Norikazu Yamada

Rho/Rho-Kinase Pathway Contributes to C-Reactive Protein–Induced Plasminogen Activator Inhibitor-1 Expression in Endothelial Cells

Objective—Rho/Rho-kinase pathway plays pivotal roles in cardiovascular diseases including arteriosclerosis and hypertension. Recently it has become evident that C-reactive protein (CRP), a powerful marker for cardiovascular events, has direct proatherothrombotic effects on vascular cells. However, its molecular mechanism has not been fully investigated. We examined the involvement of Rho/Rho-kinase signaling in CRP-induced plasminogen activator inhibitor-1 (PAI-1) expression in bovine aortic endothelial cells (BAECs). Methods and Results—PAI-1 expression was determined by Western blotting. RhoA activation was determined by an affinity pull-down assay using Rho-binding fragment of rhotekin. NF-&kgr;B activity was determined using the luciferase reporter gene. Incubation of BAECs with human recombinant CRP (≥25 &mgr;g/mL) induced a significant increase in PAI-1 expression. Stimulation of BAECs with CRP significantly increased RhoA activation. Pretreatment with TAT-C3 (a membrane-permeable RhoA inhibitor) and Y-27632 (Rho-kinase inhibitor) significantly inhibited CRP-induced PAI-1 expression. NF-&kgr;B activity was markedly enhanced by CRP and pretreatment with Y-27632 inhibited its activation. Parthenolide, SN50, and BAY 11-7082 (NF-&kgr;B inhibitors) significantly blocked CRP-mediated PAI-1 expression. Conclusions—These data suggested that CRP activates Rho/Rho-kinase signaling, which in turn activates NF-&kgr;B activity, resulting in PAI-1 expression in BAEC. These observations provide evidence for the possible involvement of Rho/Rho-kinase signaling in CRP-induced atherothrombogenesis.

Prospective evaluation of three different diagnostic criteria for disseminated intravascular coagulation

There are three different diagnostic score systems for disseminated intravascular coagulation (DIC) established by the Japanese Ministry Health and Welfare (JMHW), the International Society on Thrombosis and Haemostasis (ISTH) and the Japanese Association for Acute Medicine (JAAM). The JMHW criteria are still used in Japan. In the present study, all three diagnostic criteria were used to prospectively evaluate 413 patients with different underlying diseases of DIC who were treated at the Mie University Hospital (JMHW, n= 166; ISTH, n=143; JAAM, n=291). The odds ratio (95% confidence interval) for death was 1.88 (1.22 - 2.90) in JMHW, 2.55 (1.65 - 3.95) in ISHT and 1.99 (1.19 - 3.32) in JAAM. The platelet count, prothrombin time, fibrin and fibrinogen degradation products and fibrinogen were significantly important for diagnosis of DIC by all three diagnostic criteria. Haemostatic molecular markers were significantly high in all patients and were useful for the diagnosis of DIC. The JAAM diagnostic criteria displayed a high sensitivity for DIC and the ISTH overt-DIC diagnostic criteria displayed a high specificity for DIC. All three diagnostic criteria for DIC were related to a poor patient outcome.

Prognostic significance of early diagnosis in acute pulmonary thromboembolism with circulatory failure

Abstract. Despite the advances in our understanding of venous thromboembolic disease, the prevalence of pulmonary thromboembolism (PTE) at autopsy has not changed over 3 decades. When patients survive long enough to have a diagnosis of massive PTE and start receiving treatment, the outlook is considered to be moderately good. However, the diagnosis is often difficult to obtain and is frequently missed. We hypothesize that mortality of acute PTE is reduced by early diagnosis. Eighty-five patients with acute PTE with circulatory failure who survived 1 h after the onset were divided into two groups: the early Dx group consisted of the patients whose disease was diagnosed as acute PTE within 24 h of the onset, and the Late Dx group included patients whose disease was not diagnosed within 24 h of onset, or died without clinical diagnosis between 1 and 24 h after the onset. Overall mortality was significantly low in the Early Dx group compared with that of the Late Dx group (21.6% vs 67.6%, P < 0.0001). Multiple logistic regression analysis demonstrated that a reduction in in-hospital mortality was associated with early diagnosis (odds ratio for in-hospital death, 0.094; 95% confidence interval, 0.03–0.33). The results of our study suggested that early diagnosis might favorably affect the in-hospital clinical outcome of hemodynamically unstable patients with acute PTE.

Reversible Right Ventricular Regional Non-Uniformity Quantified by Speckle-Tracking Strain Imaging in Patients With Acute Pulmonary Thromboembolism

BACKGROUND The aim of this study was to evaluate the effects of acute right ventricular (RV) pressure overload (RVPO) on RV systolic function and its regional uniformity using speckle-tracking strain analysis in patients with acute pulmonary thromboembolism (APTE). METHODS Twenty-three patients with APTE (mean age, 59 +/- 16 years) and 23 age-matched and gender-matched normal subjects (the control group) were examined using echocardiography. Global and segmental longitudinal RV peak systolic strain (PSS) was analyzed using speckle-tracking strain echocardiography. The heterogeneity of RV regional function was assessed by calculating the standard deviation from 6-segmental PSS divided by the absolute value of global PSS. The standard deviation of the heart rate-corrected intervals from QRS onset to PSS for the 6 segments was used to quantify RV dyssynchrony. RESULTS Patients with APTE had reduced regional PSS, resulting in reduced global PSS and augmented regional heterogeneity, and had delayed myocardial contraction in the basal and mid RV lateral walls, resulting in large dyssynchrony (global PSS, -14 +/- vs -25 +/- 3%; heterogeneity, 0.54 +/- 0.26 vs 0.24 +/- 0.09; dyssynchrony, 91 +/- 38 vs 25 +/- 10 ms; P < .05 vs controls for all comparisons). After the amelioration of acute RVPO by primary treatment, both RV heterogeneity and dyssynchrony returned to normal values. CONCLUSION Speckle-tracking strain echocardiography can effectively quantify reversible RV regional nonuniformity caused by acute RVPO and can characterize the pattern of RV regional impairment in patients with APTE.

Increased tissue factor pathway inhibitor in patients with acute myocardial infarction.

We examined hemostatic abnormalities in 23 patients with acute myocardial infarction (AMI), 10 with pulmonary embolism (PE), and 10 with deep vein thrombosis (DVT). At the onset of AMI, plasma levels of tissue‐type plasminogen activator (t‐PA), PA inhibitor‐I (PAI‐I), fibrin‐D‐dimer, thrombin‐antithrombin complex (TAT), and plasmin‐plasmin inhibitor complex (PPIC) were significantly increased. Both the plasma total TFPI and free‐TFPI levels in the AMI patients were significantly higher than those in the healthy volunteers, PE patients, and DVT patients. There was no significant difference in total TFPI or free‐TFPI among patients with PE, those with DVT, and healthy volunteers. One hour after percutaneous transluminal coronary angioplasty (PTCA) in the AMI group, the total TFPI level was further increased, and it was significantly reduced 24 hr after PTCA, to a level similar to that in healthy volunteers. Free‐TFPI showed a pattern similar to that of total TFPI. The ratio of free‐TFPI/total TFPI was highest 1 hr after PTCA. Increased TFPI in AMI patients might be released from ischemic tissues. Am. J. Hematol. 55:183–187, 1997.

Role of Radial Strain and Displacement Imaging to Quantify Wall Motion Dyssynchrony in Patients With Left Ventricular Mechanical Dyssynchrony and Chronic Right Ventricular Pressure Overload

Left ventricular (LV) deformation with ventricular septal shift is one of the most distinctive echocardiographic observations in patients with chronic right ventricular (RV) pressure overload (PO). However, little is known about the effects of RVPO on LV performance and regional synchrony. Accordingly, our objective was to test the hypothesis that chronic RVPO affects regional wall motion, synchronicity, and global LV function using a novel speckle-tracking approach to quantify and characterize regional LV wall motion dyssynchrony. Displacement and strain imaging echocardiographic studies were performed in 20 patients with RVPO from pulmonary arterial hypertension or pulmonic stenosis (mean age 53 +/- 16 years, New York Heart Association class 2.6 +/- 0.7, and peak RV systolic pressure 73 +/- 28 mm Hg) and 20 age-matched normal subjects (mean age 47 +/- 16 years). Segmental signals from 6 segments around the mid-LV short axis were defined as dyssynchronous if their changes were opposite to that of the global LV signal at each time frame, and overall LV dyssynchrony was calculated as the percentage of dyssynchrony in all 6 segments within the specified time interval from onset of QRS to the end of isovolumic relaxation. RVPO was associated with a large degree of regional dyssynchrony with paradoxical ventricular septal motion observed by displacement imaging (21 +/- 6%, p <0.05 vs control group), which was closely associated with LV eccentricity index (r = 0.79, p <0.05) and LV myocardial performance index with linear regression (r = 0.76, p <0.05). In contrast, strain imaging showed uniform segmental radial thickening in the RVPO group, which was similar to the control group, and suggests that there was no intrinsic LV contractile dyssynchrony. In conclusion, LV wall motion dyssynchrony assessed by displacement imaging, not intrinsic contractile dyssynchrony by strain imaging, coexists with LV chamber deformation with ventricular septal shift and is closely associated with impairment of LV performance.

Oral rivaroxaban for Japanese patients with symptomatic venous thromboembolism – the J-EINSTEIN DVT and PE program

BackgroundThe global EINSTEIN DVT and PE studies compared rivaroxaban (15 mg twice daily for 3 weeks followed by 20 mg once daily) with enoxaparin/vitamin K antagonist therapy and demonstrated non-inferiority for efficacy and superiority for major bleeding. Owing to differences in targeted anticoagulant intensities in Japan, Japanese patients were not enrolled into the global studies. Instead, a separate study of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) in Japanese patients was conducted, which compared the Japanese standard of care with a reduced dose of rivaroxaban.MethodsWe conducted an open-label, randomized trial that compared 3, 6, or 12 months of oral rivaroxaban alone (10 mg twice daily or 15 mg twice daily for 3 weeks followed by 15 mg once daily) with activated partial thromboplastin time-adjusted intravenous unfractionated heparin (UFH) followed by warfarin (target international normalized ratio 2.0; range 1.5–2.5) in patients with acute, objectively confirmed symptomatic DVT and/or PE. Patients were assessed for the occurrence of symptomatic recurrent venous thromboembolic events or asymptomatic deterioration and bleeding.ResultsEighty-one patients were assigned to rivaroxaban and 19 patients to UFH/warfarin. Three patients were excluded because of serious non-compliance issues. The composite of symptomatic venous thromboembolic events or asymptomatic deterioration occurred in 1 (1.4%) rivaroxaban patient and in 1 (5.3%) UFH/warfarin patient (absolute risk difference, 3.9% [95% confidence interval, -3.4–23.8]). No major bleeding occurred during study treatment. Clinically relevant non-major bleeding occurred in 6 (7.8%) patients in the rivaroxaban group and 1 (5.3%) patient in the UFH/warfarin group.ConclusionsThe findings of this study in Japanese patients with acute DVT and/or PE suggest a similar efficacy and safety profile with rivaroxaban and control treatment, consistent with that of the worldwide EINSTEIN DVT and PE program.Trial registrationClinicaltrials.gov: NCT01516840 and NCT01516814.

Reversible left ventricular regional non-uniformity quantified by speckle-tracking displacement and strain imaging in patients with acute pulmonary embolism.

BACKGROUND The aim of this study was to investigate the impact of acute right ventricular pressure overload (RVPO) on left ventricular (LV) function and regional uniformity using speckle-tracking displacement and strain analyses in patients with acute pulmonary embolism (PE). METHODS Twenty-five patients with acute PE (mean age, 59 ± 16 years) and 25 normal subjects were enrolled. Radial, longitudinal, and circumferential LV wall motion and myocardial deformation were analyzed using speckle-tracking displacement and strain imaging echocardiography, respectively, from the mid-LV short-axis and apical four-chamber views. The standard deviation of the heart rate-corrected intervals from QRS onset to peak systolic displacement (PSD) and peak systolic strain for the six segments was used to quantify LV systolic dyssynchrony. The standard deviation of regional PSD and peak systolic strain divided by their global values was used to quantify LV systolic heterogeneity. Mechanical discoordination of LV regional wall motion and myocardial deformation was assessed by averaging the frame-by-frame percentage discordance between segmental and global signal changes in the six segments. RESULTS Patients with acute PE had reduced radial PSD and peak systolic strain and a large extent of displacement-derived nonuniformities (PSD dyssynchrony, 74 ± 32 vs 40 ± 20 m sec; PSD heterogeneity, 0.39 ± 0.13 vs 0.17 ± 0.08; and PSD discoordination, 23 ± 2% vs 15 ± 3%; P < .05 vs normal subjects for all comparisons) associated with a leftward shift of the interventricular septum. In contrast, all indices of strain-derived radial LV nonuniformities were not augmented by acute RVPO in patients with acute PE. Patients with acute PE also had impaired LV systolic function and regional uniformities in the longitudinal and circumferential directions. After the amelioration of acute RVPO by primary treatment, most of the indices of LV function and regional uniformity were restored to normal values. Multiple regression analysis indicated that only radial LV wall motion discoordination was a significant determinant of cardiac index. CONCLUSIONS Acute RVPO induces reversal LV regional uniformities, which are closely associated with reduced LV function and abnormal geometry of the left ventricle, and radial LV wall motion coordination plays a key role in the short-term regulation of cardiac output in patients with acute PE.

Elevated Levels of Prothrombin Fragment 1 + 2 Indicate High Risk of Thrombosis

Prothrombin fragment 1 + 2 (F1 + 2) is considered to be useful for diagnosis of thrombosis. However, the evidence for a diagnosis of thrombosis by F1 + 2 is still not well established. The plasma concentrations of F1 + 2, soluble fibrin, D-dimer, and thrombin-antithrombin complex were measured in 694 patients suspected of having thrombosis and then were correlated with thrombosis. Plasma concentrations of F1 + 2, soluble fibrin, D-dimer, and thrombin-antithrombin complex were significantly higher in patients with thrombosis, compared with patients without thrombosis. When cutoff values of more than 300 pmol/L for F1 + 2 were used for the diagnosis, more than 50% of the patients were thus found to have thrombosis. The findings showed that F1 + 2, soluble fibrin, D-dimer, and thrombin-antithrombin complex have similar diagnostic ability. The plasma concentration of F1 + 2 closely was well correlated with thrombin-antithrombin complex, soluble fibrin, and D-dimer. Finally, F1 + 2 is one of the most useful parameters for the diagnosis of thrombosis.

Risk factors of acute pulmonary thromboembolism in Japanese patients hospitalized for medical illness: results of a multicenter registry in the Japanese society of pulmonary embolism research

AbstractBackground: Although the prophylaxis of acute pulmonary thromboembolism (APTE) in hospitalized patients has been improving in Japan, there is no report concerning APTE of Japanese medical patients. Therefore, the present study was designed to investigate the characteristics of APTE in Japanese patients hospitalized for medical illness, through a retrospective study. Methods: In a total of 1,438 registry patients with pulmonary thromboembolism for recent 10 years, 1,027 patients with APTE were analyzed with respect to underlying diseases or predisposing factors, and clinical course. Results: A hundred thirty three patients hospitalized for medical illness developed APTE, among 433 in-hospital APTE patients. The prevalence of APTE in women was more than in men. The mean age of the patients at diagnosis was 61 ± 17 years. Main risk factors were a prolonged immobilization, stroke, cancer, indwelling central venous catheter. Fifty-four patients had 3 or more risk factors. In-hospital mortality rate was 23%. Conclusions: Japanese patients in this registry had almost the same findings as in western patients, except for some points that had the possibility of demonstrating a difference between westerners and Japanese in the development of APTE. Our results will be available for establishing the prevention of APTE in medical patients in Japan.