Aging is a major risk factor for cardiovascular diseases (CVDs) and accumulating evidence indicates that biological aging has a significant effect on the onset and progression of CVDs. In recent years, therapies targeting senescent cells (senotherapies), particularly senolytics that selectively eliminate senescent cells, have been developed and show promise for treating geriatric syndromes and age-associated diseases, including CVDs. In 2 pilot studies published in 2019 the senolytic combination, dasatinib plus quercetin, improved physical function in patients with idiopathic pulmonary fibrosis and eliminated senescent cells from adipose tissue in patients with diabetic kidney disease. More than 30 clinical trials using senolytics are currently underway or planned. In preclinical CVD models, senolytics appear to improve heart failure, ischemic heart disease, valvular heart disease, atherosclerosis, aortic aneurysm, vascular dysfunction, dialysis arteriovenous fistula patency, and pre-eclampsia. Because senotherapies are completely different strategies from existing treatment paradigms, they might alleviate diseases for which there are no current effective treatments or they could be used in addition to current therapies to enhance efficacy. Moreover, senotherapies might delay, prevent, alleviate or treat multiple diseases in the elderly and reduce polypharmacy, because senotherapies target fundamental aging mechanisms. We comprehensively summarize the preclinical evidence about senotherapies for CVDs and discuss future prospects for their clinical application.

Background: Takayasu arteritis, affecting primarily young women, damages large arteries and organs. We examined the impact of disease duration and sex on organ damage and quality of life using Japan’s Intractable Disease Registry.

Methods and Results: After refining data, 2,013 of 2,795 patients were included in the study. Longer disease duration was related to a lower prevalence of disease activity symptoms, a higher prevalence of organ damage, and a higher proportion of patients requiring nursing care. Compared with men, women tended to have an earlier onset age, exhibiting longer disease duration. A higher proportion of women had aortic regurgitation and required nursing care. The proportion of female patients in employment was lower than that of the general female population, whereas no difference was observed between male patients and the general male population. Logistic regression analysis revealed that age at surveillance, brain ischemia, visual impairment/loss, and ischemic heart disease were significant factors associated with high nursing care needs (Level ≥2, with daily activity limitations).

Conclusions: Early diagnosis and effective treatment, particularly to prevent brain ischemia, visual impairment, and ischemic heart disease, may improve the quality of life of patients with Takayasu arteritis, especially women.

Background: Acute aortic dissection (AAD) has high morbidity and a high fatality rate for a cardiovascular disease. Recent studies suggested that the incidence of AAD is increasing. However, the actual incidence and mortality rates of AAD are not well known. This study investigated the current epidemiology of AAD within the Yatsushiro medical jurisdictional area.

Methods and Results: A population-based review of patients with AAD was performed in a geographically well-defined area. Data were collected retrospectively from January 2011 to December 2020 for a total of 196 patients with AAD (Stanford Type A, n=126 [64.3%]; Stanford Type B, n=70 [35.7%]). The mean patient age was 74.3 years, and 55.6% (109/196) were women. The crude and age-standardized incidence rates of AAD in our medical jurisdictional area were 13.6 and 11.4 per 100,000 inhabitants per year, respectively. The crude and age-standardized 30-day mortality rates of AAD were 4.9 and 4.0 per 100,000 inhabitants per year, respectively. There were upward tendencies for both the incidence and 30-day mortality rate of AAD with age, with both being significantly higher in patients aged ≥85 years (P<0.001).

Conclusions: This population-based study detected a higher incidence of AAD than previous studies, but reported a lower incidence of AAD in men than in women. Increasing age was associated with an increased incidence and mortality rate of AAD.

Background: In Taiwan, infective native aortic aneurysms (INAAs) are relatively common, so the aim of present study was to demonstrate the comparative outcomes of endovascular repair for thoracic and abdominal INAAs.

Methods and Results: Patients with naïve thoracic or abdominal INAAs managed with endovascular repair between 2001 and 2018 were included in this multicenter retrospective cohort. The confounding factors were adjusted with propensity score (PS). Of the 39 thoracic and 43 abdominal INAA cases, 41 (50%) presented with aneurysmal rupture, most of which were at the infrarenal abdominal (n=35, 42.7%) or descending thoracic aorta (n=25, 30.5%). Salmonella spp. was the most frequently isolated pathogen. The overall in-hospital mortality rate was 18.3%. The risks of in-hospital death and death due to rupture were significantly lower with thoracic INAAs (12.8% vs. 23.3%; PS-adjusted odds ratio (OR) 0.24, 95% confidence interval (CI) 0.06–0.96; 0.1% vs. 9.3%; PS-adjusted OR 0.11, 95% CI 0.01–0.90). During a mean follow-up of 2.5 years, the risk of all-cause death was significantly higher with thoracic INAAs (35.3% vs. 15.2%; PS-adjusted HR 6.90, 95% CI 1.69–28.19). Chronic kidney disease (CKD) was associated with death.

Conclusions: Compared with thoracic INAAs, endovascular repair of abdominal INAAs was associated with a significantly higher in-hospital mortality rate. However, long-term outcomes were worse for thoracic INAAs, with CKD and infections being the most important predictor and cause of death, respectively.

Background: The latest demographics, clinical and living conditions, and comorbidities of patients with thromboangiitis obliterans (TAO) in Japan are unknown.

Methods and Results: We conducted a retrospective cross-sectional survey using the annual database of the Japanese Ministry of Health, Labour and Welfare medical support system for patients with TAO between April 2013 and March 2014. This study included 3,220 patients (87.6% male), with current age ≥60 years in 2,155 patients (66.9%), including 306 (9.5%) patients aged ≥80 years. Overall, 546 (17.0%) had undergone extremity amputation. The median interval from onset to amputation was 3 years. Compared with never smokers (n=400), 2,715 patients with a smoking history had a higher amputation rate (17.7% vs. 13.0%, P=0.02, odds ratio [OR]=1.437, 95% confidence interval [CI]=1.058–1.953). A lower proportion of workers and students was seen among patients after amputation than among amputation-free patients (37.9% vs. 53.0%, P<0.0001, OR=0.542, 95% CI=0.449–0.654). Comorbidities, including arteriosclerosis-related diseases, were found even in patients in their 20–30 s.

Conclusions: This large survey confirmed that TAO is not a life-threatening but an extremity-threatening disease that threatens patients’ professional lives. Smoking history worsens patients’ condition and extremity prognosis. Long-term total health support is required, including care of extremities and arteriosclerosis-related diseases, social life support, and smoking cessation.

Background: Acute limb ischemia (ALI) is a limb- and life-threatening condition and urgent treatment including revascularization should be offered to patients unless the limb is irreversibly ischemic. The aim of this study was to investigate 1-year clinical outcomes and prognostic factors following revascularization in patients with ALI.

Methods and Results: A retrospective, multicenter, nonrandomized study examined 185 consecutive patients with ALI treated by surgical revascularization (SR), endovascular revascularization (ER), or hybrid revascularization (HR) in 6 Japanese medical centers from January 2015 to August 2021. The 1-year amputation-free survival (AFS) rate was estimated to be 69.2% (95% confidence interval [CI], 62.8–76.2%). There were no significant differences among SR, ER, and HR regarding both technical success and perioperative complications. Multivariate analysis revealed that Rutherford category IIb and III ischemia (hazard ratio [HR]: 1.86; 95% CI: 1.06–3.25), supra- to infrapopliteal lesion (HR: 2.06; 95% CI: 1.08–3.95), and technical failure (HR: 2.58; 95% CI: 1.49–4.46) were independent risk factors for 1-year AFS.

Conclusions: Rutherford category IIb and III ischemia, supra- to infrapopliteal lesions, and technical failures were identified as independent risk factors for 1-year AFS. Furthermore, patients with multiple risk factors had a lower AFS rate.

Background: The mechanism underlying a poor prognosis in patients with lower-extremity artery disease (LEAD) with heart failure is unknown. We examined the prognostic impact of the left ventricular ejection fraction (LVEF) in patients with LEAD who underwent endovascular therapy (EVT).

Methods and Results: From August 2014 to August 2016, 2,180 patients with LEAD (mean age, 73.2 years; male, 71.9%) underwent EVT and were stratified into low-LVEF (LVEF <40%; n=234, 10.7%) and not-low LVEF groups. In the low- vs. not-low LVEF groups, there was a higher prevalence of heart failure (i.e., history of heart failure hospitalization or New York Heart Association functional class III or IV symptoms) (44.0% vs. 8.3%, respectively), diabetes mellitus, chronic kidney disease, below-the-knee lesion, critical limb ischemia, and incidence of major cardiovascular and cerebrovascular events (MACCEs) and major adverse limb events (MALEs) (P<0.001, all). Low LVEF independently predicted MACCEs (hazard ratio: 2.23, 95% confidence interval: 1.63–3.03; P<0.001) and MALEs (hazard ratio: 1.85, 95% confidence interval: 1.15–2.96; P=0.011), regardless of heart failure (P value for interaction: MACCEs: 0.27; MALEs: 0.52).

Conclusions: Low LVEF, but not symptomatic heart failure, increased the incidence of MACCEs and MALEs. Intensive cardiac dysfunction management may improve LEAD prognosis after EVT.

Background: Endovascular treatment devices of the femoropopliteal artery have evolved, improving clinical results. However, the effects of dynamic changes in the popliteal artery during knee flexion have not been sufficiently investigated. In this study we performed a 3-dimensional analysis to clarify the dynamic changes in the popliteal artery during knee flexion and their effects on hemodynamics.

Methods and Results: To analyze dynamic changes in the popliteal artery in the knee flexion position, a computed tomography protocol was developed in the right-angled and maximum flexion knee positions. Thirty patients with lower extremity artery disease were recruited. V-Modeler software was used for anatomical and hemodynamic analyses. Various types of deformations of the popliteal artery were revealed, including hinge points and accessory flexions. Kinks can occur in the maximum flexion position; however, they rarely occur in the right-angled flexion position. In addition, hemodynamic analysis revealed a tendency for lower minimum wall shear stress and a higher maximum oscillatory shear index at the maximum curvature of the popliteal artery.

Conclusions: Kinks in the maximum flexion position suggested that the outcome of endovascular treatment may change in areas such as Japan, where knee flexion is customary. Hemodynamics at the maximum curvature of the popliteal artery indicated that the luminal condition was unfavorable for endovascular treatment.

Background: A large-scale prospective study of the efficacy and safety of warfarin for the treatment of venous thromboembolism (VTE) has not been conducted in Japan. Therefore, we conducted a real-world prospective multicenter observational cohort study (AKAFUJI Study; UMIN000014132) to investigate the efficacy and safety of warfarin for VTE.

Methods and Results: Between May 2014 and March 2017, 352 patients (mean [±SD] age 67.7±14.8 years; 57% female) with acute symptomatic/asymptomatic VTE were enrolled; 284 were treated with warfarin. The cumulative incidence of recurrent symptomatic VTE was higher in patients without warfarin than in those treated with warfarin (8.7 vs. 2.2 per 100 person-years, respectively; P=0.018). The cumulative incidence of bleeding complications was not significantly different between the 2 groups. The mean prothrombin time-international normalized ratio (PT-INR) during warfarin on-treatment was <1.5 in 180 patients, 1.5–2.5 in 97 patients, and >2.5 in 6 patients. The incidence of bleeding complications was significantly higher in patients with PT-INR >2.5, whereas the incidence of recurrent VTE was not significantly different between the 3 PT-INR groups. The cumulative incidence of recurrent VTE and bleeding complications did not differ significantly among those in whom VTE was provoked by a transient risk factor, was unprovoked, or was associated with cancer.

Conclusions: Warfarin therapy with an appropriate PT-INR according to Japanese guidelines is effective without increasing bleeding complications, regardless of patient characteristics.

Background: The effectiveness and safety of edoxaban for venous thromboembolism (VTE) in unselected real-world patients have not been fully evaluated.

Methods and Results: In the Japanese nationwide administrative database, we identified 6,262 VTE patients in whom edoxaban was initiated; these patients were divided into 3 groups based on their index doses: 15 mg/day (n=235), 30 mg/day (n=4,532), and 60 mg/day (n=1,495). We evaluated patient characteristics, recurrent VTEs, and a composite endpoint of intracranial hemorrhage (ICH) and gastrointestinal (GI) bleeding. Patient characteristics among the 15-, 30-, and 60-mg edoxaban groups varied widely regarding several aspects, including age (mean 81.0, 76.2, and 65.0 years, respectively) and body weight (mean 49.5, 51.8, and 70.3 kg, respectively). At 180 days, the cumulative incidence of recurrent VTEs in the 15-, 30-, and 60-mg edoxaban groups was 4.4%, 2.6%, and 1.8%, respectively, whereas that of ICH or GI bleeding was 7.3%, 5.4%, and 3.3%, respectively. Subgroup analyses showed that the cumulative incidence of ICH or GI bleeding in patients in the 15-mg edoxaban group was 3.6% for patients aged ≥80 years, 8.4% for those with a body weight <60 kg, and 31.3% for those with renal dysfunction.

Conclusions: Only a minority of patients with VTEs received a super low dose (15 mg) of edoxaban, and these patients may be at higher risk of bleeding as well as VTE recurrence.

Background: We investigated the clinical effect of intravenous thrombolysis using a magnetic resonance imaging (MRI)-guided approach in cardioembolic stroke (CE) patients with unknown time of onset.

Methods and Results: This subanalysis of the THAWS trial assessed the efficacy and safety of alteplase 0.6 mg/kg in CE patients with unknown time of onset and showing diffusion-weighted imaging–fluid-attenuated inversion recovery mismatch. Patients were classified as CE and non-CE using the SSS-TOAST classification system during the acute period. The efficacy outcome was a modified Rankin Scale score of 0–1 at 90 days. In all, 126 patients from the THAWS trial were included in this study, of whom 45 (35.7%) were diagnosed with CE. In the CE group, a favorable outcome was numerically more frequent in the alteplase than control group (52% vs. 35%; adjusted odds ratio [aOR] 2.25; 95% confidence interval [CI] 0.50–9.99). However, in the non-CE group, favorable outcomes were comparable between the alteplase and control groups (44% vs. 55%, respectively; aOR 0.39; 95% CI 0.12–1.21). Treatment-by-cohort interaction for a favorable outcome was modestly significant between the CE and non-CE groups (P=0.069). In the CE group, no patients experienced symptomatic intracranial hemorrhage (ICH) or parenchymal hematoma Type II following thrombolysis.

Conclusions: When an MRI-guided approach is used, CE patients with unknown time of onset appear to be suitable candidates for thrombolysis.

Background: Despite the importance of implementing the concept of social determinants of health (SDOH) in the clinical practice of cardiovascular disease (CVD), the tools available to assess SDOH have not been systematically investigated. We conducted a scoping review for tools to assess SDOH and comprehensively evaluated how these tools could be applied in the field of CVD.

Methods and Results: We conducted a systematic literature search of PubMed and Embase databases on July 25, 2023. Studies that evaluated an SDOH screening tool with CVD as an outcome or those that explicitly sampled or included participants based on their having CVD were eligible for inclusion. In addition, studies had to have focused on at least one SDOH domain defined by Healthy People 2030. After screening 1984 articles, 58 articles that evaluated 41 distinct screening tools were selected. Of the 58 articles, 39 (67.2%) targeted populations with CVD, whereas 16 (27.6%) evaluated CVD outcome in non-CVD populations. Three (5.2%) compared SDOH differences between CVD and non-CVD populations. Of 41 screening tools, 24 evaluated multiple SDOH domains and 17 evaluated only 1 domain.

Conclusions: Our review revealed recent interest in SDOH in the field of CVD, with many useful screening tools that can evaluate SDOH. Future studies are needed to clarify the importance of the intervention in SDOH regarding CVD.

Background: Data regarding the relationship between benign prostatic hyperplasia (BPH) and incident cardiovascular disease (CVD) are scarce. We aimed to clarify the association of BPH with the risk of developing CVD using a nationwide epidemiological database.

Methods and Results: This retrospective observational cohort study analyzed data from the JMDC Claims Database between 2005 and 2022, including 2,370,986 men (median age 44 years). The primary endpoints were myocardial infarction (MI), angina pectoris (AP), stroke, heart failure (HF), and atrial fibrillation (AF), which were assessed separately. BPH was observed in 48,651 (2.1%) men. During a mean (±SD) follow-up of 1,359±1,020 days, 7,638 MI, 52,167 AP, 25,355 stroke, 58,183 HF, and 16,693 AF events were detected. Hazard ratios of BPH for MI, AP, stroke, HF, and AF were 1.04 (95% confidence interval [CI] 0.92–1.18), 1.31 (95% CI 1.25–1.37), 1.26 (95% CI 1.18–1.33), 1.21 (95% CI 1.16–1.27), and 1.15 (95% CI 1.07–1.24), respectively. We confirmed the robustness of our primary findings through a multitude of sensitivity analyses. In particular, a history of BPH was associated with a higher risk of developing CVD, even in participants without obesity, hypertension, diabetes, or dyslipidemia.

Conclusions: Our analysis of a nationwide epidemiological dataset demonstrated that BPH was associated with a greater risk of developing CVD in middle-aged men.

Background: This study aimed to investigate the association between estimated pulse wave velocity (ePWV) and mortality outcomes among individuals with hypertension.

Methods and Results: Based on the National Health and Nutrition Examination Survey (NHANES) 1999–2018, a total of 14,396 eligible participants with hypertension were enrolled. The ePWV was calculated using the equation based on blood pressure and age. The mortality outcomes of included participants were directly acquired from the National Death Index database. The multivariable Cox regression analysis was used to examine the relationship between ePWV and mortality outcomes. Moreover, the restricted cubic spline (RCS) was also used to explore this relationship. Receiver operating characteristics curves (ROC) were adopted to evaluate the prognostic ability of ePWV for predicting mortality outcomes of patients with hypertension. The median follow-up duration was 10.8 years; individuals with higher an ePWV had higher risks of mortality from both all causes (HR: 2.79, 95% CI: 2.43–3.20) and cardiovascular diseases (HR: 3.41, 95% CI: 2.50–4.64). After adjusting for confounding factors, each 1 m/s increase in ePWV was associated with a 43% increase in all-cause mortality risk (HR: 1.43, 95% CI: 1.37–1.48) and a 54% increase in cardiovascular mortality risk (HR: 1.54, 95% CI: 1.43–1.66).

Conclusions: This study indicates that ePWV is a novel prognostic indicator for predicting the risks of mortality among patients with hypertension.

Background: Resistance exercise is beneficial in patients with lower extremity arterial disease. Muscle-derived exosomes contain many types of signaling molecules, including microRNAs (miRNAs). Here, we tested the hypothesis that exosomal miRNAs secreted by growing muscles promote an angiogenic response in endothelial cells (ECs).

Methods and Results: Skeletal muscle-specific conditional Akt1 transgenic (Akt1-TG) mice, in which skeletal muscle growth can be induced were used as a model of resistance training. Remarkable skeletal muscle growth was observed in mice 2 weeks after gene activation. The protein amount in exosomes secreted by growing muscles did not differ between Akt1-TG and control mice. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway frequency analysis of 4,665 target genes, identified using an miRNA array miRNAs, revealed a significant increase in Akt and its downstream signaling pathway genes. Among the upregulated miRNAs, miR1, miR133, and miR206 were significantly upregulated in the serum of Akt1-TG mice. miR206 was also increased in insulin-like growth factor (IGF)-1-stimulated hypertrophied myotubes. Exogenous supplementation of exosomal miR206 to human umbilical vein ECs promoted angiogenesis, as assessed using the spheroid assay, and increased the expression of angiogenesis-related transcripts.

Conclusions: Exosomal miR206 is upregulated in the blood of Akt1-TG mice and in IGF-stimulated cultured myotubes. Exogenous supplementation of miR206 promoted an angiogenic response in ECs. Our data suggest that miR206 secreted from growing muscles acts on ECs and promotes angiogenesis.