Coronavirus disease 2019 (COVID-19) has become a major health problem worldwide since 2020. Although the main pathophysiology of COVID-19 is a respiratory infectious disease, it could also cause cardiovascular complications, including thrombosis. Thus, anticoagulation therapy has been thought to help prevent thrombosis, leading to improved survival. However, to date, several aspects of the optimal anticoagulation strategies for COVID-19 remain unclear. Considering the status of COVID-19-related thrombosis and some domestic issues in Japan, the optimal anticoagulation strategies for COVID-19 might have to be based on Japanese domestic clinical data considering racial difference. Racial disparities in terms of thromboembolic risk have been well known in the pre-COVID-19 era, and the risk of COVID-19-associated thrombosis depending on race could be an important issue. Considering a potential higher risk of bleeding with anticoagulation therapy in the Asian population, it might be important to maintain a good balance between the risks of thrombosis and bleeding. Latest evidences of COVID-19-related thrombosis and anticoagulation strategies, including some domestic issues in Japan, showed a different status of COVID-19-related thrombosis in Japan from that in Western countries, suggesting the potential benefit of different anticoagulation strategies, specifically for the Japanese population. Although these insights could be useful for the consideration of anticoagulation strategies for the Japanese population, the final decision should be based on balancing the benefits and risks of anticoagulation therapy in each patient.

Aims: Pharmacological blockade of mineralocorticoid receptors (MRs) is a potential therapeutic approach to reduce cardiovascular complications since MRs play a crucial role in cardiovascular regulation. Recent studies suggest that MR antagonists affect several extrarenal tissues, including vessel function. We investigated the effect of a novel nonsteroidal selective MR blocker, esaxerenone, on diabetes-induced vascular dysfunction.

Methods: Diabetes was induced by a single dose of streptozotocin in 8-week-old male C57BL/6 mice. Esaxerenone (3 mg/kg/day) or a vehicle was administered by gavage to diabetic mice for 3 weeks. Metabolic parameters, plasma aldosterone levels, and parameters related to renal function were measured. Endothelium-dependent or -independent vascular responses of the aortic segments were analyzed with acetylcholine or sodium nitroprusside, respectively. Human umbilical vein endothelial cells (HUVECs) were used for the in vitro study.

Results: Induction of diabetes elevated plasma aldosterone level (P＜0.05) and impaired endothelium-dependent vascular relaxation (P＜0.05). The administration of esaxerenone ameliorated the endothelial dysfunction (P＜0.01) without the alteration of metabolic parameters, blood pressure, and renal function. Esaxerenone improved the eNOS^Ser1177 phosphorylation in the aorta obtained from diabetic mice (P＜0.05) compared with that in the vehicle-treated group. Furthermore, a major MR agonist, aldosterone, decreased eNOS^Ser1177 phosphorylation and increased eNOS^Thr495 phosphorylation in HUVECs, which recovered with esaxerenone. Esaxerenone ameliorated the endothelium-dependent vascular relaxation caused by aldosterone in the aortic segments obtained from C57BL/6 mice (P＜0.001).

Conclusion: Esaxerenone attenuates the development of diabetes-induced endothelial dysfunction in mice. These results suggest that esaxerenone has potential vascular protective effects in individuals with diabetes.

Aim: This study aimed to investigate whether the impact of body mass index (BMI) on the risk of cardiovascular disease (CVD) has changed among the 1960s, 1970s, 1980s, 1990s, and early 2000s in Japan.

Methods: The study population consisted of residents in Japan aged 40–69 years who had no history of CVD. The baseline surveys have been conducted every year since 1963. We defined the first, second, third, fourth, and fifth cohorts as 1963–1969 (n=4,248), 1970–1979 (n=6,742), 1980–1989 (n=12,789), 1990–1999 (n=12,537), and 2000–2005 (n=9,140) respectively. The participants were followed up for a median of 15 years for each cohort to determine the incidence of CVD. We classified them into four categories (BMI ＜21.0, 21.0–＜23.0, 23.0–＜25.0, and ≥ 25.0 kg/m²).

Results: From 1963–1969 to 2000–2005, the prevalence of BMI ≥ 25.0 increased over time. Compared with BMI 23.0–＜25.0, the age-, sex- and community-adjusted hazard ratios (95% confidence interval [CIs]) of CVD for BMI ≥ 25.0 were 1.10 (0.77–1.57), 0.89 (0.68–1.18), 1.03 (0.85–1.26), 1.28 (1.04–1.58), and 1.36 (1.04–1.78) in the first, second, third, fourth, and fifth cohorts, respectively. The corresponding population attributable fractions were 2.0% (nonsignificant), −2.6% (nonsignificant), 0.9% (nonsignificant), 7.6%, and 10.9%. Further adjustment for systolic blood pressure and antihypertensive medication use in the fourth and fifth cohorts attenuated the associations, which may reflect that blood pressure may mediate the BMI-CVD association.

Conclusion: The proportion of CVD attributable to overweight/obesity has increased during the periods between 1963–1969 and 2000–2005. The significant associations between overweight/obesity and risk of CVD after the 1990s were mediated by blood pressure levels.

Aims: Active cigarette smoking was intensively reported to increase the risk of aortic mortality while research on the association between smoking cessation and aortic mortality remains scarce. This study aimed to reconfirm the associations of exposure to cigarettes and smoking cessation associated with aortic mortality in a large Japanese population.

Methods: In the Japan Collaborative Cohort (JACC) Study, 91,141 residents (57±10 years; men, 43%) who were free of stroke, coronary heart disease, and cancer were followed up from 1989–90 until 2009 during which 110 deaths from aortic dissection and 112 deaths from aneurysm were identified. Cox proportional hazard model was used to estimate multivariable hazard ratios (95%CI) for total and specific aortic mortality.

Results: Compared to never smoking, HRs for total aortic mortality were 2.39 (1.40-4.08) for ＜20, 3.57 (2.19-5.83) for 20-39, and 3.92 (2.37-6.48) for ≥ 40 pack-years exposure. Compared to current smoking, HRs for total aortic mortality were 0.42 (0.18-0.97) for 10-15 years, 0.27 (0.11-0.66) for ＞15 years of cessation, and 0.24 (0.13-0.44) for never smoking. Similar inverse dose-response pattern was observed between smoking cessation duration and risk of mortality from aortic aneurysm (p for trend=0.001), but the association with aortic dissection mortality did not reach statistical significance.

Conclusions: Cigarette smoking was associated with an increased risk of aortic mortality while smoking cessation was so with a reduced risk among the Japanese population.

Aims: Pericoronary adipose tissue (PCAT) attenuation on coronary computed tomography angiography (CTA) is a noninvasive biomarker for pericoronary inflammation and is associated with cardiac mortality. We aimed to investigate the association between PCAT attenuation and endothelial dysfunction assessed using flow-mediated dilation (FMD).

Methods: A total of 119 outpatients who underwent both coronary CTA and FMD measurements were examined. PCAT attenuation values were assessed at the proximal 40-mm segments of all three major coronary arteries on coronary CTA. Endothelial function was assessed using FMD. Patients were then classified into two groups: those with endothelial dysfunction (FMD ＜4%, n=44) and those without endothelial dysfunction (FMD ≥ 4%, n=75).

Results: In all three coronary arteries, PCAT attenuation was significantly higher in patients with endothelial dysfunction than in those without endothelial dysfunction. Multivariate logistic regression analysis revealed that PCAT attenuation in the right coronary artery (odds ratio [OR]=1.543; 95% confidence interval [CI]=1.004–2.369, p=0.048) and left anterior descending artery (OR=1.525, 95% CI=1.004–2.369, p=0.049) was an independent predictor of endothelial dysfunction. Subgroup analysis of patients with adverse CTA findings (significant stenosis and/or high-risk plaque) and those with coronary artery calcium score ＞100 showed that high PCAT attenuation in all three coronary arteries was a significant predictor of endothelial dysfunction.

Conclusion: High PCAT attenuation was significantly associated with FMD-assessed endothelial dysfunction in patients with suspected coronary artery disease. Our results suggest that endothelial dysfunction is one of the pathophysiological mechanisms linking pericoronary inflammation to cardiac mortality.

Aim: Various embolic sources and pathogenetic mechanisms underlie cryptogenic stroke (CS). We investigated the association of etiological diversity with short-term outcomes in patients with CS using a modified atherosclerosis (A), small-vessel disease (S), cardiac pathology (C), other causes (O), and dissection (D) (ASCOD) system.

Methods: Patients with CS who underwent transesophageal echocardiography were registered in this multicenter, observational study. In the modified classification system, O and D were inapplicable and thus excluded. Instead, atherosclerosis, small-vessel disease, cardiac pathology-CS classification was specifically constructed for the etiological diagnosis of CS. We utilized this system to explore the mechanism of CS by grading each pathology and evaluated its association with poorer modified Rankin Scale scores of 3–6 at hospital discharge.

Results: A total of 672 patients (68.7±12.8 years, 220 females) were analyzed. In the multiple logistic regression model, female sex (odds ratio [OR], 1.87 [1.15–3.04]; P =0.012), body mass index (OR, 0.93 [0.88–0.99]; P =0.025), National Institute of Health Stroke Scale score (OR, 1.16 [1.12–1.21]; P＜0.001), CHADS₂ score (OR, 1.56 [1.30–1.86]; P＜0.001), D-dimer (OR, 1.04 [1.01–1.08]; P =0.015), diffusion-weighted image (DWI) lesion size (OR, 1.44 [1.10–1.89]; P =0.009), and S＋C score (OR, 1.26 [1.03–1.56]; P =0.029) were associated with poor functional outcome at discharge whereas the S＋C score was marginally associated with poor functional outcome after excluding 137 patients with a premorbid modified Rankin Scale score of ≥ 3.

Conclusions: The coexistence of small-vessel disease and cardiac pathology might be associated with poor in-hospital functional outcome in CS.

Aim: The Controlling Nutritional Status (CONUT) score and the Prognostic Nutritional Index (PNI) reflect the immunonutritional status of patients. However, the associations of these two indices with cardiovascular disease (CVD) have not been characterized in patients with chronic kidney disease (CKD). Therefore, the current study aimed to determine whether the CONUT score or PNI was associated with prior CVD in patients with CKD.

Methods: A cross-sectional study of 2,751 patients with CKD who were not on dialysis was performed. The patients were grouped into tertiles (T1–T3) of PNI and placed into three groups following their CONUT score: low- (CONUT score, 0), mild- (CONUT score, 1–2), and moderate-to-high- (CONUT score, ≥ 3) risk groups.

Results: Prior CVD was present in 655 (24%) of the participants. Multivariable logistic regression analyses, with adjustment for potential confounders, showed that high CONUT score was associated with prior CVD than the low score (mild-risk group: odds ratio [OR]=1.35, 95% confidence interval [CI]=1.04–1.76; moderate-to-high-risk group: OR=1.66, 95% CI=1.19–2.30). In addition, the lower PNI tertiles were independently associated with prior CVD compared with T3 of PNI (T1: OR=1.45, 95% CI=1.09–1.92; T2: OR=1.32, 95% CI=1.01–1.72).

Conclusions: Both CONUT score and PNI were found to be independently associated with prior CVD in patients with CKD in the present cross-sectional study. A longitudinal study is needed to elucidate whether these two indices are associated with subsequent cardiovascular events.

Aims: Evidence of the effects of physical activity on mortality from aortic diseases, especially in Asian populations, remains limited. This study aimed to examine these effects using data from a large long-term cohort study of Japanese men and women.

Methods: Between 1988 and 1990, 32,083 men and 43,454 women in Japan, aged 40–79 years with no history of coronary heart disease, stroke, aortic diseases, or cancer, filled in questionnaires on time spent walking and participating in sports and were followed up until 2009. Multivariable hazard ratios (HRs) with 95% confidence intervals (CIs) of aortic disease mortality and its types (aortic aneurysm and dissection) according to the time spent walking and participating in sports were calculated after adjusting for potential confounding factors using the Cox proportional hazards model.

Results: During a median follow-up of 19.1 years, a total of 173 deaths from aortic disease (91 cases of aortic dissection and 82 of aortic aneurysm) were documented. Sports participation time was inversely associated with the risk of death from aortic aneurysm: the multivariable HRs (95% CIs) were 0.68 (0.40–1.16) for ＜1 h/week, 0.50 (0.19–1.35) for 3–4 h/week, and 0.31 (0.10–0.93) for ≥ 5 h/week (p for trend=0.23) compared with 1–2 h/week. The time spent walking was not associated with death from aortic aneurysm, dissection, and total aortic diseases.

Conclusions: Greater time spent in sports participation was associated with a reduced risk of mortality from aortic aneurism in the Japanese population. Further studies are needed to investigate the relationship between physical activity and aortic dissection.

Aims: The evidence for the impact of alcohol consumption on long-term mortality among myocardial infarction (MI) survivors was limited. We aimed to examine whether alcohol consumption was associated with cause-specific and all-cause mortality in men with or without a history of MI.

Methods: A total of 32,004 men aged 40-79 years with no history of MI and 1,137 male MI survivors, free of stroke and cancer, were followed through the end of 2009. Alcohol consumption was assessed using self-administered questionnaires at baseline and five years.

Results: In MI survivors, consuming 23-45 g/day of alcohol was associated with a lower risk of coronary heart disease (CHD) mortality compared to never drinkers: the multivariable hazard ratio was 0.36 (95% confidence interval: 0.16-0.80). In non-MI men, a 10-26% lower risk was observed at ＜23 or 23-45 g/day with the U-shaped association for CHD, cardiovascular disease, other causes, and all causes (P-quadratic ＜0.001).

Conclusion: Alcohol consumption of 23-45 g/day was associated with a lower CHD mortality in MI survivors as so in men without MI.