C/EBP homologous protein deficiency attenuates myocardial reperfusion injury by inhibiting myocardial apoptosis and inflammation.

OBJECTIVE: To investigate whether and how the endoplasmic reticulum (ER) stress-induced, CCAAT/enhancer-binding protein-homologous protein (CHOP)-mediated pathway regulates myocardial ischemia/reperfusion injury. METHODS AND RESULTS: Wild-type and chop-deficient mice underwent 50 minutes of left coronary artery occlusion followed by reperfusion. Expression of chop and spliced x-box binding protein-1 (sxbp1) mRNA was rapidly and significantly increased in reperfused myocardium of wild-type mice. chop-deficient mice exhibited markedly reduced injury size after reperfusion compared with wild-type mice, accompanied by a decreasing number of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cardiomyocytes. Interestingly, myocardial inflammation, as assessed by expression of inflammatory cytokines and chemokines and numbers of infiltrated inflammatory cells, was also attenuated in chop-deficient mice. Moreover, expression of interleukin-6 mRNA in response to lipopolysaccharide was enhanced by simultaneous stimulation with thapsigargin, a potent ER stressor, in wild-type cardiomyocytes but not in chop-deficient cardiomyocytes. Finally, we found that superoxide was produced in reperfused myocardium and that intravenous administration of edaravone, a free radical scavenger, immediately before reperfusion significantly suppressed the superoxide overproduction and subsequent expression of sxbp1 and chop mRNA, followed by reduced injury size in wild-type mice. CONCLUSIONS: The ER stress-induced, CHOP-mediated pathway, which is activated in part by superoxide overproduction after reperfusion, exacerbates myocardial ischemia/reperfusion injury by inducing cardiomyocyte apoptosis and myocardial inflammation.

Passive exercise using whole-body periodic acceleration enhances blood supply to ischemic hindlimb.

OBJECTIVE: Whole-body periodic acceleration (WBPA) has been developed as a passive exercise technique to improve endothelial function by increasing shear stress through repetitive movements in spinal axis direction. We investigated the effects of WBPA on blood flow recovery in a mouse model of hindlimb ischemia and in patients with peripheral arterial disease. METHODS AND RESULTS: After unilateral femoral artery excision, mice were assigned to either the WBPA (n=15) or the control (n=13) group. WBPA was applied at 150 cpm for 45 minutes under anesthesia once a day. WBPA significantly increased blood flow recovery after ischemic surgery, as determined by laser Doppler perfusion imaging. Sections of ischemic adductor muscle stained with anti-CD31 antibody showed a significant increase in capillary density in WBPA mice compared with control mice. WBPA increased the phosphorylation of endothelial nitric oxide synthase (eNOS) in skeletal muscle. The proangiogenic effect of WBPA on ischemic limb was blunted in eNOS-deficient mice, suggesting that the stimulatory effects of WBPA on revascularization are eNOS dependent. Quantitative real-time polymerase chain reaction analysis showed significant increases in angiogenic growth factor expression in ischemic hindlimb by WBPA. Facilitated blood flow recovery was observed in a mouse model of diabetes despite there being no changes in glucose tolerance and insulin sensitivity. Furthermore, both a single session and 7-day repeated sessions of WBPA significantly improved blood flow in the lower extremity of patients with peripheral arterial disease. CONCLUSIONS: WBPA increased blood supply to ischemic lower extremities through activation of eNOS signaling and upregulation of proangiogenic growth factor in ischemic skeletal muscle. WBPA is a potentially suitable noninvasive intervention to facilitate therapeutic angiogenesis.

Complete response to rivaroxaban in a case of invaginated thrombus thought to have extended through a patent foramen ovale with an accompanying pulmonary embolism.

Occurrence of paradoxical embolisms caused by deep venous thrombosis (DVT) is often encountered in the clinical setting. However, a thrombus that is invaginated from the right atrium into the left atrium (an impending paradoxical embolism) is rare. We report a case of an 80-year-old woman who had the complication of an impending paradoxical embolism and a pulmonary embolism. Because an indication of new anticoagulants was expanded to treatment of venous thromboembolism and oral administration became available, we initially administered edoxaban, which did not cause the thrombus to disappear. Therefore, we switched to rivaroxaban, which resulted in successful elimination of the thrombus. Our findings indicate the differences in effects between each novel oral anticoagulant. .

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.