Discovery of new strategy for AF

Atrial fibrillation（AF） is one of the most common arrhythmia. Various tools such as portable electrocardiogram（ECG） and implantable cardiac monitor have been available for diagnosis of AF. In addition, the treatment for AF has progressed remarkably in accompany with the development of anticoagulant therapy and catheter ablation. However, it remains unknown about the pathophysiology of AF such as inflammation. In this regard, there is still room for the further progress in diagnostic and therapeutic methods for AF. We reported previously that local production of pentraxin（PTX） 3 in the left atrium might reflect the local inflammation of AF. In addition, we also reported that local production of microRNA（miR）-328 in the left atrium might be involved in the process of atrial remodeling in patients with AF. Based on these results, it is suggested that plasma concentrations of PTX3 or miR-328 might be used as a new biomarker for AF. For the development of preventive strategies, the ability to identify risk markers for new-onset AF is critical. We have shown that a new combined score including age, premature atrial contraction count, maximum RR interval, and left atrial diameter could help characterize the risk of new-onset AF. Activated factor X（FXa）, which contributes to chronic inflammation via protease-activated receptor 2（PAR-2）, might play an important role in AF arrhythmogenesis. We have recently shown that angiotensin II-treated PAR-2 deficient mice had a lower incidence of AF and less atrial fibrosis compared to wild-type mice treated with angiotensin II. We also have shown that rivaroxaban, but not warfarin, reduced AF inducibility and collagen volume fraction in the atrium. These findings suggested the possibility of Xa inhibitors as therapeutic agents for the onset and progression of AF through the new mechanism. I would like to continue working on the development of new diagnostic and therapeutic methods for arrhythmia including AF

A novel Doppler echocardiographic index integrating left and right ventricular function is superior to conventional indices for predicting adverse outcome of acute myocardial infarction

The ratio of peak diastolic early velocity (E) of left ventricular (LV) inflow to peak diastolic longitudinal velocity (e’) of the mitral annulus (E/e’) is thought to reflect LV filling pressure, and tricuspid annulus velocity at systole (s’-T) is thought to reflect right ventricular function. However, it has not been reported on significance of the combined use of E/e’ and (s’-T) to predict outcome of acute myocardial infarction (AMI). Over 21 months, beginning in January 2007, we enrolled 65 AMI patients who were measured hemodynamic and echocardiographic parameters by Swan-Ganz (SG) catheterization just after reperfusion therapy and echocardiography immediately after reperfusion therapy. Cardiac index (CI) and pulmonary capillary wedge pressure (PCWP) via SG catheter were measured, and routine echocardiographic indices, including E, e’, E/e’, and (s’-T) were determined. In addition, we defined the functional integrated bi-myocardial tissue Doppler (FIT) index as (s’-T)÷E/e’. The relationships between CI, PCWP, and echocardiographic indices were investigated, including FIT index. Moreover, we investigated whether FIT index could predict adverse cardiac events. FIT index was significantly associated with not only CI but also PCWP. In the Cox proportional hazards model, FIT index<1.0 was a significant predictor for adverse outcome of AMI after adjustment for age, Killip class, history of previous coronary revascularization, location of culprit lesion, and LV ejection fraction. The novel index defined as (s’-T)÷E/e’ could be quite useful predictor of prognosis in AMI

Ipragliflozin Attenuates Endothelial Dysfunction

Background: Endothelial dysfunction caused by increased oxidative stress is a critical initiator of macro- and micro-vascular disease development in diabetic patients. Ipragliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, offers a novel approach for the treatment of diabetes by enhancing urinary glucose excretion. The aim of this study was to examine whether ipragliflozin attenuates endothelial dysfunction in diabetic mice. Methods: Eight-week-old male C57BL/6 mice were treated with streptozotocin (150 mg/kg) by a single intraperitoneal injection to induce diabetes mellitus. At 3 days of injection, ipragliflozin (3 mg/kg/day) was administered via gavage for 3 weeks. Vascular function was assessed by isometric tension recording. Human umbilical vein endothelial cells (HUVEC) were used for in vitro experiments. RNA and protein expression were examined by quantitative RT-PCR (qPCR) and western blot, respectively. Oxidative stress was determined by measuring urine 8-hydroxy-2′-deoxyguanosine (8-OHdG) level. Results: Ipragliflozin administration significantly reduced blood glucose level (P < 0.001) and attenuated the impairment of endothelial function in diabetic mice, as determined by acetylcholine-dependent vasodilation (P < 0.001). Ipragliflozin did not alter metabolic parameters, such as body weight and food intake. Ipragliflozin administration ameliorated impaired phosphorylation of Akt and eNOSSer1177 in the abdominal aorta and reduced reactive oxygen species generation as determined by urinary excretion of 8-OHdG in diabetic mice. Furthermore, qPCR analyses demonstrated that ipragliflozin decreased the expression of inflammatory molecules [e.g., monocyte chemoattractant protein-1 (MCP-1) vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule (ICAM)-1] in the abdominal aorta (P < 0.05). In in vitro studies, incubation with methylglyoxal, one of the advanced glycation end products, significantly impaired phosphorylation of Akt and eNOSSer1177 (P < 0.01) and increased the expression of MCP-1, VCAM-1, and ICAM-1 in HUVEC. Conclusion: Ipragliflozin improved hyperglycemia and prevented the development of endothelial dysfunction under a hyperglycemic state, at least partially by attenuation of oxidative stress

Azilsartan, an angiotensin II type 1 receptor blocker, restores endothelial function by reducing vascular inflammation and by increasing the phosphorylation ratio Ser1177/Thr497 of endothelial nitric oxide synthase in diabetic mice

BACKGROUND: Azilsartan, an angiotensin II type 1 (AT1) receptor blocker (ARB), has a higher affinity for and slower dissociation from AT1 receptors and shows stronger inverse agonism compared to other ARBs. Possible benefits of azilsartan in diabetic vascular dysfunction have not been established. METHODS: We measured vascular reactivity of aortic rings in male KKAy diabetic mice treated with vehicle, 0.005% azilsartan, or 0.005% candesartan cilexetil for 3 weeks. Expression of markers of inflammation and oxidative stress was measured using semiquantitative RT-PCR in the vascular wall, perivascular fat, and skeletal muscle. Phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser(1177) and Thr(495) was measured using Western blotting, and the ratio of phosphorylation at Ser(1177) to phosphorylation at Thr(495) was used as a putative indicator of vascular eNOS activity. RESULTS: (1) Vascular endothelium–dependent relaxation with acetylcholine in KKAy mice was improved by azilsartan treatment compared to candesartan cilexetil; (2) the ratio of Ser(1177)/Thr(495) phosphorylation of eNOS was impaired in KKAy and was effectively restored by azilsartan; (3) anomalies in the expression levels of monocyte chemotactic protein 1 (MCP1), F4/80, NAD(P)H oxidase (Nox) 2, and Nox4 of the aortic wall and in the expression of TNFα in the perivascular fat were strongly attenuated by azilsartan compared to candesartan cilexetil. CONCLUSIONS: These results provide evidence that azilsartan prevents endothelial dysfunction in diabetic mice, more potently than does candesartan cilexetil. Azilsartan’s higher affinity for and slower dissociation from AT1 receptors may underlie its efficacy in diabetic vascular dysfunction via a dual effect on uncoupled eNOS and on Nox

シンボウ サイドウ ト ソクセンショウ : イツ ドノヨウナ チリョウ オ ハジメルカ

Atrial fibrillation（AF）is a common arrhythmia and the prevalence of this arrhythmia is increasing as aging. Secondary AF is defined as AF with organic heart disease and lone AF as AF without it. The AF is divided into paroxysmal, persistent and chronic by its onset and persistence. It is clinically important that any type AF causes thromboembolic stroke. The preventive Qumadin therapy should be applied to patients with AF. Transesophageal echocardiography has been utilized for the diagnosis of left atrial thrombus and for the prediction of stroke. CHADS２ score is a clinical prediction rule for estimating the risk of stroke in patients with non-rheumatic AF. Patients with CHADS２ score_１should be treated with Qumadin. Rhythm control and rate control are two different strategies for the treatment of AF. There is no evidence that indicate better choice between rhythm control and rate control. Recently, inhibitors of the renin-angiotensin system have a potential to prevent new onset of AF in patients who has risk factors

3Dマッピングシステムを用いた両心房Stimulus-V mapによる順行性速伝導路入口部の解剖学的位置並び特徴の検討

Purpose Previous studies examined the right atrial (RA) input site of the antegrade fast pathway (AFp) (AFpI). However, the left atrial (LA) input to the atrioventricular (AV) node has not been extensively evaluated. In this study, we created three-dimensional (3-D) bi-atrial stimulus-ventricle (St-V) maps and analyzed the input site and characteristics of the AFp in both the RA and LA. Methods Forty-four patients diagnosed with atrial fibrillation or WPW syndrome were included in this study. Three-dimensional bi-atrial St-V mapping was performed using an electroanatomical mapping system. Sites exhibiting the minimal St-V interval (MinSt-V) were defined as AFpIs and were classified into seven segments, four in the RA (F, S, M, and I) and three in the LA (M1, M2, and M3). By combining the MinSt-V in the RA and LA, the AFpIs were classified into three types: RA, LA, and bi-atrial (BA) types. The clinical and electrophysiological characteristics were compared. Results AFpIs were most frequently observed at site S in the RA (34%) and M2 in the LA (50%), and the BA type was the most common (57%). AFpIs in the LA were recognized in 75% of the patients. There were no clinical or electrophysiological indicators for predicting AFpI sites. Conclusions Three-dimensional bi-atrial St-V maps could classify AFpIs in both the RA and LA. AFpIs in the LA were frequently recognized. There were no significant clinical or electrophysiological indicators for predicting AFpI sites, and 3-D bi-atrial St-V mapping was the only method to reveal the precise AFp input site

Effects of dabigatran on diabetic endothelial dysfunction

Diabetic patients have coagulation abnormalities, in which thrombin plays a key role. Whereas accumulating evidence suggests that it also contributes to the development of vascular dysfunction through the activation of protease-activated receptors (PARs). Here we investigated whether the blockade of thrombin attenuates endothelial dysfunction in diabetic mice. Induction of diabetes by streptozotocin (STZ) increased the expression of PAR1, PAR3, and PAR4 in the aorta. STZ-induced diabetic mice showed impairment of endothelial function, while the administration of dabigatran etexilate, a direct thrombin inhibitor, significantly attenuated endothelial dysfunction in diabetic mice with no alteration of metabolic parameters including blood glucose level. Dabigatran did not affect endothelium-independent vasodilation. Dabigatran decreased the expression of inflammatory molecules (e.g., MCP-1 and ICAM-1) in the aorta of diabetic mice. Thrombin increased the expression of these inflammatory molecules and the phosphorylation of IκBα, and decreased the phosphorylation of eNOSSer1177 in human umbilical endothelial cells (HUVEC). Thrombin significantly impaired the endothelium-dependent vascular response of aortic rings obtained from wild-type mice. Inhibition of NF-κB attenuated thrombin-induced inflammatory molecule expression in HUVEC and ameliorated thrombin-induced endothelial dysfunction in aortic rings. Dabigatran attenuated the development of diabetes-induced endothelial dysfunction. Thrombin signaling may serve as a potential therapeutic target in diabetic condition

Inhibition of activated factor X by rivaroxaban attenuates neointima formation after wire-mediated vascular injury

Accumulating evidence suggests that activated factor X (FXa), a key coagulation factor, plays an important role in the development of vascular inflammation through activation of many cell types. Here, we investigated whether pharmacological blockade of FXa attenuates neointima formation after wire-mediated vascular injury. Transluminal femoral artery injury was induced in C57BL/6 mice by inserting a straight wire. Rivaroxaban (5 mg/kg/day), a direct FXa inhibitor, was administered from one week before surgery until killed. At four weeks after surgery, rivaroxaban significantly attenuated neointima formation in the injured arteries compared with control (P<0.01). Plasma lipid levels and blood pressure were similar between the rivaroxaban-treated group and non-treated group. Quantitative RT-PCR analyses demonstrated that rivaroxaban reduced the expression of inflammatory molecules (e.g., IL-1β and TNF-α) in injured arteries at seven days after surgery (P<0.05, respectively). In vitro experiments using mouse peritoneal macrophages demonstrated that FXa increased the expression of inflammatory molecules (e.g., IL-1β and TNF-α), which was blocked in the presence of rivaroxaban (P<0.05). Also, in vitro experiments using rat vascular smooth muscle cells (VSMC) demonstrated that FXa promoted both proliferation and migration of this cell type (P<0.05), which were blocked in the presence of rivaroxaban. Inhibition of FXa by rivaroxaban attenuates neointima formation after wire-mediated vascular injury through inhibition of inflammatory activation of macrophages and VSMC

P2Y12阻害薬チカグレロールはアポリポ蛋白E欠損マウスの血管障害を軽減して動脈硬化形成を抑制する

Background and aims: Ticagrelor reduces cardiovascular events in patients with acute coronary syndrome (ACS). Recent studies demonstrated the expression of P2Y12 on vascular cells including endothelial cells, as well as platelets, and suggested its contribution to atherogenesis. We investigated whether ticagrelor attenuates vascular dysfunction and inhibits atherogenesis in apolipoprotein E-deficient (apoe-/-) mice. Methods: Eight-week-old male apoe-/- mice were fed a western-type diet (WTD) supplemented with 0.1% ticagrelor (approximately 120 mg/kg/day). Non-treated animals on WTD served as control. Atherosclerotic lesions were examined by en-face Sudan IV staining, histological analyses, quantitative RT-PCR analysis, and western blotting. Endothelial function was analyzed by acetylcholine-dependent vasodilation using aortic rings. Human umbilical vein endothelial cells (HUVEC) were used for in vitro experiments. Results: Ticagrelor treatment for 20 weeks attenuated atherosclerotic lesion progression in the aortic arch compared with control (p < 0.05). Ticagrelor administration for 8 weeks attenuated endothelial dysfunction (p < 0.01). Ticagrelor reduced the expression of inflammatory molecules such as vascular cell adhesion molecule-1, macrophage accumulation, and lipid deposition. Ticagrelor decreased the phosphorylation of JNK in the aorta compared with control (p < 0.05). Ticagrelor and a JNK inhibitor ameliorated impairment of endothelium-dependent vasodilation by adenosine diphosphate (ADP) in wild-type mouse aortic segments. Furthermore, ticagrelor inhibited the expression of inflammatory molecules which were promoted by ADP in HUVEC (p < 0.001). Ticagrelor also inhibited ADP-induced JNK activation in HUVEC (p < 0.05). Conclusions: Ticagrelor attenuated vascular dysfunction and atherogenesis through the inhibition of inflammatory activation of endothelial cells. These effects might be a potential mechanism by which ticagrelor decreases cardiovascular events in patients with ACS