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Aims Impairment in activities of daily living (ADL) is an independent predictor of poor prognosis in older patients. Nevertheless, the effects of instrumental ADL (IADL) frequency on prognosis in older patients with cardiovascular disease (CVD) are unclear. We investigate the associations between IADL frequency and all-cause mortality and hospital readmission due to cardiovascular events in older patients with CVD. Methods and results A total of 638 consecutive outpatients ≥65 years old with CVD were enrolled. A questionnaire, including Frenchay Activities Index (FAI) parameters, was used to determine IADL frequency at the start of the study as the baseline observation. The primary endpoint was all-cause mortality, and the secondary endpoint was readmission for cardiovascular events. We examined the relationship between IADL frequency and each endpoint. Among the 632 patients evaluated {median age 74.0 [interquartile range (IQR) 70.0–78.0] years; 439 males}, there were 39 deaths and 105 cardiovascular events during the median follow-up period of 4.0 (IQR, 2.3–4.0) years. After adjusting for clinical confounding factors, the hazard ratios for all-cause mortality and cardiovascular events in the FAI points were 0.957 [95% confidence interval (CI), 0.920–0.996] and 0.973 (95% CI, 0.950–0.997), respectively. Conclusion A higher IADL frequency was independently associated with better outcomes in older patients with CVD, suggesting that the preservation of instrumental activities should be focused on as the components of cardiovascular rehabilitation.

International audience; Many works focus on the use of polyesters like poly(lactic acid) (PLA) to produce nanofibrous scaffolds for cardiac tissue engineering. However, such scaffolds are hydrophobic and difficult to functionalize. Here, we show that adding 30% of poly(glycerol sebacate) (PGS) elastomer within PLA leads to PLA:PGS scaffolds with improved biological properties, depending on the processing parameters. Two categories of fibers were produced by blend electrospinning, with diameters of 600 and 1300 nm. The resulting fibers were cured at 90°C or 120°C in order to achieve two different crosslinking densities. The designed scaffolds were considered for cytocompatibility, biocompatibility, biodegradability, chemical and mechanical properties. Our results demonstrated that the presence of PGS increases the hydrophilicity of the material and thus improves surface functionalization by Matrigel and laminin coating, a commonly used cell culture matrix. PLA:PGS scaffolds associated with Matrigel and laminin allow an increased material-cell interaction. Moreover, the cardiomyocytes seeded on such scaffolds acquire a morphology similar to that observed in native tissue, this result being more remarkable on fibers having the smallest diameter and the highest PGS crosslinking density. In addition, these scaffolds induce neovascularization without inflammatory response and foreign body giant cell response after grafting on mice’s heart. Hence, the improved biocompatibility and the ability to support cardiomyocytes development suggest that thin PLA:PGS scaffolds could be promising biomaterials for cardiac application.

Aim: Fractional flow reserve (FFR) reflects on the diffuse atherosclerosis per coronary artery. It is unknown whether the statin therapy affects long term FFR after stenting. The aim of this study was to evaluate the long term FFR after stent implantation in patients who are intaking fixed-dose rosuvastatin. Methods: A total of 22 patients with stable angina pectoris were enrolled. The values of FFR were measured before, immediately after, and 18 months after (follow-up day) the implantation of everolimus eluting stent (EES; Promus Element™ or Promus Element Plus™). A fixed dose of rosuvastatin at 5 mg/day was administrated to all patients. Results: Of the 22 patients, 2 were excluded because of adverse effect of rosuvastatin and in-stent total occlusion after EES implantation. Overall, the values of FFR immediately after and 18 months after EES implantation did not show significant change (from 0.90 ± 0.05 to 0.88 ± 0.06, p = 0.16). However, there was a significant negative correlation between low density lipoprotein (LDL) cholesterol level at follow-up day and changes in the value of FFR (p = 0.01, r = −0.74). There was an increase in the FFR value after stenting in 8 out of 9 patients with LDL cholesterol level below 75 mg/dl (area under the curve 0.92, p = 0.0005). Conclusions: LDL cholesterol level was associated with the change in the FFR value in patients following stent implantation. Lower LDL cholesterol tended to improve in the long-term FFR, underscoring the importance of lowering LDL cholesterol to prevent the progression of coronary atherosclerosis.

Ezetimibe reduces plasma levels of low-density lipoprotein cholesterol by inhibiting Niemann–Pick C1-like protein 1 (NPC1L1). A recent study demonstrated that NPC1L1 plays an important role in absorption of fat-soluble vitamins including vitamin K. We evaluated whether the add-on treatment of ezetimibe affects anticoagulation in patients taking warfarin. Between October 2007 and March 2015, the administration of ezetimibe was started to a total of 101 outpatients who were already on oral anticoagulation with warfarin. We retrospectively analyzed blood lipid levels, prothrombin time international normalized ratio (PT-INR) and time in therapeutic INR range (TTR). Seventy-one patients (70 %) showed increase in PT-INR after ezetimibe treatment (1.96 ± 0.45 to 2.20 ± 0.61, p

Background Stroke prevention by warfarin, a vitamin K antagonist, has been an integral part in the management of atrial fibrillation. Vitamin K-dependent matrix Gla protein (MGP) has been known as a potent inhibitor of arterial calcification and osteoporosis. Therefore, we hypothesized that warfarin therapy affects bone mineral metabolism, vascular calcification, and vascular endothelial dysfunction. Methods We studied 42 atrial fibrillation patients at high-risk for atherosclerosis having one or more coronary risk factors. Twenty-four patients had been treated with warfarin for at least 12 months (WF group), and 18 patients without warfarin (non-WF group). Bone alkaline phosphatase (BAP) and under carboxylated osteocalcin (ucOC) and receptor activator of nuclear factor-kappa B ligand (RANKL) were measured as bone metabolism markers. Reactive hyperemia-peripheral arterial tonometry (RH-PAT) index measured by Endo-PAT2000 was used as an indicator of vascular endothelial function. Results There were no significant differences in patient background characteristics and other clinical indicators between the two groups. In WF group, the ucOC levels were significantly higher than those in the non-WF group (10.3 ± 0.8 vs. 3.4 ± 0.9 ng/mL; P, Highlights • Stroke prevention by warfarin has been an integral part in the management of atrial fibrillation. • Warfarin prevents the activation of vitamin K-dependent proteins, MGP and Gas-6. • Long-term warfarin therapy increases the serum levels of ucOC and RANKL. • Long-term warfarin therapy is associated with vascular endothelial dysfunction.

Incretin hormones have been reported to have cytoprotective actions in addition to their glucose-lowering effects. We evaluated whether teneligliptin, a novel dipeptidyl peptidase-4 (DPP-4) inhibitor, affects left ventricular (LV) function in patients with type 2 diabetes mellitus (T2DM). Twenty-nine T2DM patients not receiving any incretin-based drugs were enrolled and prescribed with teneligliptin for 3 months. Compared to baseline levels, hemoglobin A1c levels decreased (7.6 ± 1.0 % to 6.9 ± 0.7 %, p < 0.01) and 1,5-anhydro-d-glucitol levels increased (9.6 ± 7.2 μg/mL to 13.5 ± 8.7 μg/mL, p < 0.01) after treatment. Clinical parameters, including body mass index and blood pressure, did not show any difference before and after treatment. Three months after treatment, there were improvements in LV systolic and diastolic function [LV ejection fraction, 62.0 ± 6.5 % to 64.5 ± 5.0 %, p = 0.01; peak early diastolic velocity/basal septal diastolic velocity (E/e′) ratio, 13.3 ± 4.1 to 11.9 ± 3.3, p = 0.01]. Moreover, there was an improvement in endothelial function (reactive hyperemia peripheral arterial tonometry [RH-PAT] index; 1.58 ± 0.47 to 2.01 ± 0.72, p < 0.01). There was a significant negative correlation between changes in the E/e’ ratio and RH-PAT values. Furthermore, circulating adiponectin levels increased (27.0 ± 38.5 pg/mL to 42.7 ± 33.2 pg/mL, p < 0.01) without changes in patient body weight. Teneligliptin treatment was associated with improvements in LV function and endothelial functions, and an increase in serum adiponectin levels. These results support the cardio-protective effects of teneligliptin in T2DM patients and increase in serum adiponectin levels.

The target lesion revascularization of paclitaxel-eluting stents (PES) has been reported to be lower than that of sirolimus-eluting stents in patients on hemodialysis (HD). However, the comparison of PES and second generation drug-eluting stents in CKD patients has not been fully investigated. We compared clinical outcomes of everolimus-eluting stents (EES) and PES in CKD patients.Hundred and forty seven CKD patients (eGFR60mLmin(-1)1.73m(-2)) treated with PES (n=74, from May 2007 to December 2009) and EES (n=73, from January 2010 to January 2013) were enrolled in the study. Major adverse cardiac events (MACEs) were defined as death, non-fatal myocardial infarction, and ischemia driven target lesion revascularization.The incidence of 36-month MACE was significantly lower in EES, non-HD group compared to PES, non HD group (0% in EES group and 13.5% in PES group, respectively, P0.01). There was no significant difference in MACE between EES and PES in HD patients (5.4% in PES group and 5.5% in EES group, P=0.98). In multivariate analysis, PES group and PES ISR were independent factors for worse incidence of MACE.In CKD patients, PES was associated with worse clinical outcomes in non-HD patients as compared with EES.

Cell migration, proliferation, and differentiation of cardiac fibroblasts (CFs) play a central role in cardiac fibrosis. Factor Xa (FXa)-dependent protease-activated receptor (PAR)-1 and PAR-2 have been reported as important targets in proinflammatory and fibroproliferative diseases. From this viewpoint, we aimed to investigate whether treatment of rivaroxaban, an approved oral direct FXa inhibitor, attenuates functional changes in angiotensin (Ang) II-induced mouse CFs.Confluent cultured mouse CFs were pretreated with or without rivaroxaban. Ang II-induced cell migration was decreased by 73% in rivaroxaban induced cells. Rivaroxaban inhibited Ang II-induced cell proliferation by 27% at 0.01 μg/ mL, 69% at 0.1 μg/mL, 71% at 1 μg/mL, and 69% at 5 μg/mL. In mouse cytokine array measuring 40 cytokines, the productions of interleukin-16, TIMP-1, and tumor necrosis factor-α (TNF-α) were significantly reduced with 0.1 μg/mL of rivaroxaban pretreatment (all P < 0.05). TIMP-1 levels in the culture supernatant measured by ELISA were also decreased by rivaroxaban pretreatment in Ang II-induced CFs (35% decrease at 0.01 μg/mL, 47% at 0.1 μg/mL, 47% at 1 μg/mL, and 57% at 5 μg/mL). In the dual reporter assay analysis, rivaroxaban inhibited various inflammatory signal pathways, including the nuclear factor-kappa B (NF-κB), active protein-1 (AP-1), and mitogen-activated protein kinase (MAPK) pathways (decreases of 82%, 78%, and 75%, respectively).These data suggest that rivaroxaban inhibits Ang II-induced functional activation in cultured mouse CFs via inhibiting NF-κB and MAPK/AP-1 signaling pathways, which may be a possible target of heart failure, through the antifibrotic and anti-inflammatory efficacy of rivaroxaban in Ang II-stimulated cardiac fibroblasts.

In recent years, direct oral anticoagulants (DOACs) of dabigatran, rivaroxaban, apixaban, edoxaban, which are all alternatives to warfarin, have been released. The use of DOACs is becoming more widespread in the clinical management of thrombotic stroke risk in patients with atrial fibrillation (AF). In large-scale clinical trials of each drug, DOACs were reported to inhibit intracranial hemorrhage, stroke, and death compared to warfarin. Warfarin is an endogenous vitamin K antagonist; therefore, patients who are taking warfarin must be prohibited from taking vitamin K. Vitamin K is an essential cofactor required for the ɤ-carboxylation of vitamin K-dependent proteins including coagulation factors, osteocalcin (OC), matrix Gla protein (MGP), and the growth arrest-specific 6 (GAS6). OC is a key factor for bone matrix formation. MGP is a local inhibitor of soft tissue calcification in the vessel wall. GAS6 prevents the apoptosis of vascular smooth muscle cells. Therefore, decrease of blood vitamin K levels may cause osteoporosis, vascular calcification, and the inhibition of vessels angiogenesis. This study aimed to evaluate the effects of changing from warfarin to rivaroxaban on bone mineral metabolism, vascular calcification, and vascular endothelial dysfunction. We studied 21 consecutive patients with persistent or chronic AF, who were treated with warfarin at least for 12 months. Warfarin administration was changed to rivaroxaban (10 or 15 mg/day) in all patients. Osteopontin (OPN), bone alkaline phosphatase (BAP), and under-carboxylated osteocalcin (ucOC) were measured. Pulse wave velocity (PWV) and augmentation index (AI) were also measured as atherosclerosis assessments. All measurements were done before and six months after the rivaroxaban treatment. There was a significant increase in serum level of BAP compared to baseline (12.5 ± 4.6 to 13.4 ± 4.1 U/L, P

Incomplete neointimal coverage and malapposed struts after stenting are associated with increased risk of stent thrombosis. We aimed to evaluate neointimal coverage early after Resolute zotarolimus-eluting stent (R-ZES) implantation using optical coherence tomography (OCT). A total of 20 patients with de novo native coronary lesions with R-ZES were enrolled. Among these patients, 20 stented lesions in 19 patients were evaluated at 1, 2, and 3 months after R-ZES implantation. The strut apposition and neointimal coverage were evaluated by OCT. Neointimal hyperplasia (NIH) thickness and percentage of covered struts and the proportion of incompletely apposed struts were measured at 1-mm intervals. The mean percentages of covered stent struts were over 85 % within 3 months (88.4 ± 6.3 % at 1 month, 95.5 ± 5.5 % at 2 months, 93.6 ± 3.5 % at 3 months). The percentages of incompletely apposed struts were not significantly different among the groups (4.4 ± 4.2 % at 1 month, 1.9 ± 1.9 % at 2 months, 3.1 ± 2.2 % at 3 months, p = 0.51). Mean NIH thickness (38.9 ± 8.1 μm at 1 month, 70.6 ± 18.8 μm at 2 months, 54.1 ± 5.9 at 3 months, p = 0.0016) was thickest in the 2 months group. Most of all OCT findings within 2 months demonstrated neointimal coverage with low signal intensity. The neointimal coverage of ZES-R was over 85 % within 3 months. These data may support shorter requirement of dual antiplatelet therapy duration with R-ZES.

Soluble fms-like tyrosine kinase 1 (sFlt-1) is an endogenous inhibitor of vascular endothelial growth factor, which is involved in cardiovascular remodeling and atherosclerosis development. To examine the predictive role of sFlt-1 levels in patients with asymptomatic heart failure, we measured circulating sFlt-1 in patients with or without coronary artery disease (CAD). We analyzed 88 Japanese patients with CAD or patients at high risk for atherosclerosis and who were undergoing total risk management for cardiovascular disease prevention. Circulating sFlt-1 levels correlated with the increase in plasma brain natriuretic peptide levels (ΔBNP) from baseline to the observed levels 5 years later in CAD patients, patients with previous myocardial infarction, and men. ΔBNP levels correlated with sFlt-1 levels in the high-sFlt-1 patients with CAD (r = 0.511, P < 0.01). In all patients, end-systolic volume index (ΔESVI) increased in correlation with a decrease in left ventricular ejection fraction (ΔEF) in the long-term observation, independent of their history of myocardial infarction (ΔESVI = 2.5 mL/m(2) increase/year). Baseline level of sFlt-1 was independent of ΔESVI or ΔEF. The present 5-year observational study demonstrated that high sFlt-1 levels predicted moderate increases in BNP levels in CAD patients. Moreover, ΔBNP was correlated with ΔESVI/year in CAD patients with high-sFlt-1 levels. These data suggest that high sFlt-1 levels may be an effective biomarker to predict the progression of heart failure in patients with CAD.

In recent years, direct oral anticoagulants (DOACs) of dabigatran, rivaroxaban, apixaban, edoxaban, which are all alternatives to warfarin, have been released. The use of DOACs is becoming more widespread in the clinical management of thrombotic stroke risk in patients with atrial fibrillation (AF). In large-scale clinical trials of each drug, DOACs were reported to inhibit intracranial hemorrhage, stroke, and death compared to warfarin. Warfarin is an endogenous vitamin K antagonist; therefore, patients who are taking warfarin must be prohibited from taking vitamin K. Vitamin K is an essential cofactor required for the ɤ-carboxylation of vitamin K-dependent proteins including coagulation factors, osteocalcin (OC), matrix Gla protein (MGP), and the growth arrest-specific 6 (GAS6). OC is a key factor for bone matrix formation. MGP is a local inhibitor of soft tissue calcification in the vessel wall. GAS6 prevents the apoptosis of vascular smooth muscle cells. Therefore, decrease of blood vitamin K levels may cause osteoporosis, vascular calcification, and the inhibition of vessels angiogenesis. This study aimed to evaluate the effects of changing from warfarin to rivaroxaban on bone mineral metabolism, vascular calcification, and vascular endothelial dysfunction. We studied 21 consecutive patients with persistent or chronic AF, who were treated with warfarin at least for 12 months. Warfarin administration was changed to rivaroxaban (10 or 15 mg/day) in all patients. Osteopontin (OPN), bone alkaline phosphatase (BAP), and under-carboxylated osteocalcin (ucOC) were measured. Pulse wave velocity (PWV) and augmentation index (AI) were also measured as atherosclerosis assessments. All measurements were done before and six months after the rivaroxaban treatment. There was a significant increase in serum level of BAP compared to baseline (12.5 ± 4.6 to 13.4 ± 4.1 U/L, P 0.01). In contrast, there was a significant decrease in the serum level of ucOC (9.5 ± 5.0 to 2.7 ± 1.3 ng/ml, P 0.01). Also, in the ucOC levels, there was a significant negative correlation between baseline values and baseline to 6-months changes in high ucOC group (r = -0.97, P 0.01). The atherosclerosis- and osteoporosis-related biomarker, serum level of OPN were significantly decreased compared to baseline (268.3 ± 46.8 to 253.4 ± 47.1 ng/ml, P 0.01). AI and PWV were significantly decreased after 6 months of treatment with rivaroxaban (33.9 ± 18.4 to 24.7 ± 18.4%, P = 0.04; 1638.8 ± 223.0 to 1613.0 ± 250.1 m/s, P = 0.03, respectively). Switching to rivaroxaban from warfarin in patients with atrial fibrillation was associated with an increase of bone formation markers and a decrease of bone resorption markers, and also improvements of PWV and AI.

Although in flies the atypical cadherin Fat is an upstream regulator of Hippo signalling, the closest mammalian homologue, Fat4, has been shown to regulate tissue polarity rather than growth. Here we show in the mouse heart that Fat4 modulates Hippo signalling to restrict growth. Fat4 mutant myocardium is thicker, with increased cardiomyocyte size and proliferation, and this is mediated by an upregulation of the transcriptional activity of Yap1, an effector of the Hippo pathway. Fat4 is not required for the canonical activation of Hippo kinases but it sequesters a partner of Yap1, Amotl1, out of the nucleus. The nuclear translocation of Amotl1 is accompanied by Yap1 to promote cardiomyocyte proliferation. We, therefore, identify Amotl1, which is not present in flies, as a mammalian intermediate for non-canonical Hippo signalling, downstream of Fat4. This work uncovers a mechanism for the restriction of heart growth at birth, a process which impedes the regenerative potential of the mammalian heart., Growth of the mammalian heart is controlled by Hippo signalling but how this is regulated is unclear. Here, the authors show that Fat4 (an atypical cadherin) acts upstream of Hippo signalling and Fat4 mutant mice have thicker myocardium, which is mediated by the scaffold Amot1 and transcription factor Yap1.

A 61 years old male with a history of multiple treatments ofpercutaneous coronary intervention (PCI) with bare-metal stents (BMS)was admitted for the treatment of acute coronary syndrome (ACS).Sixteen years prior to this admission when he was 45 years old, heexperienced inferior ST-elevation myocardial infarction. He receivedone Palmaz-Schatz Stent (PS) for the treatment of lesion in distal rightcoronary artery (RCA). During the hospitalization, he received one PSfor the treatment of stable lesion in proximal left anterior descendingartery (LAD) (Fig. 1). Routine 3-year follow up angiography revealed norestenosis. The controls of other coronary risk factors were good exceptforobesity(BMI=36).SixteenyearsafterPSimplantation,hefeltsuddenchest pain suggestive of ACS, although there was no signi ficant ST-Tchange in electrocardiography at rest. The angiography revealed focalsevere stenoses in both the PS at the RCA and LAD. Optical coherencetomography(OCT)wasperformedtodecidewhichlesionwastheculprit.OCT findings within both lesion demonstrated intimal hyperplasia overthe BMSs. OCT in the RCA demonstrated diffusely thickened neointimathat exhibited low signal intensity with attenuation, partially coveredwith layered tissue pattern. Disrupted thin fibrous cap with intraluminalthrombus was observed at the culprit lesion ( Fig. 2,PanelA1,A2),whichpresumably caused plaque rupture responsible for ACS. In contrast, OCTin the LAD showed neointima accompanied with homogeneousconcentric high backscatte r structure with calcification in all of thestent area. Within the stable neointima, microvessels with tubularstructures differentiated from any side branches were observed ( Fig. 2,Panel B1, B2). In this LAD lesion, thin cap fibroatheroma was notobserved, which is compatible with a stable plaque. PCI was performedfor in-stent neoatherosclerotic lesions in both distal RCA and proximalLAD with zotarolimus-eluting stents.Inthepresentcase,OCTrevealedtypicalunstableplaquemorphologyin the RCA in-stent lesion, which was the culprit of acute myocardialinfarction treated 16 years prior to the event. Also, OCT found stableplaque morphology in the LAD in-stent segment whose underlyingsegment was the stable lesion. Theref ore, the types of neoatherosclerosiswere different according to the unde rlying plaque, although the BMSimplantation was performed 16years ago.PCI with stenting is the most widely performed procedure for thetreatmentofischemicheartdisease,andthisdeviceimprovedtheclinicalperformance as well [1]. In addition to in-stent restenosis (ISR) and latestent thrombosis, neoatherosclerosis within the stent has been recentlybrought into focus [2,3]. Traditionally, intimal hyperplasia after BMSimplantation has been considered stable, with an early peak between6 months and 1 year at late quiescent period thereafter [4].However,Kimura et al. demonstrated that lat e luminal re-narrowing was commonbeyond 4years following BMS implantation [5]. Hasegawa et al. reportedthat atherosclerotic progression occurred in the in-stent intima of BMSmore than 5years after stent deployment based on pathological analysis[6]. OCT has demonstrated its potential capacity to accurately char-acterize or evaluate the responses after stent deployment. Habara et al.reported that the qualitative OCT findings of BMS restenosis tissuebetween very-late-ISR and early-ISR are signi ficantly different [6].Basedon their OCT analysis, the restenosis lesions N5years after BMSimplantation were found with a high incidence (90.7%) accompaniedwith heterogeneous OCT appearance with low-density area, whereaslesions b1 year after BMS implantation showed extremely lowerincidence (17.9%) of neoatherosclerosis [7]. Nakazawa et al. reportedthat an underlying unstable lesion, which included ruptured plaque andthin-cap fibroatheroma, is an independent risk factor for neo-atheroscrelosis [3]. It has been reported that the quality of underlyingplaque has influenced the incidence of neatherosclerosis after stenting[3], however, it is not known whether the quality of the underlyingplaque affects neoatherosclerotic process. In the present case, based onOCT analysis, the observed neointima demonstrated very similar

Coagulation factors are known to play a role in wound healing by stimulating fibroblasts and might be associated with tissue fibrosis, however, only limited data exist. Protease-activated receptor 1 (PAR1), activated by thrombin or factor (F) Xa, and PAR2, activated by FXa, have recently been reported to play roles not only in the coagulation system, but also in cardiac fibrosis. Furthermore, a previous report found that FX deficiency in mice led to the development of cardiac fibrosis. Therefore, in the present study, we evaluated cellular biological function under conditions of overexpressed thrombin and FXa in fibroblasts.Cell migration and proliferation with FXa (1U/mL) and thrombin (1U/mL) stimulation were evaluated. Cells incubated without FXa or thrombin were used as control. H2O2 and TGF-β1 production were measured using ELISA. Signal pathways were evaluated using a signal pathway reporter assay.Cell migration and proliferation were increased in FXa-stimulated cells (4.1-fold increase for migration, 1.3-fold for proliferation compared with control, respectively) and thrombin (4.1-fold increase for migration, 1.3-fold for proliferation as compared to control, respectively). H2O2 production was higher in FXa-stimulated cells compared to thrombin (1.3-fold increase) and control cells (1.4-fold increased). TGF-β1 production was up-regulated after FXa addition (12.6-fold increase compared with thrombin, 1.8-fold increase compared with control, respectively). In FXa-stimulated cells, AP-1 and NF-kB were increased compared to control (P < 0.05).These data suggest that FXa and thrombin play important roles in the fibrotic process that could also lead to cardiac fibrosis, and that at least some of these signalings are more accelerated with FXa compared to thrombin.

Soluble fms-like tyrosine kinase 1 (sFlt-1) is an endogenous inhibitor of vascular endothelial growth factor, which is involved in cardiovascular remodeling and atherosclerosis development. To examine the predictive role of sFlt-1 levels in patients with asymptomatic heart failure, we measured circulating sFlt-1 in patients with or without coronary artery disease (CAD). We analyzed 88 Japanese patients with CAD or patients at high risk for atherosclerosis and who were undergoing total risk management for cardiovascular disease prevention. Circulating sFlt-1 levels correlated with the increase in plasma brain natriuretic peptide levels (ΔBNP) from baseline to the observed levels 5 years later in CAD patients, patients with previous myocardial infarction, and men. ΔBNP levels correlated with sFlt-1 levels in the high-sFlt-1 patients with CAD (r = 0.511, P0.01). In all patients, end-systolic volume index (ΔESVI) increased in correlation with a decrease in left ventricular ejection fraction (ΔEF) in the long-term observation, independent of their history of myocardial infarction (ΔESVI = 2.5 mL/m(2) increase/year). Baseline level of sFlt-1 was independent of ΔESVI or ΔEF. The present 5-year observational study demonstrated that high sFlt-1 levels predicted moderate increases in BNP levels in CAD patients. Moreover, ΔBNP was correlated with ΔESVI/year in CAD patients with high-sFlt-1 levels. These data suggest that high sFlt-1 levels may be an effective biomarker to predict the progression of heart failure in patients with CAD.

Purpose: Factor Xa inhibitors are anticoagulants to reduce in stroke and other thromboembolic events. Fondaparinux (FDP) is an approved indirect factor Xa inhibitor to prevent venous thromboembolism. It is known that the proliferation of cardiac fibroblasts leads the fibrosis of coronary vessels, which are deeply associated with the progression of coronary atherosclerosis, and cardiac remodeling to cause heart failure in clinical settings. However, the effect of FDP in cardiac fibroblasts for the development of atherosclerosis and cardiac remodeling is still remaining unclear. Therefore, we aim to evaluate the functional role of FDP in mouse cardiac fibroblasts stimulated by hydrogen peroxide (H2O2). Materials and methods: Confluent fibroblasts were pretreated with or without FDP (0.34 μg/ml) for 6 hours, and then stimulated by H2O2 in various times. Reactive oxygen species (ROS) were measured by DCFDA method. Cell proliferation was measured by MTT assay after 12 and 24 hours of H2O2 stimulation (25 μM). Interleukin (IL)-6, tumor necrosis factor (TNF)-α, and tissue growth factor (TGF)-β productions were evaluated by ELISA after 12, 24 and 48 hours of H2O2 stimulation (25 μM), respectively. Results: H2O2 stimulation by itself induced excessive ROS production and cell proliferation in mouse cardiac fibroblast. H2O2 (25 mM) induced cell proliferation was significantly decreased in FDP-pretreated cardiac fibroblasts compared to cells without FDP (86% decrease in 24 hours). Although H2O2 had no effect in TNF-α and TGF-β production, IL-6 production was significantly enhanced by FDP pretreatment (84% increase in 48 hours). Conclusion: These data suggest that the pleiotropic effects of factor Xa inhibitor may provide favorable effects on cardiovascular disease prevention, at least part of in vitro model.

Purpose: Placental growth factor (PlGF) is a member of the vascular endothelial growth factor family, has been reported to be rapidly produced in acute phase of myocardial infarction and that the loss of PlGF reduces lesion growth in atherosclerosis animal models. On the other hand, it is known that the proliferation of cardiac fibroblasts (CFs) lead the fibrosis to coronary vessels which are associated with the progression of atherosclerosis. However, the molecular signals of PlGF in fibroblasts for the development of atherosclerosis are still unclear. Therefore, we analyzed cellular biological function of PlGF under Angiotensin II (AngII) stimulation, a potent inflammatory agent, using mouse cardiac and retrovirally introduced PlGF embryonic fibroblasts. Materials and methods: Retrovirally introduced PlGF mouse embryonic fibroblasts derived from C57BL/6 mice, were made by deficient retrovirus vector and were designated as C57/PlGF. Only retrovirus vector introduced C57 cells (C57/EV) were used as control. After AngII stimulation, cell migration, proliferation, reactive oxygen species (ROS), NF-kB activation, IL-6 and TNF-α production of C57/PlGF were evaluated. Cell proliferation was also measured in presence of MAPK-p38 inhibitor, SB205580. Then we assessed AngII-induced cell proliferation of mouse CFs incubated with10% supernatant of C57/PlGF. Results: The products of introduced PlGF in C57/PlGF were confirmed by ELISA (1093.48±3.5 pg/ml, mean ±SE). AngII-induced cell migration, proliferation and H2O2 production were significantly increased in C57/PlGF compared with C57/EV (6.5-time for migration, 1.3-time for proliferation, 1.9-time higher for H2O2 production, respectively). SB205580 inhibited the AngII-induced cell proliferation in C57/PlGF (32% decrease). In C57/PlGF cells, NF-kB activation was dramatically high, followed by significant up-regulation of IL-6 production. TNF-α production was also significantly increased in C57/PlGF cells compared to C57EV (1.8-time higher). CFs cell proliferation increased significantly in cells stimulated with C57/PlGF supernatant (1.3 times higher than those with 10% C57/EV supernatant, P

The risk of cardiovascular complication in a diabetes patient is similar to that in a nondiabetic patient with a history of myocardial infarction. Although intensive control of glycemia achieved by conventional antidiabetic agents decreases microvascular complications such as retinopathy and nephropathy, no marked effect has been reported on macrovascular complications or all-cause mortality. Evidence from VADT, ACCORD, and ADVANCE would suggest that glycemic control has little effect on macrovascular outcomes. Moreover, in the case of ACCORD, intensive glycemic control may be associated with an increased risk of mortality. There is sufficient evidence that suggests that postprandial hyperglycemia may be an independent risk factor for cardiovascular disease in diabetes patients. However, there are no prospective clinical trials supporting the recommendation that lowering postprandial blood glucose leads to lower risk of cardiovascular outcomes. Mitiglinide is a short-acting insulinotropic agent used in type 2 diabetes treatment. It has a rapid stimulatory effect on insulin secretion and reduces postprandial plasma glucose level in patients with type 2 diabetes. Because of its short action time, it is unlikely to exert adverse effects related to hypoglycemia early in the morning and between meals. Mitiglinide reduces excess oxidative stress and inflammation, plays a cardioprotective role, and improves postprandial metabolic disorders. Moreover, mitiglinide add-on therapy with pioglitazone favorably affects the vascular endothelial function in type 2 diabetes patients. These data suggest that mitiglinide plays a potentially beneficial role in the improvement of postprandial hyperglycemia in type 2 diabetes patients and can be used to prevent cardiovascular diseases. Although the results of long-term, randomized, placebo-controlled trials for determining the cardiovascular effects of mitiglinide on clinical outcomes are awaited, this review is aimed at summarizing substantial insights into this topic.