Taiki Tojo

Elevated circulating levels of an incretin hormone, glucagon-like peptide-1, are associated with metabolic components in high-risk patients with cardiovascular disease

BackgroundGlucagon-like peptide-1 (GLP-1) is an incretin hormone that has a wide range of effects on glucose metabolism and cardiovascular function (e.g., improving insulin sensitivity, reduction in appetite, modulation of heart rate, blood pressure and myocardial contractility). Metabolic syndrome (MetS) is associated with an increased risk of developing atherosclerotic cardiovascular diseases. Novel glycemic control drugs, the dipeptidyl-peptidase-4 (DPP-4) inhibitors, work by inhibiting the inactivation of incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). In spite of good effects of these drugs in diabetic patients, circulating levels of incretins and their role in MetS are largely unknown.MethodsTo examine relationships between incretin hormones and MetS risk factors, we measured circulating levels of incretins in obese high-risk patients for cardiovascular disease. Fasting serum GLP-1 and GIP levels were measured by ELISA. We performed a cross-sectional analysis of metabolic variables in the fasting state in two subject groups: with MetS (n = 60) and pre-MetS (n = 37).ResultsFasting levels of Serum GLP -1 in the peripheral circulation were significantly increased correlated with the accumulation of MetS risk factors components (r = 0. 470, P < 0.001). There was a significant interaction between circulating GLP-1 and GIP, serum high-density lipoprotein cholesterol, triglyceride, and serum uric acid concentrations but not waist circumference, fasting glucose, HbA1c, or presence of diabetes.ConclusionCirculating levels of GLP-1 in relation to the accumulation in MetS factors suggested that MetS patients with elevated levels of GLP-1 are high-risk patients for cardiovascular disease, independent with the presence of diabetes.

C-reactive protein-induced production of interleukin-18 in human endothelial cells: a mechanism of orchestrating cytokine cascade in acute coronary syndrome

The circulating interleukin (IL)-18 level is a strong predictor of death from cardiovascular causes in patients with coronary artery disease. However, the mechanisms of IL-18 in orchestrating the cytokine cascade and the accelerator of IL-18 production in atherosclerosis are still unknown. In the present study, we measured the serum concentration of IL-18 and other markers of inflammation in 35 patients with acute coronary syndrome. To determine the mechanism of accelerating IL-18 production, we examined the release of IL-18 in human endothelial cells using human recombinant (hr) C-reactive protein (CRP) as a stimulator of IL-18. Furthermore, we investigated the inhibitory effects of hr IL-10 on IL-18 production by hr CRP in human endothelial cells. Circulating levels of IL-18 were significantly higher in patients with acute myocardial infarction than in patients with unstable angina. Incubation with hr CRP, which was equivalent to the serum concentration in patients with acute coronary syndrome, induced IL-18 release. Treatment with hr IL-10 inhibited IL-18 release in the cells stimulated with hr CRP. The serum level of IL-18 was identified as a marker of severity in acute coronary syndrome. Our findings reveal the possibility that circulating CRP by itself could cause a deterioration of the inflammatory cascade in endothelial cells associated with the upregulation of IL-18. This suggests that CRP may contribute to the mechanism of coronary artery disease in addition to being an incidental product of various types of systemic inflammation.

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.

Circulating interleukin-18: A specific biomarker for atherosclerosis-prone patients with metabolic syndrome

BackgroundMetabolic syndrome (MetS) is associated with an increased risk of the development of atherosclerotic cardiovascular disease (CVD). Interleukin-18 (IL-18), which is a pleiotropic proinflammatory cytokine with important regulatory functions in the innate immune response system, plays a crucial role in vascular pathologies. IL-18 is also a predictor of cardiovascular death in patients with CVD and is involved in atherosclerotic plaque destabilization.ResultsIn order to determine if circulating levels of IL-18 can serve as a specific biomarker for distinguishing MetS patients from pre-MetS subjects, we studied 78 patients with visceral fat deposition and 14 age-matched control subjects. Increased levels of IL-18 were observed more frequently in patients with MetS than in pre-MetS subjects and were positively associated with waist circumference. Serum levels of IL-18 were significantly reduced by a change in weight caused by lifestyle modifications. There was a significant interaction between waist circumference and serum IL-18 concentration. Weight loss of at least 5% of the body weight caused by lifestyle modification decreased IL-18 circulating levels relative to the reduction in waist circumference and blood pressure, suggesting that this degree of weight loss benefits the cardiovascular system.ConclusionIL-18 may be a useful biomarker of the clinical manifestations of MetS and for the management of the risk factors of CVD.

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.

Two-week interval optical coherence tomography: imaging evidence on neointimal coverage completion after implantation of the Endeavor zotarolimus-eluting stent.

To obtain imaging evidence by 2‐week optical coherence tomography (OCT) on the completion of neointimal coverage (NIC; the percentage of stent strut coverage and thickness of the formed neointima) completion after implantation of the Endeavor zotarolimus‐eluting stent (E‐ZES).

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.

Ezetimibe and Reactive Oxygen Species

Ezetimibe is a potent inhibitor of cholesterol absorption that has been approved for the treatment of hypercholesterolemia. Statin, 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is an inhibitor of cholesterol synthesis. Statin is the first-choice drug to reduce low-density lipoprotein (LDL)-cholesterol for patients with hypercholesterolemia, due to its strong effect to lower the circulating LDL-cholesterol levels. Because a high dose of statins causes concern about rhabdomyolysis, it is sometimes difficult to achieve the guideline-recommended levels of LDL-cholesterol in patients with high LDL-cholesterol treated with statin monotherapy. Ezetimibe has been reported to reduce LDL-cholesterol safely with both monotherapy and combination therapy with statins. Ezetimibe is especially expected to be the best pharmacological option for the treatment of patients unable to achieve LDL-cholesterol goals with statins. Reactive oxygen species (ROS) are produced at low levels to maintain physiological redox balance. Oxidative stress results when ROS production exceeds the ability of cells to detoxify ROS. Overproduction of ROS damages cellular components, including lipids, leading to decline in physiological function and cell death. Oxidative stress exacerbates atherosclerosis, the major risk factor for coronary artery disease and ischemic stroke, at every step involves the accumulation of oxidized LDL in the arteries, leading to foam cell formation, plaque development, and plaque rupture. This review focuses on the recent findings of ezetimibe-related atheroprotective effects in vasculature. Moreover, known and proposed mechanisms of how ezetimibe could improve ROS-induced pro-atherosclerotic conditions in vasculature are discussed; these effects may help to explain the mechanisms by which ezetimibe may protect vascular from atherosclerosis.

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.

Lower limb ischemia due to popliteal artery compression by Baker cyst

A Baker cyst is the most common mass around the knee joint. It is mostly asymptomatic; however, it may cause knee pain or focal swelling because of compression of vein or nerve. Herein, we report a case of Baker cyst obstructing arterial flow and causing intermittent claudication. An attached polycystic mass was found posterior to the popliteal artery. Needle aspiration was ineffective, and the patient experienced recurrent lower leg pain. Surgical resection was performed, and the patient became symptom free. Baker cyst may cause lower limb ischemia through obstruction of arterial flow, requiring surgical intervention.