calculate odds ratios (ORs) for low FMD according to the serum UA levels.

Results: In total, 203 participants (138 males and 65 females) with %FMD ≤ 5.0% were identified to have endothelial dysfunction. The multivariable OR of low FMD for highest quartiles vs. lowest quartiles was 2.39 (95% confidence interval [CI]: 1.32–4.34), while OR per 1-standard deviation (SD) increment was 1.28 (95% CI: 1.04–1.56). The positive association was noted to be more evident in females (OR per 1-SD increment: 1.46; 95% CI: 1.08–1.96) than in males and confined to individuals not using antihypertensive medications. The ORs per 1-SD increment were 1.01 (95% CI: 0.68–1.50) among individuals using antihypertensive medications and 1.43 (95% CI: 1.12–1.81) among individuals not using antihypertensive medications.

Conclusion: Higher serum UA was positively associated with the prevalence of endothelial dysfunction in samples of the general Japanese population and that positive association was confined to individuals not using antihypertensive medications.

Aim: We aimed to examine the association of obesity-related cancer and cardiovascular disease (CVD) with body mass index (BMI) and the estimated population attributable fraction in lean Asians.

Methods: We studied 102,535 participants aged 40–79 years without histories of cancer or CVD at baseline between 1988 and 2009. The cause-specific hazard ratios (csHRs) of BMI categories (＜18.5, 18.5–20.9, 21.0–22.9 [reference], 23.0–24.9, 25.0–27.4, and ≥ 27.5 kg/m²) were estimated for each endpoint. The events considered were mortalities from obesity-related cancer (esophageal, colorectal, liver, pancreatic, kidney, female breast, and endometrial cancer) and those from CVD (coronary heart disease and stroke). Population attributable fractions (PAFs) were calculated for these endpoints.

Results: During a 19.2-year median follow-up, 2906 died from obesity-related cancer and 4532 died from CVD. The multivariable-adjusted csHRs (95% confidence interval) of higher BMI categories (25–27.4 and ≥ 27.5 kg/m²) for obesity-related cancer mortality were 0.93 (0.78, 1.10) and 1.18 (0.92, 1.50) in men and 1.25 (1.04, 1.50) and 1.48 (1.19, 1.84) in women, respectively. The corresponding csHRs for CVD mortality were 1.27 (1.10, 1.46) and 1.59 (1.30, 1.95) in men and 1.10 (0.95, 1.28) and 1.44 (1.21, 1.72) in women, respectively. The PAF of a BMI ≥ 25 kg/m² for obesity-related cancer was −0.2% in men and 6.7% in women and that for CVD was 5.0% in men and 4.5% in women.

Conclusion: A BMI ≥ 25 kg/m² is associated with an increased risk of obesity-related cancer in women and CVD in both sexes.