Masakazu Matsukawa

Reduced von Willebrand factor‐cleaving protease (ADAMTS13) activity in acute myocardial infarction

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Pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, attenuates myocardial ischemia–reperfusion injury in mice with metabolic disorders

Although considerable attention has focused on obesity, insulin resistance and abnormal lipid metabolism as coronary risk factors, it remains unclear how these pathogenic factors affect the inflammatory response after myocardial ischemia-reperfusion. This study was conducted to evaluate whether these metabolic disorders exacerbate myocardial ischemia-reperfusion injury, and to determine if ischemia-reperfusion injury could be modified with the thiazolidinedione, pioglitazone. Experiments were performed in KK-A(y) and C57BL/6J mice subjected to 40 min of ischemia followed by reperfusion. Infiltration of inflammatory cells in ischemic myocardium, and infarct size 3 days after reperfusion were significantly higher in KK-A(y) than C57BL/6J mice (p<0.05 and p<0.001, respectively). Furthermore, expression of chemokines, inflammatory cytokines and extracellular matrix proteins in ischemic myocardium was significantly higher in KK-A(y) than C57BL/6J mice 1 day after reperfusion. Pioglitazone treatment of KK-A(y) mice for 14 days significantly reduced the accumulation of inflammatory cells in ischemic myocardium, and infarct size 3 days after reperfusion compared to vehicle treatment (p<0.05 and p<0.05, respectively). Pioglitazone also attenuated expression of chemokines, inflammatory cytokines and extracellular matrix proteins in ischemic myocardium 1 day after reperfusion. In vitro experiments demonstrated that tumor necrosis factor-alpha (TNF-alpha) was significantly higher in cultured peritoneal macrophages from KK-A(y) than C57BL/6J mice, and pioglitazone significantly reduced TNF-alpha in macrophages from both types of mice. These findings suggest that metabolic disorders exacerbate ischemia-reperfusion injury as a result of overexpression of inflammatory mediators, and this effect might be improved, in part by the anti-inflammatory effects of pioglitazone.

Prognostic value of plasma von Willebrand factor-cleaving protease (ADAMTS13) antigen levels in patients with coronary artery disease

High plasma level of von Willebrand factor (VWF) is a marker of future cardiovascular events in patients at high risk of coronary artery disease (CAD). The purpose of this study was to examine the changes and the prognostic value of plasma VWF-cleaving protease (ADAMTS13) levels in patients with CAD. Plasma VWF and ADAMTS13 levels were measured in 225 patients with CAD (152 men and 73 women, age, 70.3 +/- 8.9 years, mean +/- SD) and 100 patients without CAD who were age- and gender-matched to the CAD patients (60 men and 40 women, age, 68.6 +/- 8.9 years). The CAD patients had higher VWF and lower ADAMTS13 antigen levels compared to patients without CAD. During 22.3 +/- 10.4 months follow-up period, 20 major adverse cardiac and cerebrovascular events (MACCE) occurred in 222 patients with CAD who could be followed up. Kaplan-Meier analysis demonstrated that CAD patients with high plasma VWF antigen levels were significantly more likely to develop MACCE. Furthermore, eight cardiac and cerebrovascular thrombotic events [acute coronary syndrome (n=4) and cerebral infarction (n=4)] occurred in CAD patients with both high plasma VWF and low ADAMTS13 antigen levels. Multivariate Cox hazards regression analysis identified high plasma VWF and low ADAMTS13 antigen levels as significant and independent predictors of future MACCE and thrombotic events during the follow-up period in CAD patients. Our findings suggest that low plasma ADAMTS13 as well as high VWF level is a useful predictor of cardiac and cerebrovascular events in CAD patients.

Changes in plasma von Willebrand factor and ADAMTS13 levels associated with left atrial remodeling in atrial fibrillation.

INTRODUCTION Previous studies have shown raised plasma von Willebrand factor (VWF) levels in patients with atrial fibrillation (AF). However, little is known about changes of VWF associated with VWF-cleaving protease (ADAMTS13) in AF. The aim of this study was to examine the relationship between changes in plasma VWF and ADAMTS13 levels, and left atrial remodeling in AF patients. MATERIALS AND METHODS We measured plasma VWF and ADAMTS13 antigen levels in 70 paroxysmal AF (PAF) patients, 56 chronic AF (CAF) patients, and 55 control subjects. RESULTS Plasma VWF levels (mU/ml) were significantly higher in CAF and PAF patients compared with the controls (2103 +/- 743, 1930 +/- 676, 1532 +/- 555, respectively, P < 0.0001 in CAF vs. controls, P = 0.001 in PAF vs. control), while ADAMTS13 levels (mU/ml) were significantly lower in CAF and PAF patients compared with the controls (795 +/- 169, 860 +/- 221, 932 +/- 173, respectively, P = 0.0002 in CAF vs. controls, P = 0.04 in PAF vs. control). The VWF/ADAMTS13 ratio was significantly higher in patients with CAF than PAF or controls (2.81 +/- 1.30, 2.34 +/- 0.92, 1.73 +/- 0.83, respectively; P = 0.01 in CAF vs. PAF, P < 0.0001 in CAF vs. controls). There was a significant correlation between the VWF/ADAMTS13 ratio and left atrial diameter (positive correlation; r = 0.275, P = 0.0002) and left atrial appendage flow velocity (negative correlation; r = -0.345, P = 0.0018). CONCLUSIONS These findings suggest that the imbalance between plasma VWF and ADAMTS13 levels caused by left atrial remodeling might be closely associated with intra-atrial thrombus formation in AF patients.

Changes in plasma Von Willebrand factor-cleaving protease (ADAMTS13) levels in patients with unstable angina

INTRODUCTION Increased plasma levels of von Willebrand factor (VWF) have been reported in acute myocardial infarction (AMI). Recently, we showed reduced activity of a VWF-cleaving protease (ADAMTS13) in AMI patients. However, there is no information as to whether ADAMTS13 affects the pathogenesis of unstable angina (UA). Thus, the purpose of this study was to examine changes in plasma VWF and ADAMTS13 levels in UA patients. MATERIALS AND METHODS Plasma VWF and ADAMTS13 levels (mU/ml) were measured in 45 patients with UA, 55 with stable exertional angina (SEA) and 47 with chest pain syndrome (CPS) at the time of coronary angiography. Levels were also measured in 15 UA patients after 6 months of follow-up. RESULTS VWF antigen levels (mU/ml) increased significantly in UA patients compared with SEA or CPS (2129.3+/-739.5, 1571.8+/-494.2 and 1569.5+/-487.0, respectively; P < 0.0001 in UA vs. SEA or CPS). ADAMTS13 antigen levels (mU/ml) were significantly lower in UA patients than SEA or CPS (737.3+/-149.5, 875.3+/-229.0 and 867.7+/-195.5, respectively; P < 0.01 in UA vs. SEA or CPS). Furthermore, there was a significant inverse correlation between VWF and ADAMTS13 antigen levels (r = -0.302, P = 0.0002). The antigen levels at 6 months of follow-up were not different compared to the acute phase in the 15 UA patients that had repeated blood sampling. CONCLUSIONS These findings suggest that there is prolonged thrombogenicity in UA patients represented as an imbalance between VWF and ADAMTS13 activity.