The detrimental effects of cigarette smoking on cardiovascular health, particularly atherosclerosis and thrombosis, are well established, and more detailed mechanisms continue to emerge. As the fundamental pathophysiology of the adverse effects of smoking, endothelial dysfunction, inflammation, and thrombosis are considered to be particularly important. Cigarette smoke induces endothelial dysfunction, leading to impaired vascular dilation and hemostasis regulation. Factors contributing to endothelial dysfunction include reduced bioavailability of nitric oxide, increased levels of superoxide anion, and endothelin release. Chronic inflammation of the vascular wall is a central pathogenesis of smoking-induced atherosclerosis. Smoking systemically elevates inflammatory markers and induces the expression of adhesion molecules and cytokines in various tissues. Pattern recognition receptors and damage-associated molecular patterns play crucial roles in the mechanism underlying smoking-induced inflammation. Smoking-induced DNA damage and activation of innate immunity, such as the NLRP3 inflammasome, cyclic GMP–AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, and Toll-like receptor 9, are shown to amplify inflammatory cytokine expression. Cigarette smoke-induced oxidative stress and inflammation influence platelet adhesion, aggregation, and coagulation via adhesion molecule upregulation. Furthermore, it affects the coagulation cascade and fibrinolysis balance, causing thrombus formation. Matrix metalloproteinases contribute to plaque vulnerability and atherothrombotic events. The impact of smoking on inflammatory cells and adhesion molecules further intensifies the risk of atherothrombosis. Collectively, exposure to cigarette smoke exerts profound effects on endothelial function, inflammation, and thrombosis, contributing to the development and progression of atherosclerosis and atherothrombotic cardiovascular diseases. Understanding these intricate mechanisms highlights the urgent need for smoking cessation to protect cardiovascular health. This comprehensive review investigates the multifaceted mechanisms through which smoking contributes to these life-threatening conditions.

Aims: Andexanet alfa, a specific antidote to factor Xa (FXa) inhibitors, has been approved for clinical use in several countries, including Japan, based on the results from the phase 3 trial ANNEXA-4. We aimed to assess the efficacy and safety of andexanet alfa treatment in FXa inhibitor–related acute major bleeding in patients enrolled for ANNEXA-4 in Japan.

Methods: This prespecified analysis included patients enrolled at Japanese sites in the prospective, open-label, single-arm ANNEXA-4 trial. Eligible patients had major bleeding within 18 hours of oral FXa inhibitor administration. The coprimary efficacy endpoints were percent change in anti-FXa activity and proportion of patients achieving excellent or good hemostatic efficacy 12 hours post-treatment.

Results: A total of 19 patients were enrolled, all of whom had intracranial hemorrhage; 16 patients were evaluable for efficacy. Median percent reduction in anti-FXa activity from baseline to nadir was 95.4% in patients taking apixaban, 96.1% in patients taking rivaroxaban, and 82.2% in patients taking edoxaban. Overall, 14/16 patients (88%) achieved excellent or good hemostasis (apixaban, 5/5; rivaroxaban, 6/7; edoxaban, 3/4). Within 30 days, treatment-related adverse events (AEs) and serious AEs occurred in 2 and 5 patients, respectively. One patient died during follow-up, and 2 patients experienced thrombotic events.

Conclusion: Treatment with andexanet alfa rapidly reduced anti-FXa activity with favorable hemostatic efficacy in Japanese patients with acute major bleeding. Serious AEs of thrombotic events during rapid reversal of anti-FXa activity arose as particular safety concerns in this population as with previous studies.

Aim: Sudden death is one of the most common causes of death among hemodialysis patients. Electrocardiography (ECG) is a noninvasive and inexpensive test that is regularly performed in hemodialysis clinics. However, the association between abnormal ECG findings and the risk of sudden death in hemodialysis patients is yet to be fully elucidated. Thus, the aim of this study was to determine the ECG parameters linked to sudden death in patients undergoing hemodialysis.

Methods: The Q-Cohort Study is a multicenter, longitudinal, observational study of hemodialysis patients. In this study, 1,153 Japanese hemodialysis patients aged ≥ 18 years with ECG data recorded within 1 year of study enrollment were followed up for 10 years. Cox proportional hazards models were used to estimate the multivariate-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for the association between ECG parameters and sudden death.

Results: During the median follow-up period of 9.0 years, 517 patients died, 76 of whom exhibited sudden death. After adjusting for confounding factors, higher heart rate, QT prolongation, and left ventricular hypertrophy as per the Sokolow–Lyon voltage criteria were found to be independently associated with an increased risk of sudden death. The adjusted HRs [95% CIs] for each abnormal ECG parameter were 2.02 [1.05–3.89], 2.10 [1.30–1.77], and 1.91 [1.18–3.09], respectively.

Conclusions: Higher heart rate, QT prolongation, and left ventricular hypertrophy on ECG have been determined to be associated with an increased risk of sudden death. Therefore, regular ECG recording could enable medical practitioners to identify hemodialysis patients who require intervention to prevent lethal arrhythmia.

Aim: A high level of directly measured small dense low-density lipoprotein cholesterol (sdLDL-C) is a strong risk factor for ischemic heart disease (IHD). However, it remains unclear whether estimated sdLDL-C level is a predictor for IHD. We investigated the associations of new onset of IHD with levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides (TG), LDL-C and calculated sdLDL-C by Sampson’s equation.

Methods: After exclusion of subjects with IHD or those with TG ≥ 800 mg/dL, a total of 18,176 subjects (men/women: 11,712/6,464, mean age: 46 years) were recruited among 28,990 Japanese individuals who received annual health checkups.

Results: During the 10-year follow-up period, 456 men (3.9%) and 121 women (1.9%) newly developed IHD. Multivariable Cox proportional hazard analyses after adjustment of age, sex, obesity, smoking habit, family history of IHD, estimated glomerular filtration rate, hypertension and diabetes mellitus at baseline showed that the hazard ratio (HR) (1.38 [95% confidence interval: 1.03-1.85]) for new onset of IHD in subjects with the 4^th quartile (Q4) of sdLDL-C (≥ 42 mg/dL) was significantly higher than that in subjects with the 1^st quartile (Q1) (≤ 24 mg/dL) as the reference, though the adjusted HRs in subjects with Q2-Q4 of TC, HDL-C, non-HDL-C, LDL-C and TG were comparable with those in subjects with Q1 of the respective lipid fractions. The adjusted HR with a restricted cubic spline increased with a higher level of calculated sdLDL-C as a continuous value at baseline.

Conclusions: sdLDL-C level calculated by Sampson’s equation is a predominant predictor for the development of IHD in a general Japanese population.

Aims: Inflammation is associated with vascular events. We aimed to investigate the relationship between high-sensitivity C-reactive protein (hsCRP) levels with and without intracranial arterial stenosis (ICAS) and the prognosis of patients with minor stroke or transient ischemic attack.

Methods: We used data from the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events trial (derivation cohort) and the Third China National Stroke Registry (validation cohort). Patients were divided into four groups according to the dichotomy of hsCRP level and ICAS status. The primary outcome was new ischemic stroke within 90 days, and the secondary outcome was dependence or death (Modified Rankin Scale score of 3–6) at 90 days. The associations between hsCRP level with and without ICAS and risk of outcomes were analyzed using multivariate Cox regression and logistic regression models.

Results: In the derivation cohort, compared with patients with nonelevated hsCRP levels and no ICAS, those with both elevated hsCRP levels and ICAS had increased risk of recurrent stroke (adjusted hazard ratio [HR], 2.62; 95% confidence interval [CI], 1.28–5.34; p=0.008) and dependence or death (adjusted odds ratio [OR], 7.58; 95% CI, 1.30–44.13; p=0.02). Consistent relationships of elevated hsCRP levels and presence of ICAS with recurrent stroke (adjusted HR, 1.67; 95% CI, 1.13–2.45; p=0.009) and dependence or death (adjusted OR, 1.87; 95% CI, 1.23–2.84; p=0.003) were observed in the validation cohort.

Conclusion: Concomitant presence of increased hsCRP levels and ICAS was associated with increased risk of stroke recurrence and dependence or death in patients with minor ischemic stroke or transient ischemic attack.

Aim: Estimating the risk of developing ischemic stroke (IS) may assist health professionals in motivating individuals to modify their risk behavior.

Methods: A predictive model was derived from 178,186 participants from Fukushima Health Database, aged 40-74 years, who attended the health checkup in 2014 and completed at least one annual health checkup by 2018 (Cohort I). Cox proportional hazard regression model was used to build a 4-year prediction model, thus the risk scores were based on the regression coefficients. External validation for the risk scores was conducted in another cohort of 46,099 participants following between 2015 and 2019 (Cohort II).

Results: The 4-year cumulated incidence rate of IS was 179.80/100,000 person-years in Cohort I. The predictive model included age, sex, blood pressure, hypertension treatment, diabetes, low- and high-density lipoprotein cholesterol, smoking, walking pace, and body weight change of 3 kg within one year. Risk scores were interpreted based on the Cohort I predictive model function. The Harrell’s C-statistics of the discrimination ability of the risk score model (95% confidence interval) was 0.744 (0.729-0.759) in Cohort I and 0.770 (0.743-0.797) in Cohort II. The overall agreement of the risk score probability of IS incidence for the observed/expected case ratio and 95% CI was 0.98 (0.92-1.05) in Cohort I and 1.08 (0.95-1.22) in Cohort II.

Conclusions: The 4-year risk prediction model revealed a good performance for IS incidence, and risk scores could be used to estimate individual incidence risk of IS. Updated models with additional confirmed risk variables may be needed.

Aim: Wide volume scan (WVS) coronary computed tomography angiography (CCTA) enables aortic arch visualization. This study assessed whether the thoracic aortic plaque burden (TAPB) score can predict major cardiovascular adverse events (MACE) in addition to and independently of other obstructive coronary artery disease (CAD) attributes.

Methods: This study included patients with suspected CAD who underwent CCTA (n=455). CCTA-WVS was used to assess CAD and the prognostic capacity of TAPB scores. Data analysis included the coronary artery calcification score (CACS), CAD status and extent, and TAPB score, calculated as the sum of plaque thickness and plaque angle at five thoracic aortic segments. The primary endpoint was MACE defined as a composite event comprised of ischemic stroke, acute coronary syndrome, and cardiovascular death.

Results: During a mean follow-up period of 2.8±0.9 years, 40 of 455 (8.8%) patients experienced MACE. In the Cox proportional hazards model adjusted for clinical risks (Suita cardiovascular disease risk score), we identified TAPB score (T3) as a predictor of MACE independent of CACS ＞400 (hazards ratio [HR], 2.91; 95% confidence interval [CI], 1.26–6.72; p=0.012) or obstructive CAD (HR, 2.83; 95% CI, 1.30–6.18; p=0.009). The area under the curve for predicting MACE improved from 0.75 to 0.795 (p value=0.008) when TAPB score was added to CACS ＞400 and obstructive CAD.

Conclusions: We found that comprehensive non-invasive evaluation of TAPB and CAD has prognostic value in MACE risk stratification for suspected CAD patients undergoing CCTA.

Aim: Ezetimibe administration with ongoing statin therapy is an effective option for further lowering low-density lipoprotein cholesterol (LDL-C) levels. Thus, we investigated the long-term efficacy and safety of fixed-dose combination of pitavastatin/ezetimibe (K-924 LD: 2 mg/10 mg; K-924 HD: 4 mg/10 mg).

Methods: We conducted a phase III, multicenter, open-label trial involving patients with hypercholesterolemia receiving pitavastatin (2 or 4 mg) who had not achieved their LDL-C management target. Patients were enrolled into the K-924 LD and HD groups based on whether they had received pitavastatin 2 and 4 mg, respectively, and treated for 52 weeks. K-924 was administered orally once daily. The primary objective was to examine the percent change in LDL-C from baseline at week 52 with last observation carried forward imputation (LOCF) in all patients.

Results: Of the 109 patients evaluated, 62 and 47 were assigned to the K-924 LD and HD groups, respectively. In all patients, LDL-C decreased by -30.3±14.3% (p＜0.001) from baseline (134.4±37.9 mg/dL). Consequently, 91.8% and 37.5% of the patients for primary and secondary prevention reached their LDL-C management target, respectively. These results were consistent in both the K-924 LD and HD groups. In the safety analysis, a single adverse drug reaction occurred in a patient in the K-924 HD group.

Conclusion: After replacing pitavastatin monotherapy, K-924 was found to be effective and well-tolerated over 52 weeks. Thus, K-924 can contribute to intensifying LDL-C-lowering therapy without increasing the number of medications.

Aims: Urinary immunoglobulin G (IgG) may be a stronger marker of atherosclerosis than microalbuminuria are because urinary IgG reflects proteinuria level and size-selectivity loss. Microalbuminuria—not urinary IgG—is associated with mild acute ischemic stroke (MAIS).

Methods: Using the Jikei University School of Medicine Stroke Registry, we selected and screened patients with symptomatic acute ischemic stroke (onset-to-door time ≤ 24 h). The exclusion criteria were (1) on-admission NIHSS scores ＞10, (2) a modified Rankin Scale (mRS) score ≥ 2 prior to stroke onset, (3) incomplete data (no urinalysis ≤ 3 days after admission or no mRS score at 90 days from stroke onset), and (4) an active malignancy. Patients at 90 days post-discharge were divided into those with favorable mRS scores of 0–1 and those with unfavorable mRS scores of 2–6. Clinical backgrounds were compared for (1) patients with positive and negative urinary IgG results, and (2) patients with favorable and unfavorable outcomes.

Results: Of our study’s 210 patients (164=male, median age=68, median eGFR=53.2 ml/min/1.73 m²), 30 (14%) presented with positive urinary IgG, which was associated with cardiovascular risk factors. Higher BNP, higher D-dimer, lower eGFR, and higher CAVI were associated with higher positive urinary IgG. The favorable group, comprising 155 (74%) patients, had higher negative urinary IgG than the unfavorable group (89% vs 76%, P=0.026). No statistical difference emerged regarding microalbuminuria (29% vs 29%, P=1.000).

Conclusion: In MAIS, urinary IgG was associated with both the presence of atherosclerosis and an unfavorable outcome at 90 days after stroke onset.

Aim: This study aimed to investigate whether skin autofluorescence (SAF) is associated with clinical outcomes in patients with coronary artery disease. Advanced glycation end products (AGE) play a crucial role in atherosclerosis. Accumulation of AGE can be measured non-invasively by SAF.

Methods: We performed a single-center prospective study of 896 patients with coronary artery disease treated with percutaneous coronary intervention (PCI) between January 2014 and December 2015. SAF was measured before the PCI procedure. The primary endpoint was patient-oriented composite endpoints (POCE) defined as a composite of all-cause death, any myocardial infarction, any stroke, and any revascularization.

Results: Patients were significantly older and suffered higher rates of chronic kidney disease (CKD) in the high SAF group. A higher SAF was associated with an increased risk for POCE (HR 1.43; 95% CI 1.19–1.71, p＜0.001) that was mainly driven by any coronary revascularization (HR 1.33; 95% CI 1.08–1.65, p=0.01) including target lesion revascularization (HR 1.41; 95% CI 1.02–1.94, p=0.04). The higher SAF group also experienced worse outcomes in stroke (HR 2.08; 95% CI 1.38–3.15, p=0.001). Multivariate analyses indicated that SAF was an independent predictor of POCE (HR 1.36; 95% CI 1.13–1.63, p=0.001).

Conclusions: SAF as a measure of AGE deposition is independently associated with cardiovascular events amongst patients with coronary artery disease treated with PCI. SAF also predicts the incidence of restenosis and stroke.

Aim: A pro-inflammatory diet may increase the risk of cardiovascular disease (CVD) and all-cause mortality. However, this remains inconclusive as there is yet no study using a dietary record method that has been conducted in a large general population. Furthermore, an underestimation of the pro-inflammatory diet may exist due to the unmeasured effect of salt intake. Thus, in this study, we aimed to examine how pro-inflammatory diet is associated with the long-term risk of all-cause and CVD mortality in a representative Japanese population.

Methods: A national nutrition survey was conducted throughout Japan in 1980. After considering the exclusion criteria, 9284 individuals (56% women aged 30–92 years) were included in this study. In total, 20 dietary parameters derived from 3-day weighed dietary records were used to calculate the dietary inflammatory index (DII). The causes of death were monitored until 2009. The Cox proportional hazards model was used to determine multivariable-adjusted hazard ratios (HRs). Stratified analysis according to salt intake level was also performed.

Results: Compared with the lowest quartile of DII, multivariable-adjusted HRs (95% confidence intervals) in the highest quartile were 1.28 (1.15, 1.41), 1.35 (1.14, 1.60), 1.48 (1.15, 1.92), 1.62 (1.11, 2.38), and 1.34 (1.03, 1.75) for all-cause mortality, CVD mortality, atherosclerotic CVD mortality, coronary heart disease mortality, and stroke mortality, respectively. Stratified analysis revealed stronger associations among individuals with higher salt intake.

Conclusions: As per our findings, a pro-inflammatory diet was determined to be positively associated with the long-term risk of all-cause and CVD mortality in a representative Japanese population. Thus, considering both salt intake and pro-inflammatory diet is deemed crucial for a comprehensive assessment of CVD risk.