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Background Neointimal maturation after bioresorbable-polymer (BP) drug-eluting stent (DES) implantation will not be complete in the absorption phase of the polymer. We have previously reported local persistent hypercoagulation after sirolimus-eluting stent (SES) implantation by measuring local plasma prothrombin fragment 1+2 (F1+2) levels. The aim of this study is to examine time-dependent local coagulative response after BP-DES implantation. Methods Sixty-four patients who were treated about ten months earlier with coronary angioplasty, with no evidence of restenosis, were studied [durable-polymer (DP)-DES {SES; Cypher®: 26pts and everolimus-eluting stent (EES); Xience®: 16pts} and BP-DES (BP-EES; Synergy®: 10pts and BP-SES; Ultimaster®: 12pts)]. We measured plasma levels of F1+2 sampled in coronary sinus (CS) and sinus of Valsalva (V) at the early (2±1 months) and chronic (10±2 months) phases. The transcardiac gradient (Δ) was defined as CS level minus V level. Results No significant differences were observed in the percent diameter stenosis between the DP- and BP- DES groups (11.5±15.5 vs 14.1±11.9%). The ΔF1+2 was significantly lower in the BP-DES group than in the DP-DES group at the chronic phase (7.5±16.1 vs 16.4±17.1pmol/l, p Conclusion Lower local coagulative response was observed at the chronic phase after BP-DES implantation compared to DP-DES implantation, and local hypercoagulation after BP-DES implantation was not observed at the early phase compared to the chronic phase. These findings might lead to the possibility of shorter dual antiplatelet therapy after BP-DES implantation. Funding Acknowledgement Type of funding sources: None.

Background There are several recommendations for the use of echocardiography in acute hospitalized HF. Echocardiography requires a high degree of skill on the part of the examiner, and the skill may be more improved in larger volume centers. Purpose In this study, we investigated whether the use and volume of echocardiography is associated with in-hospital mortality from the real world registry database of heart failure (HF) hospitalizations. Methods This study was based on the Diagnosis Procedure Combination database in the Japanese Registry of All Cardiac and Vascular Datasets (JROAD-DPC). We categorized the 739 hospitals into 3 groups according to the number of echocardiographic studies performed annually (first tertile: 4500 cases) and compared the groups of patients who were first admitted to the categorized hospitals with heart failure between April 2015 and March 2016. We estimated the odds ratios and their 95% confidence interval for in-hospital mortality using multivariable models. The variables of multivariable analysis were selected by stepwise method. Results A total of 80,496 HF patients were hospitalized, and 73.2% were examined for echocardiography. We found that the use and volume of echocardiography exams were associated with significantly lower odds of all-cause hospital mortality in heart failure (adjusted OR: 0.48 for use of echocardiography and 0.78 for the third tertile; both P Conclusions The use of echocardiography was associated with decreased odds of hospital mortality in HF. The volumes of echocardiographic examinations were also associated with hospital mortality; thus, this study suggests that the skill of echocardiography may be improved in the large volume center and provide good outcomes in HF. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Japan Society for the Promotion of Science (JSPS) Flowchart of this studyOdds ratio of in-hospital mortality

Background Atrial fibrillation (AF) is the most common type of arrhythmia seen in clinical practice. Recent studies suggest that inflammation contributes to the pathogenesis of AF. On the other hand, several evidence suggests that toll-like receptor (TLR) 9 recognizes bacterial DNA, activating innate immunity, whereas it also provokes inflammation in response to fragmented DNA released from mammalian cells. Recently, we have reported that TLR 9 plays a pivotal role in the development of vascular inflammation and atherogenesis through proinflammatory activation of macrophages. Purpose This study aimed to assess whether TLR9 contributes to the AF arrhythmogenesis. Methods TLR9 deficient (TLR9−/−) and wild-type mice were infused with angiotensin II (Ang II) or vehicle via an osmotic minipump for 4 weeks. Blood pressure and body weight were measured serially. Then, we examined AF inducibility by intracardiac electrophysiological study and the inflammation-induced atrial remodeling by biochemical analysis after 4 weeks of Ang II infusion. Results There was no significant difference in blood pressure and pulse rate between TLR9−/− and wild-type mice both before and after Ang II infusion. Ang II-treated TLR9−/− mice showed lower incidence of AF compared with wild-type mice treated with Ang II. Genetic deletion of TLR9 significantly reduced the interstitial fibrosis in atrium of Ang II-treated mice. TLR9−/− mice also showed less mRNA expressions of inflammatory and fibrosis-related biomarkers (TNF-α, interleukin-6, TGF-β, collagen-1, collagen-3) in atrium compared with wild-type mice. Conclusions TLR9 might contribute to the AF arrhythmogenesis associated with atrial inflammation. TLR9 might serve as a potential therapeutic target for AF. Funding Acknowledgement Type of funding source: None

Background Atrial fibrillation (AF) is the most common arrhythmia in clinical practice, increasing the incidence of ischemic stroke. Diabetes mellitus (DM) is a predictor of stroke and thromboembolism, and it was reported to be an independent risk factor for AF. A recent study has shown that, in obese mice with diabetes, dipeptidyl peptidase-4 (DPP-4) inhibitor prevents myocardial fibrosis, active oxygen stress, weight loss and improves myocardial hypertrophy. However, the effects of DPP-4 inhibitors on atrial remodeling associated with diabetes and atrial fibrillation have not yet been clarified. Purpose This study was performed to assess whether a DPP-4 inhibitor (vildagliptin) ameliorates atrial remodeling in spontaneously hypertensive rats (SHR) with streptozotocin-induced diabetes. Methods Rats were divided into 3 groups: SHR without DM, SHR with DM treated with vehicle and SHR-DM treated with vildagliptin (3mg/kg/day; intragastric gavage). For each group, blood pressure, blood glucose level and body weight were measured serially. Cardiac function was also evaluated by echocardiography. Then, we examined AF inducibility by intracardiac electrophysiological study and the inflammation-induced atrial remodeling by biochemical analysis after 4 weeks of treatment. Results There was no significant difference in blood pressure and blood gucose level between vehicle and vildagliptin groups. Administration of vildagliptin significantly reduced AF inducibility compared with rats with vehicle. In DM rats treated with vehicle, rapid atrial pacing promoted the gene expression of inflammatory and fibrosis-related biomarkers (TNF-α, MCP-1, collagen-1) in atrium. Vildagliptin reduced these gene expression levels. In addition, administration of vildagliptin significantly reduced the interstitial fibrosis in atrium. Conclusions DPP-4 inhibitor, vildagliptin. could prevent atrial inflammation and reduce the AF inducibility in SHR complicated with DM.

Background Canagliflozin is a SGLT-2 inhibitor, a novel type of drug for type 2 diabetes mellitus treatment. Recent studies have shown that SGLT-2 inhibitors reduce cardiovascular events, although the mechanism is still unknown. Purpose The aim of our study was to examine the effect of canagliflozin on vascular endothelial cell. Method Eight-week-old apolipoprotein E-deficient (ApoE−/−) mice were treated with streptozotocin (STZ, 75 mg/kg/day) in three consecutive days by intraperitoneal injection to induce diabetes. Diabetic ApoE−/− mice were treated with canagliflozin (30 mg/kg/day) by gavage for 12 weeks or 8 weeks to examine its effect on atherosclerosis or endothelial function, respectively. Results Canagliflozin significantly decreased blood glucose level (P Conclusion Glucose lowering effect by canagliflozin attenuates the development of endothelial dysfunction and atherogenesis in diabetic ApoE−/− mice. Anti-inflammatory effect due to the reduction of glucose toxicity on endothelial cells might be one of the mechanisms.

Background Ageing is a significant risk factor for atherosclerotic diseases. Vascular senescence has been considered to play an important role in the progression of atherosclerosis; however, it remains unclear whether endothelial cell (EC) senescence is causally involved in the pathogenesis of atherosclerosis. Purpose The purpose of this study is to elucidate a causative role of senescent EC in the progression of atherosclerosis. Methods Telomeric repeat-binding factor 2 (TRF2) plays a central role in telomere maintenance and protection against end-to-end fusion of chromosome. We previously reported that overexpression of TRF2-dominant negative mutant (TRF2DN) induced premature senescence in EC. We recently generated EC-specific progeroid mice by overexpressing TRF2DN specifically in EC (TRF2DN-Tg), and then generated ApoE-KO/TRF2DN-Tg mice to analyze a role of EC senescence in atherosclerosis. These mice were fed with a high cholesterol-diet, and atherosclerosis was assessed by en face analysis of whole aorta and histological analysis of aortic sinus. In vitro studies to analyze the underlying mechanisms were performed using replicative senescent HUVECs. Results En face analysis of aorta revealed that atherosclerotic lesions were significantly increased in ApoE-KO/TRF2DN-Tg mice comparing with that in ApoE-KO mice at as early as 2 weeks after high-cholesterol diet. Histological analysis of aortic sinus also exhibited accelerated atherosclerosis in ApoE-KO/TRF2DN-Tg mice in association with increased macrophage infiltration. Mechanistically, we found that the induction of adhesion molecules such as VCAM-1, ICAM-1, and E-selectin in response to low-grade inflammatory stimuli was substantially augmented in senescent ECs comparing with that in young ECs. As a result, monocyte adhesion was significantly enhanced in senescent ECs. Of note, eNOS inhibition did not affect the hyper-reactivity of senescent EC to inflammation, while antagonizing NF-kB abolished it. Nuclear translocation of NF-kB in response to inflammation was not different between young and senescent ECs, suggesting that NF-kB transcriptional activity might be enhanced in senescent ECs. Conclusion We revealed a causative role of EC senescence in the progression of atherosclerosis in vivo using unique EC-specific progeroid mice. Our findings revealed that EC senescence is a bona fide risk for atherosclerosis, and thus senescent ECs are attracting pharmacotherapeutic targets for the prevention and/or treatment of atherosclerotic disease in elderly population.

Background Epicardial adipose tissue (EAT) locates anatomically and functionally contiguous to the myocardium and coronary arteries. It has been suggested that EAT accumulation is associated with cardiac remodeling and impaired cardiac performance. However, its role in left ventricular (LV) wall strain remains unclear. Purpose In this study, we aimed to clarify: whether EAT accumulation is related to global longitudinal (GLS), circumferential (CS) and radial strain (RS); and if so, in which extent or by which amount of EAT are required to deteriorate these strain. Methods Total 180 patients who had no obstructive coronary artery disease (CAD) on multi-detector computed tomography (MDCT) coronary angiography and normal left ventricular ejection fraction (LVEF) on conventional echocardiography were recruited. Cardiac CT was used to quantify EAT volume (EATV) and echocardiographic speckle tracking was used to measure the GLS, CS and RS. EATV index (EATV/Body surface area) was determined as: EAT volume, the sum of the EAT area from the base to the apex of the heart (cm3)/body surface area (m2). Adipose tissue was determined as the density range between −190 and −30 Hounsfield unit. According to the median value (68 cm3/m2), patients were divided into lower and higher EATV index two groups. Results In higher EATV index group (95±19 cm3/m2), mean age, body mass index (BMI), prevalence of hyperlipidemia and prevalence of CAD were larger than in lower EATV index group (48±14 cm3/m2). Male gender, hypertension, diabetes, smoking and LV mass index were comparable between two groups. Patients in higher EATV index had lower GLS than those in lower EATV index (−19.4±1.2% vs. −18.8±1.3%, p=0.002). However, there were no significant difference between two groups regarding to the CS and RS. Linear regression analysis showed that there was strong correlation between EATV index and GLS (R=0.216, p=0.004); whereas, both RS and CS were strongly associated with the interventricular septum thickness (RS: R=0.248, p=0.003; CS: R= −0.192, p=0.023) and relative wall thickness (RS: R=0.178, p=0.036; CS: R= −0.184, p=0.030) but not with EATV; on multiple regression analysis, EATV was a predictor of GLS independent of age, male gender, BMI, diabetes, hyperlipidemia, hypertension and CAD (Adjusted R2=0.238, p Conclusion EATV is independently associated with GLS despite the preserved LVEF and lacking of obstructive CAD, and may play a significant role in estimating impaired longitudinal LV performance.

Background We have previously reported local persistent hypercoagulation after sirolimus-eluting stent (SES) implantation by measuring local plasma prothrombin fragment 1+2 (F1+2) levels. The aim of this study is to examine chronic local coagulative response after each generation- drug eluting stent (DES) implantation. Methods Ninety-five patients who were treated about eight months earlier with coronary angioplasty, with no evidence of restenosis, were studied [1stgeneration durable polymer (DP)-DES {SES; Cypher®: 26pts, paclitaxel-eluting stent (PES); Taxus®:16pts}, 2ndgeneration DP-DES {everolimus-eluting stent (EES); Xience®:15pts, zotarolimus-eluting stent (ZES); Endeavor®:15pts}, and 3rdgeneration biodegradable polymer (BP)-DES {BP-biolimus-eluting stent (BES); Nobori®: 11pts and BP-SES; Ultimaster®: 12pts}]. We measured plasma levels of F1+2 sampled in coronary sinus (CS) and sinus of Valsalva (V). The transcardiac gradient (Δ) was defined as CS level minus V level. Results No significant differences were observed in the percent diameter stenosis among 1st, 2nd, and 3rd DES groups (12.5±15.5 vs 16.1±12.9 vs 13.1±11.9%). The ΔF1+2 was significantly lower in the 2nd and 3rd DES groups than in the 1st DES group (9.0±15.4 and 10.0±17.4 vs 27.3±23.8pmol/l, p Conclusions The improvement of chronic local coagulative response was observed according to the progress of DES. These findings might be associated with lower strut thickness and faster polymer resorption in the newer-generation DES.

Background Inflammation and oxidative stress associated with hyperglycemia are major causes of vascular dysfunction and cardiovascular complications in diabetes. Recent studies reported that cardioprotective effects of sodium glucose co-transporter 2 (SGLT2) inhibitors, however underlying mechanisms are still obscure. Purpose The aim of this study was to investigate whether empagliflozin attenuates atherogenesis and endothelial dysfunction in diabetic apolipoprotein E-deficient (ApoE−/−) mice and investigated underlying mechanisms. Methods ApoE−/− mice were injected with streptozotocin (75 mg/kg) for 3 consecutive days. One week after last injection, a western type diet and administration of empagliflozin (20 mg/kg/day) or vehicle via oral gavage were started. Atherosclerotic plaque area was examined by en face Sudan IV staining. Lipid deposition and inflammatory features of atherosclerotic plaques was examined on lesions in the aortic root by immunohistochemical analysis. Vascular function was assessed by isometric tension recording. mRNA or protein expression level was examined by quantitative RT-PCR (qPCR) or western blot analysis, respectively. In in vitro experiments, murine macrophage cell line, RAW264.7, was used. Results Treatment with empagliflozin for 12 weeks significantly decreased atherosclerotic plaque size in the aortic arch compared with untreated group (p Conclusions Empagliflozin attenuated endothelial dysfunction and atherogenesis in diabetic ApoE−/− mice. Reduction of inflammation in the vasculature and peri-vascular adipose tissues may have a role as underlying mechanisms at least partially.

Background Growing evidence suggests that visceral adipose tissue has systemic and local impact for the development of cardiovascular disease. Previously, we reported that epicardial adipose tissue, as one of visceral fat, was a risk factor for the development of coronary artery disease (CAD). However, the association between another visceral adiposity kidney fat and CAD remains unclear. Purpose In this study we aimed to clarify whether there exists link between adipose tissue surrounding the kidney and CAD among patients. Method The study population consisted of 201 consecutive patients who underwent 320-slice multi-detector computed tomography (MDCT) coronary angiography. Study subjects were divided into the CAD (≥1 coronary artery stenosis of ≥50%) and non-CAD groups. Adipose tissue surrounding the kidney were quantified by the computed tomography and peri-renal fat volumetric measurements were performed on axial views by manually placing the Region of Interest (ROI) on the renal fascia. The peri-renal fat area of each slice was summed and multiplied by the slice thickness and number of slices to determine the total peri-renal fat volume. Adipose tissue was determined as the density range was −190 to −30 Hounsfield unit. Peri-renal fat volume were indexed by body surface area (BSA). Results The mean age was higher in CAD group than those in non-CAD (66±11 vs. 71±10 years, p=0.005). The diabetes, hypertension and hyperlipidemia were significantly prevalent in CAD comparing to non-CAD group. BSA adjusted Peri-renal fat volume was significantly larger in CAD than those in non-CAD (43±27 vs. 60±39 ml/m2). Linear regression analysis showed that BSA adjusted peri-renal fat volume was significantly correlated with visceral fat area (VFA) (R=0.729, p Conclusion Peri-renal fat volume might be a predictor of CAD. Kidney fat at least partially may contributes to the development of CAD by impaired kidney function.