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Background: Some patients with diabetes are unaware that they are prescribed medications for diabetes. The purpose of this study is to determine, using a Japanese nationwide epidemiologic database, the association between unawareness of being prescribed medication for diabetes and the risk of developing cardiovascular disease (CVD) in patients with diabetes., Methods: This observational cohort study analyzed data from the JMDC Claims Database between 2005 and 2022, including 94,048 patients with diabetes treated with medications. The primary endpoint was a composite endpoint including myocardial infarction (MI), stroke, heart failure (HF), and atrial fibrillation (AF)., Results: We identified 7561 composite CVD endpoints during a mean follow-up of 1199 ± 902 days. Overall, 7779 (8.3 %) patients were unaware of being prescribed medications for diabetes. Those who did not know they were prescribed drugs were younger and had better glycemic control, but these individuals were at higher risk of developing combined CVD [hazard ratio (HR) 1.13, 95 % confidence interval (95 % CI) 1.04-1.22]. HRs of unawareness of being prescribed medications for diabetes were 1.33 (95 % CI 1.06-1.68) for MI, 1.13 (95 % CI 0.97-1.31) for stroke, 1.10 (95 % CI 1.00-1.21) for HF, and 1.19 (95 % CI 0.97-1.47) for AF, respectively., Conclusions: In patients with diabetes taking medications for diabetes, even if they are young and have good glycemic control, unawareness of being prescribed medications for diabetes was associated with a greater risk of developing CVD. It is important that they receive adequate education from their healthcare providers to accurately identify their treatment status., Competing Interests: Declaration of competing interest Research funding and scholarship funds (Hidehiro Kaneko and Katsuhito Fujiu) from Medtronic Japan Co., Ltd., Boston Scientific Japan Co., Ltd., Biotronik Japan, Simplex Quantum Co., Ltd., and Fukuda Denshi, Central Tokyo Co., Ltd., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The association between stage 1 hypertension and the risk of cardiovascular disease (CVD) has not been established in older adults. Furthermore, little is known about whether lowering blood pressure (BP) is beneficial in older adults with stage 1 hypertension., Methods: This cohort study analyzed nationwide data collected from the Japanese DeSC database, including 476,654 individuals aged ≥60 years. Individuals were categorized into four groups according to the 2017 ACC/AHA BP guidelines: normal BP, elevated BP, stage 1 hypertension, and stage 2 hypertension. The primary outcome was a composite CVD event, including myocardial infarction, angina pectoris, stroke, and heart failure., Results: During a mean follow-up of 3.1 years, 53,946 composite CVD events were recorded. Hazard ratios of stage 1 hypertension for composite CVD events, myocardial infarction, angina pectoris, stroke, and heart failure were 1.10 (95 % CI, 1.07-1.13), 1.16 (95 % CI, 1.03-1.31), 1.06 (95 % CI, 1.01-1.10), 1.13 (95 % CI, 1.08-1.18), and 1.13 (95 % CI, 1.09-1.16), respectively. Individuals with a ≥5 mmHg decrease in systolic BP over one year had a lower risk of stroke among individuals with stage 1 hypertension. The positive association between stage 1 hypertension and composite CVD events was attenuated in individuals aged ≥75 years., Conclusions: Stage 1 hypertension is associated with a higher risk of developing CVD events among older adults. The 2017 ACC/AHA BP guidelines could be applied to older populations; however, the applicability of these guidelines to older adults aged ≥75 years requires further investigations., Competing Interests: Declaration of competing interest Research funding and scholarship funds (Hidehiro Kaneko and Katsuhito Fujiu) from Medtronic Japan Co., LTD, Abbott Medical Japan Co., LTD, Boston Scientific Japan Co., LTD, and Fukuda Denshi, Central Tokyo Co., Ltd. Speaker fees from AstraZeneca, Ono Pharmaceutical, Nippon Boehringer Ingelheim; Scholarship donation from Idorsia, Sanofi, Toa Eiyo; Affiliation with endowed chairs from Idorsia Pharmaceuticals Japan, Novo Nordisk Pharma, Toa Eyo Co, Takara Bio Inc., Nippon Boehringer Ingelheim Co., BioStream, Inc. (Issei Komuro). Other authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: There have been limited studies examining age-dependent associations between physical inactivity and cardiovascular disease (CVD). We aimed to clarify the age-dependent relationship of physical inactivity with incident CVD., Methods: We analyzed 1,097,424 participants, aged 18 to 105 years, without histories of CVD, enrolled in the DeSC database (median age, 63 years; 46.4% men). We categorized participants into the following 4 groups based on age: ≤ 44 years (n = 203,835); 45 to 64 years (n = 403,619); 65 to 79 years (n = 437,236); and ≥ 80 years (n = 52,734). We used 3 physical inactivity components gained from the self-reported questionnaire during a health checkup. The outcomes were composite CVD events including myocardial infarction, stroke, heart failure, and each CVD event., Results: During a mean follow-up of 3.2 ± 1.9 years, 81,649 CVD events were observed. The hazard ratios of 3 physical inactivity components for CVD events increased with age category (P for interaction < 0.001). For example, the hazard ratio (95% confidence interval) of physical inactivity defined as not doing light sweaty exercise for 30 minutes at least twice a week for incident CVD in the groups aged ≤ 44 years, 45 to 64 years, 65 to 79 years, and ≥ 80 years were 0.97 (0.88-1.05), 1.08 (1.05-1.12), 1.12 (1.10-1.15), and 1.17 (1.12-1.21), respectively (P for interaction < 0.001). This association was consistent across subtypes of CVD including heart failure, myocardial infarction, and stroke., Conclusions: The association of physical inactivity with a higher risk of developing CVD increased with age. Preventive efforts for physical activity optimization may be more valuable in older people., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: It remains unclear if remnant cholesterol is associated with atherosclerotic cardiovascular disease (ASCVD) (myocardial infarction, angina pectoris and stroke), heart failure (HF), and atrial fibrillation (AF) under primary prevention settings., Objective: We aimed to clarify this issue among a general population without a history of ASCVD, HF or AF., Methods: Analyses were conducted with a nationwide health claims database collected in the JMDC Claims Database between 2005 and 2022 (n = 1,313,722; median age, 42 years; 54.6% men). We assessed the associations between remnant cholesterol calculated as total cholesterol minus HDL cholesterol minus LDL cholesterol and composite CVD outcomes, including, ASCVD, HF, and AF using Cox proportional hazard model, dividing the individuals into tertiles of remnant cholesterol (T1-T3)., Results: The mean follow-up duration was 3.0 years. In total, 43,755 events were recorded. Remnant cholesterol was significantly associated with composite CVD outcomes after adjustments (T3 vs T1: hazard ratio [HR]; 1.07, 95% confidence interval [CI]: 1.04-1.10, p-trend<0.001). Remnant cholesterol was associated with myocardial infarction (T3 vs T1:HR: 1.20, 95% CI: 1.06-1.34, p-trend=0.002), angina pectoris (T3 vs T1:HR: 1.09, 95% CI: 1.05-1.14, p-trend<0.001), stroke (T3 vs T1:HR: 1.08, 95% CI: 1.02-1.14, p-trend=0.007), and HF (T3 vs T1:HR: 1.08, 95% CI: 1.04-1.12, p-trend<0.001), while we found a marginal inverse association between remnant cholesterol and AF (T3 vs T1:HR: 0.92, 95% CI: 0.86-1.00, p-trend=0.054)., Conclusion: Remnant cholesterol was positively associated with ASCVD and HF, while we found a marginal inverse association between remnant cholesterol and AF., (Copyright © 2023. Published by Elsevier Inc.)

Background: Palliative care provided to patients with heart failure (HF) are reported to be inadequate. Herein, we examined the impact of the recently introduced financial incentive scheme for team-based palliative care for patients with HF in acute care hospitals in Japan., Methods: Using a nationwide inpatient database, we identified patients aged ≥65 years with HF who had died between April 2015 and March 2021. Interrupted time-series analyses were used to compare practice patterns in end-of-life care (symptom management and invasive medical procedures within one week before death) before and after the financial incentive scheme issuance in April 2018., Results: Overall, 53,857 patients in 835 hospitals were eligible. The adoption of the financial incentive was 1.10 to 1.22% after the introduction. There were upward pre-trends in opioid use (+0.11% per month; 95% confidence interval [CI], 0.06 to 0.15) and antidepressant use (+0.06% per month; 95% CI, 0.04 to 0.09). Opioid use showed a downward slope change during the post-period (-0.07% change in trend; 95% CI, -0.13 to -0.01). Intensive care unit stay showed a downward pre-trend (-0.09% per month; 95% CI, -0.14 to -0.04) and upward slope changes during the post-period (+0.12% change in trend; 95% CI, 0.04 to 0.19). Invasive mechanical ventilation showed downward slope changes during the post-period (-0.11% change in trend; 95% CI, -0.18 to -0.04)., Conclusions: The financial incentive scheme for team-based palliative care was rarely adopted and not associated with changes in end-of-life care. Further multifaceted strategies to promote palliative care for HF are warranted., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Data comparing kidney outcomes between individual sodium-glucose cotransporter-2 (SGLT2) inhibitors are limited. Here, we aimed to compare the subsequent risk of developing kidney outcomes between individual inhibitors. This would be the first study to compare kidney outcomes of patients with diabetes mellitus who were newly treated with individual SGLT2 inhibitors using a large-scale real-world dataset. To do this, we analyzed results from 12,100 patients with diabetes mellitus who were taking different SGLT2 inhibitors (2,573 with empagliflozin; 2,214 with dapagliflozin; 2,100 with canagliflozin; and 5,213 with other such inhibitors). The primary outcome was the rate of estimated glomerular filtration rate (eGFR) decline as assessed using a linear mixed-effects model with an unstructured covariance. The median age of the patients was 53 years, and 84.4% of the patients were men. The median fasting plasma glucose and HbA1c levels were 147 (interquartile range 126-178) mg/dL and 7.5 (6.9-8.4)%, respectively. The median eGFR was 78 mL/min/1.73 m 2 (interquartile range 68-90). The mean follow-up period was 773 days. The annual eGFR slopes of empagliflozin, dapagliflozin, canagliflozin, and other SGLT2 inhibitors were -1.15 (95% confidence interval, -1.33 to -0.96), -1.14 (-1.32 to -0.96), -1.24 (-1.44 to -1.04), and -1.06 (-1.18 to -0.94) ml/min/1.73 m 2 , respectively. No significant interaction was detected between the SGLT2 inhibitors and time using a linear mixed-effects model. A multitude of sensitivity analyses confirmed the robustness of our primary results. Thus, we found that there was no significant difference in the annual eGFR decline slopes between patients taking different SGLT2 inhibitors., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: The optimal value of BMI for the development of hypertension and the influence of BMI on the development of stage 1 or stage 2 hypertension remain unclear., Objectives: We sought to identify the BMI threshold for the prevention of hypertension and how changes in BMI would influence the risk of developing hypertension., Methods: We analyzed 1,262,356 participants (median age: 43 y; 50.9% men) with normal blood pressure [BP; systolic BP (SBP) <120 mmHg and diastolic BP (DBP) <80 mmHg] or elevated BP (SBP: 120-129 mmHg and DBP <80 mmHg). The primary outcome was stage 1 (SBP 130-139 mmHg or DBP 80-89 mmHg) or stage 2 hypertension (SBP ≥140 mmHg or DBP ≥90 mmHg). We analyzed the relation between baseline BMI, change in BMI, and the risk of developing hypertension using generalized additive models with a smoothing spline., Results: During the median follow-up of 851 d, 341,212 cases of stage 1 hypertension and 70,968 cases of stage 2 hypertension were detected. The risk of developing stage 1 or stage 2 hypertension increased steeply after BMI (kg/m 2 ) exceeded 20. The annual change in BMI was positively correlated with the risk of developing stage 1 or 2 hypertension. Contour mapping using generalized additive models demonstrated an additive increase in the risk of developing hypertension with higher baseline BMI and increases in BMI over 1 y. Body-weight gain increases the risk of developing hypertension even in underweight or normal-weight individuals based on the WHO classification., Conclusions: In Japanese adults with normal or elevated BP, the risk of developing hypertension increased with BMI when baseline BMI was >20. Body-weight gain additively interacted with baseline BMI during hypertension development. Our results underscore the importance of maintaining body weight in preventing the development of hypertension., (Copyright © 2022 American Society for Nutrition.)

Background and Aims: It is not known whether the presence of retinal atherosclerosis (RA) is associated with incident heart failure (HF) in the general population. We aimed to investigate the relationship between RA and the risk of HF development using a nationwide population-based database., Methods: We studied 319,501 adults without a history of cardiovascular disease (CVD) and with available data on retinoscopy at health check-up registered in the JMDC Claims Database between January 2005 and April 2020. We performed Cox regression analyses to assess the relationship of RA, defined as Keith-Wagener-Barker system grade ≥1, with incident HF and other CVD, including myocardial infarction (MI), angina pectoris (AP), and stroke., Results: The median age (interquartile range) was 47 (41-54) years, and 159,710 participants (50.0%) were men. RA was observed in 26,168 participants (8.2%). During a median (interquartile range) follow-up of 2.9 (1.6-4.6) years, 6,821 (2.1%) HF, 692 (0.2%) MI, 7,016 (2.2%) AP and 3,584 (1.1%) stroke events occurred. After adjustment for potential confounders, multivariable Cox regression analyses showed that RA was associated with a greater incidence of HF (hazard ratio 1.13, 95% confidence interval [CI] 1.05-1.21) and other CVDs. Hazard ratios of RA for MI, AP, and stroke were 1.17 (95% CI, 0.95-1.44), 1.13 (95% CI, 1.05-1.21), and 1.25 (95% CI, 1.14-1.37), respectively. This association was present in all subgroups., Conclusions: The assessment of RA may be useful to identify people at high-risk for the development of HF and other atherosclerotic CVD events in a general population., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Extensive data support the clinical benefit of cardiac rehabilitation (CR) for patients with chronic heart failure (HF). However, whether CR could be beneficial for patients hospitalized for acute heart failure remains unclear., Methods: We retrospectively analyzed data from the Diagnosis Procedure Combination database, a nationwide inpatient database. We included patients hospitalized for HF, who were aged ≥20 years and with New York Heart Association class ≥II, between January 2010 and March 2018. We excluded patients with length of hospital stay ≤2 days, those undergoing major procedures under general anesthesia, those requiring advanced mechanical supports within 2 days after admission, and those with disturbance of consciousness. Propensity score matching and instrumental variable analyses were conducted to compare clinical outcomes between the patients with and without acute-phase initiation of CR defined as initiation of CR within two days after hospital admission., Results: Among 430,216 eligible patients, 63,470 patients (14.8%) received the acute-phase initiation of CR. Propensity score matching created 63,470 pairs and found that the acute-phase initiation of CR was associated with lower in-hospital mortality (odds ratio [OR] 0.76, 95% confidence interval [CI] 0.73-0.80), shorter hospital stay and lower incidence of 30-day readmission due to HF. The instrumental variable analysis also showed patients with acute-phase initiation of CR was associated with lower in-hospital mortality than those without (OR, 0.73; 95% CI, 0.68-0.79)., Conclusion: Our analysis suggested a potential benefit of acute-phase initiation of CR for short-term clinical outcomes in hospitalized patients with acute HF., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Aims: Epidemiological evidence on the relationship between eating behaviors, including breakfast skipping, late night dinner, and bedtime snacking, and cardiovascular disease (CVD) events among the general population is scarce. We sought to explore the association of eating behaviors with subsequent CVD using a nationwide epidemiological database., Methods and Results: Medical records of 1,941,125 individuals without prior history of CVD were extracted from the Japan Medical Data Center contracting with more than 60 insurers from multiple regions in Japan, mainly including employed working-age individuals. Skipping breakfast <3 times per week, late night dinner <3 times per week, and bedtime snacking <3 times per week were defined as optimal eating behaviors. Median age was 45 (interquartile range 39-53) years, and 1,138,676 were men. Median follow-up period was 978 (interquartile range 481-1790) days. Among them, 948,805 individuals (48.9%) had optimal eating behaviors, whereas 647,383 individuals (33.4%), 283,017 individuals (14.6%), and 61,920 individuals (3.2%) had single, double, and triple non-optimal eating behaviors, respectively. Individuals with non-optimal eating behaviors were younger and more likely to be men. Obesity and high waist circumference were more commonly observed in those with non-optimal eating behaviors. Multivariable Cox regression analysis showed that, compared with no non-optimal eating behavior, having non-optimal eating behaviors would have higher risk of myocardial infarction, angina pectoris, stroke, and heart failure. However, the dose-response relationship was not clear in the association between the number of non-optimal eating behaviors and incident CVD. Multivariable Cox regression analysis after multiple imputation for missing values also showed the association between non-optimal eating behaviors and incident CVD., Conclusions: Using a nationwide epidemiological database, we found a possible relationship between eating behaviors including skipping breakfast, late night dinner, and bedtime snacking, and subsequent cardiovascular events among the general population, suggesting the potential importance of maintaining optimal eating behaviors for the primordial and primary CVD prevention in the general population., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Aims: Using a nationwide epidemiological database, we aimed to clarify the association of fasting plasma glucose (FPG) with subsequent cardiovascular disease (CVD) risk among young adults., Methods and Results: Medical records of 1,180,062 young adults (20-49 years old) without a prior history of CVD and who were not taking antidiabetic medications were extracted from the Japan Medical Data Center. We categorized the study population into four groups: normal, FPG level<100 mg/dL (1,007,747 individuals), normal-high, FPG level of 100-109 mg/dL (126,602 individuals), impaired fasting glucose (IFG), FPG level of 110-125 mg/dL (32,451 individuals), and diabetes mellitus (DM), FPG level ≥126 mg/dL (13,262 individuals). The mean age was 39.7 ± 6.9 years, and 57.0% of the study population were men. Mean follow-up period was 1201 ± 905 days on average. Multivariable Cox regression analysis showed that IFG (hazard ratio [HR]; 1.38) and DM (HR; 2.09) increased the risk of myocardial infarction. Normal-high (HR; 1.11), IFG (HR; 1.18), and DM (HR; 1.59) groups had an elevated angina pectoris risk. DM (HR; 1.31) increased the risk of stroke compared to normal FPG levels. Normal-high levels (HR; 1.10), IFG (HR; 1.22) and DM (HR; 1.58) elevated the risk of heart failure. DM (HR; 1.69) increased the risk of atrial fibrillation., Conclusions: Our analysis of a nationwide epidemiological database demonstrated a close association of the FPG category with subsequent CVD risk. Our results exemplify the importance of optimal FPG maintenance for the primary prevention of CVD in young adults., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Body weight (BW) gain in adulthood frequently leads to the development of obesity and is associated with subsequent cardiovascular disease (CVD). However, the pathological significance of BW gain in non-obese individuals is not fully understood., Methods and Results: Using data from a nationwide epidemiological database, we studied 1,558,774 non-obese subjects aged ≥20 years and without prior history of CVD. The subjects' mean age was 44.7 ± 11.2 years, and 853,391 subjects (54.7%) were male. BW gain, which was defined as BW gain of ≥10 kg from the age of 20 years, was seen in 302,997 subjects (19.4%). Subjects with BW gain were older and more likely to be male than those without BW gain. Body mass index and waist circumference were higher in subjects with BW gain. The prevalence of classical CVD risk factors was higher in subjects with BW gain. Kaplan-Meier curves and log-rank tests showed that subjects with BW gain had higher incidences of composite endpoints, including myocardial infarction, angina pectoris, and stroke. Multivariable Cox regression analysis including other covariates presented that BW gain was independently associated with the incidence of composite endpoint (Hazard ratio 1.10, 95% confidence interval 1.07-1.13, p < 0.001). Subgroup analyses showed that the association of BW gain with the development of CVD was observed regardless of age, sex, and body mass index., Conclusion: Subjects with BW gain of ≥10 kg from the age of 20 years had high incidence of cardiovascular events even if they did not yet develop obesity. The results suggest the significance of substantial BW gain in adulthood in the development of subsequent CVDs., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Aims: Although carotid intima-media thickness (IMT) is an established marker of atherosclerosis and carries independent risk for cardiovascular disease, its possible association with subclinical cardiac dysfunction has not been extensively evaluated. Left ventricular global longitudinal strain (LVGLS) and peak left atrial longitudinal systolic strain (PALS) can detect subclinical left heart dysfunction. This study aimed to investigate the association between carotid IMT and subclinical left heart dysfunction in a sample of the general population without overt cardiac disease., Methods: We examined 1161 participants who underwent extensive cardiovascular examination. Ultrasonography of common carotid artery was performed for the measurement of maximal carotid IMT. LVGLS and PALS were assessed by 2-dimensional speckle-tracking echocardiography., Results: Mean age was 62 ± 12 years, and 56% were male. The prevalence of abnormal LVGLS (>-18.6%) and PALS (<31.4%) was greatest in the upper quartile of carotid IMT (both p < 0.001). In multivariable analyses, carotid IMT was associated with abnormal LVGLS (adjusted odds ratio = 1.33 per 1SD increase of IMT, p = 0.003) as well as PALS (adjusted odds ratio = 1.33 per 1SD increase of IMT, p = 0.005) independent of traditional cardiovascular risk factors, echocardiographic parameters including LV ejection fraction, LV mass index and diastolic dysfunction, and pertinent laboratory parameters. The independent association between carotid IMT and PALS persisted even after adjustment for LVGLS., Conclusions: Participants with increased IMT had significantly impaired LV and LA function in an unselected community-based cohort. This association may be involved in the higher incidence of cardiovascular disease in individuals with increased carotid IMT., Competing Interests: Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for hypertension have lowered the threshold of normal blood pressure (BP). However, how this updated guideline should be applied to the general population is still under debate, and may depend on gender because of a substantial gender difference in the risk of cardiovascular disease. We aimed to clarify the gender difference in the association between BP category and cardio-ankle vascular index (CAVI), as a marker of subclinical atherosclerosis, using a community-based cohort., Methods: We examined 1,241 subjects (699 males and 542 females) who underwent health check-ups at our institute. We defined normal pressure as systolic (s)BP <130 mmHg and diastolic (d)BP <80 mmHg, stage 1 hypertension as 130 mmHg ≤ sBP < 140 mmHg or 80 mmHg ≤ dBP <90 mmHg and stage 2 hypertension as sBP ≥140 mmHg or dBP ≥90 mmHg, including subjects on antihypertensive medications. High CAVI was defined as CAVI ≥9.0., Results: Age and the prevalence of most of atherosclerotic risk factors increased with increasing BP category in both male and female subjects. A linear relationship between the prevalence of high CAVI and high BP category was observed in males, but not in females. Multivariable logistic regression analysis revealed that BP category was independently associated with high CAVI in males but not in females., Conclusion: There was a difference seen between males and females in the association between BP category, according to the updated ACC/AHA guideline, and CAVI, suggesting that the optimal management strategy for hypertension may depend on not only age, obesity, and diabetes mellitus, but also gender., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Functional tricuspid regurgitation (TR) is frequently present in patients with severe mitral regurgitation and is associated with worse outcome. While percutaneous mitral valve repair (PMVR) is on the increase, the role of TR in those patients is unclear. This study aimed to compare pre- and post-procedural TR and investigated the impact of post-procedural TR and major clinical risk factors on long-term survival in patients undergoing PMVR., Methods: In this retrospective observational cohort study, data from 213 consecutive patients at a tertiary care center undergoing PMVR from 2010 to 2016 were analyzed. Two different groups, dichotomized according to the degree of TR (none/mild and moderate/severe) were compared. Multivariable analyses were performed assessing predictors for long-term survival adjusting for major risk factors., Results: Following PMVR TR was significantly reduced by at least 1 grade in 23.0% (p=0.001), while echocardiographic pulmonary pressure was decreased (TR Vmax 3.21±0.49m/s vs. 2.98±0.53m/s; p=<0.001). Patients with moderate or severe TR presented with worse New York Heart Association functional class and elevated N-terminal pro B-type natriuretic peptide levels compared to patients with none or mild TR. Median survival time was 1458 days. Proportional hazards model, adjusted for major risk factors, revealed post-procedural TR grade (HR 2.055, CI 1.317-3.206, p=0.02), severely impaired left ventricular function (HR 3.145, CI 1.199-8.250, p=0.020), and chronic kidney disease [glomerular filtration rate (GFR) 30-60ml/min HR 1.917, CI 1.109-3.314, p=0.020; GFR<30ml/min HR 3.969, CI 1.981-7.951, p<0.001] as independent predictors for long-term survival., Conclusion: Post-procedural moderate and severe TR predicts worsened long-term survival in patients undergoing PMVR and is associated with adverse clinical outcome. Whether outcome might be improved by interventional reduction of post-procedural TR has to be investigated in the future., (Copyright © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Many candidates with ischaemic functional mitral regurgitation (FMR) have previously undergone coronary artery bypass grafting (CABG), in which transcatheter mitral valve repair can be reasonable for ameliorating the deteriorated hemodynamic and heart failure symptoms. We sought to elucidate the outcomes of MitraClip (MC) implantation in patients with symptomatic ischaemic FMR after CABG., Methods: We investigated clinical characteristics, outcomes and predictive impact of previous CABG on mortality in ischaemic FMR patients who underwent MC implantation from two high-volume centres in Germany., Results: We enrolled 159 patients who previously underwent CABG. Compared with a reference group that did not previously undergo CABG (n = 182), the cohort consisted of more elderly patients (75.0, standard deviation [SD] 7.7 versus 72.9, SD 9.6 years, p = 0.028), more men (84% vs. 69%, p < 0.001), and reduced tricuspid annular plane systolic excursion (14.0, SD 4.0, vs. 16.6, SD 4.6 mm, p < 0.0001). The CABG group showed similar outcomes regarding procedural success (91% vs. 94%, p = 0.24) and 30-day mortality (5.0% vs. 6.0%, p = 0.68), but worse survival after MC implantation (log-rank p = 0.019, hazard ratio 1.56 [95% confidence interval (CI) 1.08-2.26]). After propensity score matching (n = 224), the hazard ratio was 1.18 [95%CI 0.76-1.84] without statistical significance (p = 0.46)., Conclusions: Transcatheter mitral valve repair using the MC is a viable treatment option for patients with symptomatic ischaemic FMR after CABG. Although the baseline characteristics seemed to point to sick patients, CABG itself had only a modest impact on survival., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: MitraClip (MC; Abbott Vascular, Menlo Park, CA, USA) is a treatment option for mitral regurgitation. Renal dysfunction is closely associated with cardiovascular disease. However, the influence of renal function in MC remains not fully understood. In this study, we aimed to clarify the association between renal function and MC., Methods and Results: We examined 206 consecutive patients who underwent MC and divided patients into 3 groups according to estimated glomerular filtration rate (eGFR), normal eGFR (≥60mL/min/1.73m 2 ) (n=70), mild chronic kidney disease (CKD) (30-59mL/min/1.73m 2 ) (n=106), and severe CKD (<30mL/min/1.73m 2 ) (n=30). N-terminal pro-B type natriuretic peptide (NT-pro BNP) levels increased with decreasing eGFR. Kaplan-Meier curves revealed that the long-term survival rate significantly decreased with eGFR. After adjustment with the covariates, severe CKD was still associated with mortality. Improved renal function was observed in 30% and associated with baseline lower NT-pro BNP levels. Patients with improved renal function had higher chronic phase survival rate., Conclusion: Renal dysfunction is common in MC patients and the survival rate decreased with eGFR in association with increased NT-pro BNP levels. MC may improve renal function in approximately 30% of MC patients. Improved renal function is associated with lower NT-pro BNP levels and results in satisfactory prognosis. These results implies a close association between renal function and MC treatment., (Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: MitraClip (MC) is an alternative treatment for mitral regurgitation (MR). Although residual MR is common after MC, little was known about the impact of residual MR after MC., Methods: We examined 255 consecutive patients who underwent MC. The primary endpoint was the composite endpoint including all-cause death, left ventricular (LV) assist device, and mitral valve surgery., Results: Procedure failure defined as unsuccessful MC implantation (n=6) and residual MR ≥3+ (n=19) was associated with worse outcomes including the primary endpoint and all-cause death than those with acute procedure success (APS) defined as residual MR 2+ (n=125) or 1+ (n=105). Among patient with APS, background characteristics including age, MR etiology, heart failure severity, and LV function were not different. Although MR grade and NT-pro BNP level at 6months after MC were higher in patients with residual MR 2+, there was no significant difference in the incidence of the primary endpoint and all-cause death. Subanalysis showed that the primary endpoint occurred more frequently in patients with MR 2+ in patients with LV ejection fraction ≤40%, chronic kidney disease, and baseline NYHA-class IV., Conclusion: Procedure failure was associated with adverse outcomes after MC. Among patients with APS, residual MR 2+ was not significantly associated with overall worse outcomes than residual MR 1+. However, residual MR 2+ was associated with poorer prognosis in patients with impaired LV function, renal dysfunction, and severe heart failure, suggesting that the optimal endpoint of MC procedure should be individualized according to each patient's baseline characteristic., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and Aims: Low ankle-brachial index (ABI) is associated with increased mortality and an increased incidence of cardiovascular events. The purpose of this study was to investigate the value of borderline ABI in predicting clinical outcomes., Methods and Results: The data were derived from the Shinken Database 2004-2012, from a single hospital-based cohort study (N = 19,994). ABI was measured in 5205 subjects; 4756 subjects whose ABI was 0.91-1.39 and having no history of peripheral artery disease were enrolled. The subjects were classified into two groups as follows: borderline ABI (0.91-1.00; n = 324) and normal ABI (1.01-1.39; n = 4432). Subjects in the borderline ABI group had more comorbidities, including diabetes mellitus, aortic disease, and stroke. Moreover, the borderline ABI group was associated with higher levels of hemoglobin A1c and brain natriuretic peptide, larger diameters of left atrium and left ventricle, and lower levels of estimated glomerular filtration rate and left ventricular ejection fraction. All-cause death and cardiovascular death occurred in 9.3% and 4.6% of subjects in the borderline ABI group, and in 2.0% and 0.8% of subjects in the normal ABI group, respectively. An adjusted Cox regression model showed that borderline ABI was associated with a higher incidence of all-cause death (hazard ratio [HR] 2.27, p = 0.005) and cardiovascular death (HR 3.47, p = 0.003)., Conclusion: A borderline ABI was independently associated with worse clinical outcomes in relatively high risk population. Our data should be confirmed in larger populations including those with low risk profiles., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: The prognostic impact of worsening renal function (WRF) in acute coronary syndrome (ACS) patients is not fully understood in Japanese clinical practice, and clinical implication of persistent versus transient WRF in ACS patients is also unclear., Methods: With a single hospital-based cohort in the Shinken database 2004-2012 (n=19,994), we followed 604 ACS patients who underwent percutaneous coronary intervention (PCI). WRF was defined as an increase in creatinine during hospitalization of ≥0.3mg/dl above admission value. Persistent WRF was defined as an increase in creatinine during hospitalization of ≥0.3mg/dl above admission value and maintained until discharge, whereas transient WRF was defined as that WRF resolved at hospital discharge., Results: WRF occurred in 78 patients (13%), persistent WRF 35 patients (6%) and transient WRF 43 patients (7%). WRF patients were older and had a higher prevalence of chronic kidney disease, history of myocardial infarction (MI), and ST elevation MI. WRF was associated with elevated inflammatory markers and reduced left ventricular (LV) ejection fraction in acute, chronic phase. Incidence of all-cause death and major adverse cardiac events (MACE: all-cause death, MI, and target lesion revascularization) was significantly higher in patients with WRF. Moreover, in the WRF group, incidences of all-cause death and MACE were higher in patients with persistent WRF than those with transient WRF. A multivariate analysis showed that as well as older age, female gender, and intubation, WRF was an independent determinant of the all-cause death in ACS patients who underwent PCI., Conclusions: In conclusion, WRF might have a prognostic impact among Japanese ACS patients who underwent PCI in association with enhanced inflammatory response and LV remodeling. Persistent WRF might portend increased events, while transient WRF might have association with favorable outcomes compared with persistent WRF., (Copyright © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Seasonal variations in cardiovascular disease is well recognized. However, little is known about the presentations and outcomes of Japanese heart failure (HF) patients in the winter season., Methods and Results: We used a single hospital-based cohort from the Shinken Database 2004-2012, comprising all new patients (n=19,994) who visited the Cardiovascular Institute Hospital. A total of 375 patients who were admitted owing to acute decompensated HF were included in the analysis. Of these patients, 136 (36%) were admitted in winter. Winter was defined as the period between December and February. The HF patients admitted in winter were older, and had a higher prevalence of hypertension and diabetes mellitus than the patients admitted in other seasons. Patients with conditions categorized as clinical scenario 1 tended to be admitted more commonly in winter. HF with preserved left ventricular ejection fraction (LVEF) was more common in HF patients admitted in winter than in those admitted in other seasons. Beta-blocker use at hospital discharge was more common in the patients admitted in other seasons. Kaplan-Meier curves and log-rank test results indicated that the incidences of all-cause death, cardiovascular death, and HF admission were comparable between the patients admitted in winter and those admitted in other seasons., Conclusions: HF admission was frequently observed in the winter season and HF patients admitted in the winter season were older, and had higher prevalence of hypertension and diabetes mellitus, and preserved LVEF suggesting that we might need to pay more attention for elderly patients with hypertension, diabetes mellitus, and HF with preserved LVEF to decrease HF admissions in the winter season., (Copyright © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Clinical data on the mortality and morbidity of unselected Japanese patients with heart failure (HF) are limited. In this study, we aimed to determine the clinical characteristics, long-term outcomes, and prognostic factors of Japanese HF patients with preserved or reduced left ventricular ejection fraction (LVEF)., Methods and Results: We used a single hospital-based cohort from the Shinken Database 2004-2011 that comprised all new patients (n=17,517) visiting the Cardiovascular Institute Hospital. A total of 1,525 patients diagnosed with symptomatic HF at the initial visit were included in the analysis. Of these, 1121 patients (74%) exhibited a preserved LVEF (>50%) and 404 patients (26%) had a reduced LVEF (≤ 50%). HF patients with preserved LVEF (HFpEF) were older and more often female than patients with reduced LVEF (HFrEF). Kaplan-Meier curves and log-rank test results showed that HFpEF patients had a better prognosis than HFrEF patients. However, there were no significant differences in clinical outcomes between HFpEF and HFrEF patients when the analysis was limited to inpatients. Cox regression analysis showed that HFpEF patients had a significantly lower risk of all-cause death (p=0.027; hazard ratio, 0.547, 95% confidence interval, 0.321-0.933). Multivariate analyses performed separately showed that the independent predictors of all-cause death in HFrEF were advanced age, lower body mass index, diabetes mellitus, and the absence of statin treatment, whereas those for HFpEF were advanced age, absence of dyslipidemia, anemia, and left ventricular hypertrophy., Conclusions: This prospective cohort study identified the clinical characteristics, long-term outcomes, and prognostic factors of Japanese HF patients with reduced and preserved ejection fractions in a real-world clinical setting., (Copyright © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: The impact of obesity on Japanese patients who undergo primary percutaneous coronary intervention (PCI) remains unclear., Methods and Results: Within a single hospital-based cohort in the Shinken Database 2004-2010, which comprised all new patients (n=15227) who visited the Cardiovascular Institute, we followed patients who underwent PCI. Major adverse cardiac events (MACE)-death, myocardial infarction, or target lesion revascularization (TLR)-were defined as the composite endpoint. A total of 1205 patients were included in this study (median follow-up of 1037±703 days): 92 lean [body-mass-index (BMI)<20]; 640 normal-weight (BMI=20-24.9); 417 overweight (BMI=25-29.9); and 56 obese (BMI≥30). Mean age decreased and male gender increased with increasing BMI. Classic coronary risk factors were more common in overweight and obese patients than in normal-weight and lean patients. Chronic kidney disease (CKD) was more common in lean patients than in overweight and obese patients. Patients taking dual antiplatelet therapy, statins, beta-blockers, and renin-angiotensin-system inhibitors increased in a BMI-dependent manner. Obese patients had a significantly lower frequency of MACE, all-cause death, cardiac death, and hospital admission for heart failure than lean patients. Multivariate analysis showed that BMI category was independently associated with all-cause death after PCI., Conclusion: Over-weight and obese patients were independently associated with favorable long-term clinical outcomes after PCI, suggesting that obesity paradox was applicable to Japanese patients after PCI in real-world clinical setting., (Copyright © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: The presence of heart failure (HF) with preserved ejection fraction (HFPEF) is increasingly recognized. However, prognostic factors for HFPEF remain unclear., Methods and Results: The data were derived from Shinken Database 2004-2010, a prospective cohort study (n=15,227). We examined 301 consecutive HFPEF patients (New York Heart Association Class II or greater) and tracked them for an average 3.5 years. Cardiopulmonary exercise testing (CPX), blood exams, and ultrasound cardiogram (UCG) were performed at the first medical examination. Acute decompensated HF (ADHF) admission was observed in 19 patients (6.3%). CPX showed that the anaerobic threshold was lower (7.3±4.8mL/min/kg vs. 9.7±4.3mL/min/kg, p=0.02) and slope of the increase in ventilation to the increase in CO(2) output (VE-VCO(2) slope) was higher (40.6±8.5 vs. 34.6±7.9, p<0.01) in patients with ADHF admission than those without. Serum brain natriuretic peptide (BNP) tended to be higher and left atrial (LA) dimension was significantly greater (47.0±15.8mm vs. 41.0±9.9mm, p=0.01) in patients with ADHF admission than those without. Multivariate analysis showed that higher VE-VCO(2) slope and greater LA dimension were independent determinants of ADHF admission., Conclusion: An aggravated CPX parameter and LA dilatation were associated with ADHF admission in patients with symptomatic HFPEF, suggesting the prognostic role of cardiopulmonary dysfunction during exercise and LA remodeling in the pathogenesis of decompensated HF development in HFPEF., (Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Abdominal aortic aneurysm (AAA) expansion is characterized by chronic inflammatory cell infiltration and extracellular matrix degradation. High-mobility group box 1 protein (HMGB1) is one of the damage-associated molecular pattern molecules derived from injured/necrotic and activated inflammatory cells. We investigated the expression of HMGB1 in human AAA and mouse experimental AAA. Then, we evaluated the effect of HMGB1 blockade on AAA formation in the mouse model., Methods and Results: Human AAA samples showed increased HMGB1 expression compared with normal aortic wall. In a mouse CaCl(2)-induced AAA model, the expression of HMGB1 was increased compared with that in sham, and was positively correlated with matrix metalloproteinase (MMP)-2 and MMP-9 activity. We administered neutralizing anti-HMGB1 antibody (AAA/anti-H) or control antibody (AAA/C) to AAA mice subcutaneously every 3 days for 6 weeks. Treatment with neutralizing anti-HMGB1 antibody suppressed AAA formation, and attenuated elastin fragmentation. HMGB1 blockade markedly reduced the number of macrophages and MMP-2 and MMP-9 activity in aneurysmal tissue. The mRNA level of tumor necrosis factor-α and CD68 in the aorta was reduced in AAA/anti-H compared with AAA/C., Conclusions: Elevation of HMGB1 level in aneurysmal tissue was observed in human AAA and mouse experimental AAA. HMGB1 blockade in a mouse AAA model reduced AAA progression, in association with reduced infiltration of macrophages and MMPs activity. These findings suggest a significant role for HMGB1 in the pathogenesis of AAA., (Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Objective: Tumor necrosis factor (TNF)-α is known to be elevated in plasma and the aorta in abdominal aortic aneurysm (AAA) patients. We sought to clarify the role of TNF-α converting enzyme (Tace), which cleaves the transmembrane precursor of TNF-α, in AAA development., Methods: We obtained aortic sample of AAA during surgical operation to assess the histological features and protein expression of human AAA. AAA was induced in mice with temporal systemic deletion of Tace by the inducible Mx-1 Cre transgene (TaceMx1) and in wild-type littermates (CON) by periaortic application of CaCl(2) (AAA/TaceMx1, AAA/CON)., Results: Tace expression was increased in human AAA samples as compared with normal aorta. Six weeks postoperatively, aortic diameter in AAA/TaceMx1 was decreased than in AAA/CON in association with attenuated TNF-α expression and extracellular matrix disruption. Increased activities of matrix metalloproteinase (MMP)-9 and MMP-2, numbers of Mac-2-positive macrophages, CD3-positive T lymphocytes and CD31-positive vessels in periaortic tissues, mRNA expression of CD68, monocyte chemotactic protein-1, TNF-α, vascular endothelial growth factor-A, p47 and glutathione peroxidases, and protein expression of phospho-c-Jun N-terminal kinase in AAA were all attenuated by Tace deletion. Protein expression of transforming growth factor (TGF)-β1 was upregulated by Tace deletion in sham-operated mice. TGF-β1 expression was further increased in AAA/TaceMx1., Conclusions: Tace was overexpressed in the aortic wall in human and experimental AAA. Temporal systemic deletion of Tace prevented AAA development in association with attenuating inflammation, oxidative stress, neoangiogenesis and extracellular matrix disruption, suggesting a crucial role of Tace in AAA development., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Study Objectives: Most left ventricular (LV) thrombi that occur after acute myocardial infarction (AMI) are formed within 2 weeks, when inflammatory cells have infiltrated into the necrotic myocardium. Inflammatory changes on the endocardial surface may induce platelet deposition and fibrin net formation through interaction with proinflammatory cytokines. We sought to determine the significance of the inflammatory response reflected by serum C-reactive protein (CRP) elevation in LV thrombus formation after AMI., Design: We examined 160 patients with first anterior AMI. Peak serum creatine kinase (CK) and CRP levels were determined by serial measurements. Echocardiography was performed 10 to 14 days after the onset. We assessed the association between the elevation of serum CRP levels and LV thrombus formation after AMI., Results: LV thrombus was observed in 13 patients (8%). There was no difference in age, sex, coronary risk factors, preinfarction angina, use of revascularization therapy and anticoagulant therapy, platelet count, and fibrinogen level on hospital admission between the two groups. The mean (+/- SD) peak serum CRP level was markedly increased in patients with LV thrombus compared to those without (18.0 +/- 12.6 vs 9.4 +/- 8.1 mg/dL; p = 0.001), despite their having similar peak CK levels. Multivariate analysis showed that a peak CRP level of > or =20 mg/dL was an independent predictor of thrombus formation (relative risk, 4.82; p = 0.037) among variables including older age (> or =60 years old), peak CK level (> or =3,000 IU/L), and peak WBC count (> or =12,000 cells/ microL)., Conclusion: A greater elevation of serum CRP level was associated with a higher incidence of LV thrombus after AMI, suggesting an important role of the inflammatory response in mural thrombus formation.