Fibroblasts activation by embryonic signal switching: A novel mechanism of placental growth factor-induced cardiac remodeling.

INTRODUCTION: Cardiac remodeling is defined as cellular interstitial changes that lead dysfunction of the heart after injury. Placental growth factor (PlGF), a member of the VEGF family, has been reported to regulate cardiac hypertrophy in hemodynamic state. We therefore analyze the function of PlGF during cardiac remodeling using cardiac cells and fibroblasts, under Angiotensin II (AngII) stimulation. METHODS: PlGF overexpressed mouse embryonic fibroblasts derived from C57BL/6 mice, were made by deficient retrovirus vector, designated as C57/PlGF. Only retrovirus vector introduced C57 cells (C57/EV) were used as control. After AngII stimulation, wound scratching assay and MTT proliferation assay with or without p38 MAPK inhibitor, SB205580 were performed in retrovirally-introduced C57 cells. Reactive oxygen species (ROS) production, NF-kB activation, IL-6 and TNF-α production were also measured. Then we assessed AngII-induced cell proliferation of mouse cardiac fibroblasts (CFs) and rat primary cardiomyocytes incubating with C57/PlGF conditioned-medium. RESULTS: The PlGF production in C57/PlGF were confirmed by ELISA (1093.48 ± 3.5 pg/ml, ±SE). AngII-induced cell migration, proliferation and H2O2 production were increased in C57/PlGF compared with C57/EV. SB205580 inhibited the AngII-induced cell proliferation in C57/PlGF. In C57/PlGF cells, NF-kB activation was higher, followed by up-regulation of IL-6 and TNF-α production. CFs and cardiomyocytes proliferation increased when stimulated with C57/PlGF conditioned-medium. DISCUSSION: The activation of fibroblast is stimulated by PlGF signaling via p38 MAPK/NF-kB pathway accompanied by elevation of ROS and inflammatory response. Furthermore, these signals stimulate the activation of CFs and cardiomyocytes, indicating that high circulating level of PlGF have a potential to regulate cardiac remodeling.

Association between instrumental activities of daily living frequency and clinical outcomes in older patients with cardiovascular disease.

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.

Variation in heart rate range by 24-h Holter monitoring predicts heart failure in patients with atrial fibrillation.

AIMS: The analysis of heart rate (HR) changes, such as the HR variability or HR turbulence, has been reported as a marker of cardiovascular events during sinus rhythm; however, those relationships during atrial fibrillation (AF) remain controversial, and those parameters are not commonly used in AF patients. We sought to investigate the relationship between a simple index focused on the HR and heart failure (HF) events in patients with permanent AF. METHODS AND RESULTS: We enrolled 198 patients with permanent AF and evaluated the HR range, defined as the maximum HR minus the minimum HR on 24-h Holter electrocardiogram recordings. The patients were divided into two groups, i.e., the larger (n = 101) and smaller (n = 97) HR range (HRR) groups, determined by the median value. The HF events were defined as hospitalizations for HF or urgent hospital visits due to exacerbations of one's HF status. The observation period of this study was set at 5 years from registration. The median age was 73 (68-77) years, and 29% were female. The median HRR was 84 (63-118) beats per minutes (bpm). During the observational period of 1825 days (median), HF events occurred in 37 (0.047 per patient-year) patients. In a log-rank test, the larger HRR group had more frequent HF events than the smaller HRR group (P = 0.0078). In the adjusted Cox proportional hazards model using the significantly different factors from the univariate analysis (Model 1) and factors and medications associated with HF (Model 2), the larger HRR group had a higher prevalence of HF events than the smaller HRR group for both models [Model 1, adjusted hazard ratio = 3.21, 95% confidence interval (CI) 1.593-6.708, P = 0.0009; Model 2, adjusted hazard ratio = 3.12, 95% CI 1.522-6.685, P = 0.002]. When analysed using the time-dependent Cox proportional hazards model, the HRR was associated with HF with a statistically significant difference in both the univariate and multivariate analyses [hazard ratio = 1.01, 95% CI 1.006-1.020, P = 0.0002; Model 1, adjusted hazard ratio = 1.02, 95% CI 1.011-1.027, P < 0.0001; Model 2, adjusted hazard ratio = 1.01, 95% CI 1.008-1.021, P = 0.0003). There was no significant difference in the chronotropic medications between the two groups. CONCLUSIONS: In patients with permanent AF, a larger HRR was associated with HF events.

Design of Functional Electrospun Scaffolds Based on Poly(glycerol sebacate) Elastomer and Poly(lactic acid) for Cardiac Tissue Engineering.

Many works focus on the use of polyesters such as 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 or 120 °C to achieve two different cross-linking densities. The designed scaffolds were considered for cytocompatibility, biocompatibility, biodegradability, and 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 or laminin coating, commonly used cell culture matrices. PLA:PGS scaffolds associated with Matrigel or laminin allow an increased material-cell interaction. Moreover, the cardiomyocytes seeded on such scaffolds acquire a morphology similar to that observed in native tissue, the result being more remarkable on fibers having the smallest diameter and the highest PGS cross-linking density. In addition, these scaffolds induce neovascularization without an inflammatory response and foreign body giant cell response after grafting on a mouse heart. Hence, the improved biocompatibility and the ability to support cardiomyocyte development suggest that thin PLA:PGS scaffolds could be promising biomaterials for cardiac application.

Lower Level of Low Density Lipoprotein Cholesterol is Associated with a Higher Increase in the Fractional Flow Reserve in Patients with Fixed-dose Rosuvastatin.

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 ElementTM or Promus Element PlusTM). 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.

Amotl1 mediates sequestration of the Hippo effector Yap1 downstream of Fat4 to restrict heart growth.

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.

Effects on bone metabolism markers and arterial stiffness by switching to rivaroxaban from warfarin in patients with atrial fibrillation.

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.

Ezetimibe enhances and stabilizes anticoagulant effect of warfarin.

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 < 0.001). It was necessary to reduce the warfarin dose in 9 of 101 patients for clinical indication. There was a significant positive correlation between change in PT-INR and statin usage at baseline (p = 0.03). The mean value of changes in PT-INR of patients with taking statin was significantly larger than that of patients without taking statin (0.34 ± 0.54 vs. 0.06 ± 0.36, p = 0.03). There was an increase in the TTR (52 ± 26 to 61 ± 23 %, p < 0.0001) and a decrease in the frequency to change the dose of warfarin after the ezetimibe treatment [45 times of 735 examination days (6 %) to 20 times of 695 examination days (3 %), p = 0.02]. Our data suggest possible drug interaction between warfarin and ezetimibe. Ezetimibe may increase and stabilize the anticoagulant effect of warfarin, especially in patients taking statins.

Teneligliptin improves left ventricular diastolic function and endothelial function in patients with diabetes.

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.

Neointimal coverage of zotarolimus-eluting stent at 1, 2, and 3 months' follow-up: an optical coherence tomography study.

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.

Long-term warfarin therapy and biomarkers for osteoporosis and atherosclerosis.

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 < 0.01), similarly, the RANKL levels in the WF group were higher than those in the non-WF group (0.60 ± 0.06 vs. 0.37 ± 0.05 ng/mL; P = 0.007). Moreover, RH-PAT index was significantly lower in the WF group compared to those in the non-WF group (1.48 ± 0.11 vs. 1.88 ± 0.12; P = 0.017). CONCLUSIONS: Long-term warfarin therapy may be associated with bone mineral loss and vascular calcification in 60-80 year old hypertensive patients.

Rivaroxaban Inhibits Angiotensin II-Induced Activation in Cultured Mouse Cardiac Fibroblasts Through the Modulation of NF-κB Pathway.

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.

Clinical outcomes of chronic kidney disease patients treated with everolimus-eluting stents (EES) and paclitaxel-eluting stents (PES).

BACKGROUND: 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. METHODS: Hundred and forty seven CKD patients (eGFR<60mLmin(-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. RESULTS: 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, P<0.01). 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. CONCLUSIONS: In CKD patients, PES was associated with worse clinical outcomes in non-HD patients as compared with EES.

Factor Xa in mouse fibroblasts may induce fibrosis more than thrombin.

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-ß1 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-ß1 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 is a novel predictor of brain natriuretic peptide elevation.

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.

Postprandial hyperglycemia and endothelial function in type 2 diabetes: focus on mitiglinide.

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.