Erratum: Cardioprotective Effects of Rivaroxaban on Cardiac Remodeling After Experimental Myocardial Infarction in Mice.

[This corrects the article DOI: 10.1253/circrep.CR-19-0117.].

Cardioprotective Effects of Rivaroxaban on Cardiac Remodeling After Experimental Myocardial Infarction in Mice.

Background: Direct-activated factor X (FXa) plays an important role in thrombosis and is also involved in inflammation via the protease-activated receptor (PAR)-1 and PAR-2 pathway. We hypothesized that rivaroxaban protects against cardiac remodeling after myocardial infarction (MI). Methods and Results: MI was induced in wild-type mice by permanent ligation of the left anterior descending coronary artery. At day 1 after MI, mice were randomly assigned to the rivaroxaban and vehicle groups. Mice in the rivaroxaban group were provided with a regular chow diet plus rivaroxaban. We evaluated cardiac function by echocardiography, pathology, expression of mRNA and protein at day 7 after MI. Rivaroxaban significantly improved cardiac systolic function, decreased infarct size and cardiac mass compared with the vehicle. Rivaroxaban also downregulated the mRNA expression levels of tumor necrosis factor-α, transforming growth factor-ß, PAR-1 and PAR-2 in the infarcted area, and both A-type and B-type natriuretic peptides in the non-infarcted area compared with the vehicle. Furthermore, rivaroxaban attenuated cardiomyocyte hypertrophy and the phosphorylation of extracellular signal-regulated kinase in the non-infarcted area compared with the vehicle. Conclusions: Rivaroxaban protected against cardiac dysfunction in MI model mice. Reduction of PAR-1, PAR-2 and proinflammatory cytokines in the infarcted area may be involved in its cardioprotective effects.

Total Thrombus-Formation Analysis System can Predict 1-Year Bleeding Events in Patients with Coronary Artery Disease.

AIMS: The assessment of bleeding risk in patients with coronary artery disease (CAD) is clinically important. We recently developed the Total Thrombus-Formation Analysis System (T-TAS) for the quantitative analysis of thrombus formation using microchips with thrombogenic surfaces. Here, we assessed the utility of T-TAS parameters in predicting 1-year bleeding events in patients with CAD. METHODS: The study subjects were 561 consecutive patients who underwent coronary angiography (CAG) between August 2013 and September 2016 for suspected CAD. Blood samples collected at the time of CAG were used for T-TAS to compute the area under the curve (AUC) (AR10-AUC30) in the AR chip. Patients were divided into three groups according to AR10-AUC30 (low: ≤ 1603, intermediate, and high: ＞1765, n=187 each). One-year bleeding events were defined by the Platelet Inhibition and Patient Outcomes criteria. RESULTS: Bleeding occurred in 21 (3.7%) patients and was classified as major (8 [1.4%]) and minor (13 [2.3%]). The AR10-AUC30 levels were significantly lower in the bleeding group than the non-bleeding group (median [interquartile range] 1590 [1442-1734] vs. 1687 [1546-1797], p=0.04). Univariate Cox regression analysis demonstrated that low AR10-AUC30 , high prothrombin time-international normalized ratio levels, and diabetes correlated with bleeding events. Multivariate Cox regression analysis identified low AR10-AUC30 levels as a significant determinant of bleeding events. Kaplan-Meier survival curves showed a higher rate of bleeding events in the low than the high AR10-AUC30 group (p=0.007). CONCLUSIONS: The results highlight the potential usefulness of the AR10-AUC30 levels in the prediction of 1-year bleeding events in patients with CAD treated with various antithrombotic therapies.

Reduction in thrombogenic activity and thrombocytopenia after transcatheter aortic valve implantation - The ATTRACTIVE-TTAS study.

INTRODUCTION: Bleeding complications after transcatheter aortic valve implantation (TAVI) is a major problem in clinical practice. However, there is few information on thrombogenicity after TAVI. The aim of this study was to establish a monitoring of total thrombogenicity in perioperative TAVI using the Total Thrombus-formation Analysis System (T-TAS), a microchip-based flow chamber system for analysis of thrombus formation under flow condition. METHODS: Twenty-three patients with severe aortic stenosis who underwent TAVI between August 2017 and March 2018 at Kumamoto university hospital were enrolled. After exclusion, data of 21 patients were analyzed. Blood samples were obtained before, 2, 7, and 30 days after TAVI. Thrombogenicity were assessed by the T-TAS to compute the area under the curve (AUC) (AR10-AUC30) in the AR chip. We also measured platelet count, high-molecular-weight von Willebrand factor (HMW-vWF) multimers, and plasma thrombopoietin. Computational fluid dynamics (CFD) analysis was performed to calculate the wall shear stress (WSS). RESULTS: The AR10-AUC30 levels and platelet counts were significantly lower at 2 days post-TAVI, and then increased gradually. HMW-vWF multimers, and plasma thrombopoietin, were significantly higher at 2 days post-TAVI, compared with before TAVI. CFD analysis showed that WSS of the aortic valve and posterior ascending aortic wall were significantly lower after TAVI than before-TAVI. Multivariate analysis identified max velocity measured by echocardiography, platelet count, and D-dimer as significant determinants of AR10-AUC30, representing total thrombogenicity. CONCLUSIONS: Although HMW-vWF multimers improved earlier after TAVI, total thrombogenic activity evaluated by T-TAS remained relatively low followed by improvement in thrombogenic activity at 30 days after TAVI.Clinical Trial Registration: https://clinicaltrials.gov. Unique identifiers: NCT03248232.

Akt1-Mediated Muscle Growth Promotes Blood Flow Recovery After Hindlimb Ischemia by Enhancing Heme Oxygenase-1 in Neighboring Cells.

BACKGROUND: Resistance exercise has beneficial effects for patients with peripheral arterial diseases. The hypothesis that muscle growth promotes angiogenesis by interacting with neighboring cells in ischemic lesions was assessed. Methods and Results: Skeletal muscle-specific inducible Akt1 transgenic (Akt1-TG) mice that induce growth of functional skeletal muscles as a model of resistance training were used. Proteomics analysis identified significant upregulation of heme oxigenase-1 (HO-1) in muscle tissue in Akt1-TG mice compared with control mice. Blood flow recovery after hindlimb ischemia was significantly increased in Akt1-TG mice compared with control mice. Enhanced blood flow and capillary density in Akt1-TG mice were completely abolished by the HO-1 inhibitor, Tin-mesoporphyrin. Immunohistochemistry showed that HO-1 expression was not increased in muscle cells, but it was increased in macrophages and endothelial cells. Consistent with these findings, blood flow recovery after hindlimb ischemia was similar between control mice and skeletal muscle-specific HO-1-knockout mice. Adenoviral-mediated overexpression of Akt1 did not increase HO-1 protein expression in C2C12 myotubes; however, the conditioned medium from Akt1-overexpressing C2C12 myotubes increased HO-1 expression in endothelial cells. Cytokine array demonstrated that a panel of cytokine secretion was upregulated in Akt1-overexpressing C2C12 cells, suggesting paracrine interaction between muscle cells and endothelial cells and macrophages. CONCLUSIONS: Akt1-mediated muscle growth improves blood flow recovery after hindlimb ischemia by enhancing HO-1 expression in neighboring cells.

Edoxaban Enhances Thromboprophylaxis by Physiotherapy After Total Knee Arthroplasty　- The Randomized Controlled ESCORT-TKA Trial.

BACKGROUND: The pharmacological advantage of combining physiotherapy with anticoagulants for the prevention of venous thromboembolism (VTE) after total knee arthroplasty (TKA) is not fully known. Herein we investigated the potential benefit of this combination therapy in patients undergoing TKA.Methods and Results:The 38 patients were randomly assigned to a physiotherapy group (n=19) or a physiotherapy plus 30 mg/day edoxaban group (n=19). The occurrence of VTE was evaluated, as were serial changes in parameters measured by the Total Thrombus-formation Analysis System, a novel system for quantitatively analyzing thrombus formation using microchips with thrombogenic surfaces (collagen plus tissue factor, atheroma [AR]-chip). Combination therapy significantly reduced the incidence of VTE after TKA compared with monotherapy (P=0.038). The area under the curve (AUC) of thrombus formation for the AR-chip (AR10-AUC30) was significantly lower in the combination group (P=0.001) on Day 7 after TKA than before TKA, but no significant change was observed with monotherapy (P=0.809). In 13 VTE-positive patients, AR10-AUC30was significantly lower in the combination group (n=3) than in the monotherapy group (n=10) on Day 7 (P=0.045). CONCLUSIONS: The combination of physiotherapy and edoxaban significantly reduced the incidence of VTE after TKA compared with physiotherapy alone. However, it is possible that VTE occurrence after TKA is not only associated with thrombogenicity, but also rheological factors.

Total Thrombus-formation Analysis System Predicts Periprocedural Bleeding Events in Patients With Coronary Artery Disease Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Periprocedural bleeding events are common after percutaneous coronary intervention. We evaluated the association of periprocedural bleeding events with thrombogenicity, which was measured quantitatively by the Total Thrombus-formation Analysis System equipped with microchips and thrombogenic surfaces (collagen, platelet chip [PL]; collagen plus tissue factor, atheroma chip [AR]). METHODS AND RESULTS: Between August 2013 and March 2016, 313 consecutive patients with coronary artery disease undergoing elective percutaneous coronary intervention were enrolled. They were divided into those with or without periprocedural bleeding events. We determined the bleeding events as composites of major bleeding events defined by the International Society on Thrombosis and Hemostasis and minor bleeding events (eg, minor hematoma, arteriovenous shunt and pseudoaneurysm). Blood samples obtained at percutaneous coronary intervention were analyzed for thrombus formation area under the curve (PL24-AUC10 for PL chip; AR10-AUC30 for AR chip) by the Total Thrombus-formation Analysis System and P2Y12 reaction unit by the VerifyNow system. Periprocedural bleeding events occurred in 37 patients. PL24-AUC10 levels were significantly lower in patients with such events than those without (P=0.002). Multiple logistic regression analyses showed association between low PL24-AUC10 levels and periprocedural bleeding events (odds ratio, 2.71 [1.22-5.99]; P=0.01) and association between PL24-AUC10 and periprocedural bleeding events in 176 patients of the femoral approach group (odds ratio, 2.88 [1.11-7.49]; P=0.03). However, PL24-AUC10 levels in 127 patients of the radial approach group were not significantly different in patients with or without periprocedural bleeding events. CONCLUSIONS: PL24-AUC10 measured by the Total Thrombus-formation Analysis System is a potentially useful predictor of periprocedural bleeding events in coronary artery disease patients undergoing elective percutaneous coronary intervention.

Cardioprotective Effects of LCZ696 (Sacubitril/Valsartan) After Experimental Acute Myocardial Infarction.

LCZ696 (sacubitril/valsartan) can lower the risk of cardiovascular events in chronic heart failure. However, it is unclear whether LCZ696 can improve prognosis in patients with acute myocardial infarction (MI). The present study shows that LCZ696 can prevent cardiac rupture after MI, probably due to the suppression of pro-inflammatory cytokines, matrix metalloproteinase-9 activity and aldosterone production, and enhancement of natriuretic peptides in mice. These findings suggest the mechanistic insight of cardioprotective effects of LCZ696 against acute MI, resulting in the belief that LCZ696 might be useful clinically to improve survival after acute MI.

Clinical and morphological presentations of acute coronary syndrome without coronary plaque rupture - An intravascular ultrasound study.

BACKGROUND: Although acute coronary syndrome (ACS) mainly arises from plaque ruptures (PR), precise mechanisms underlying ACS without PR are unknown. We sought to examine clinical, angiographic and intravascular ultrasound (IVUS) characteristics of ACS without PR. METHODS AND RESULTS: Culprit lesions of 161 ACS patients were categorized by the presence or absence of PR (PR group: n=57, Non-PR group: n=104). Lower abdominal circumference (86±10cm vs 90±9cm, p=0.02), lower prevalence of myocardial infarction (53% vs 82%, p=0.0002), and higher prevalence of definite vasospasm (15% vs 2%, p=0.006) were found in Non-PR group. Morphologically, Non-PR group was associated with simpler Ambrose classification (36% vs 14%, p=0.004), less hypoechoic plaque (45% vs 65%, p=0.04) and lower incidence of IVUS-detected thrombus (21% vs 54%, p<0.0001), compared with PR group. On quantitative IVUS, although minimum lumen area (MLA) was similar between the groups, vessel (14.2±5.4mm(2) vs 17.5±5.1mm(2), p=0.0002) and plaque (11.6±5.0mm(2) vs 14.9±4.9mm(2), p<0.0001) areas were significantly smaller at MLA site in Non-PR group than in PR group. On multivariate analysis, average plaque area was only an independent IVUS-predictor of non-rupture ACS (odds ratio: 0.85, p=0.01). CONCLUSION: Compared to ACS with PR, non-rupture ACS arise from more hyperechoic (allegedly "stable") plaque with smaller vessel and plaque area, leading to lower incidence of thrombotic occlusion. Coronary vasospasm might be a possible pathogenic mechanism underlying non-rupture ACS.

Total Thrombus-Formation Analysis System (T-TAS) Can Predict Periprocedural Bleeding Events in Patients Undergoing Catheter Ablation for Atrial Fibrillation.

BACKGROUND: Non-vitamin K antagonist oral anticoagulants are used to prevent thromboembolism in patients with atrial fibrillation. The T-TAS "Total Thrombus-formation Analysis System" (Fujimori Kogyo Co Ltd) was developed for quantitative analysis of thrombus formation using microchips with thrombogenic surfaces (collagen, platelet chip [PL] ; collagen plus tissue factor, atheroma chip [AR]). We evaluated the utility of T-TAS in predicting periprocedural bleeding in atrial fibrillation patients undergoing catheter ablation (CA). METHODS AND RESULTS: After exclusion of 20 from 148 consecutive patients undergoing CA, the remaining 128 patients were divided into 2 treatment groups: the warfarin group (n=30) and the non-vitamin K antagonist oral anticoagulants group (n=98). Blood samples obtained on the day of CA (anticoagulant-free point) and at 3 and 30 days after CA were used in T-TAS to compute the thrombus formation area under the curve (AUC; AUC for the first 10 minutes for PL tested at flow rate of 24 µL/min [PL24-AUC10]; AUC for the first 30 minutes for AR tested at flow rate of 10 µL/min [AR10-AUC30]). AR10-AUC30 and PL24-AUC10 levels were similar in the 2 groups on the day of CA. Levels of AR10-AUC30, but not PL24-AUC10, were significantly lower in the 2 groups at days 3 and 30 after CA. Multiple logistic regression analyses identified the AR10-AUC30 level on the day of CA as a significant predictor of periprocedural bleeding events (odds ratio 5.7; 95% CI 1.54-21.1; P=0.009). Receiver operating characteristic analysis showed that the AR10-AUC30 level on the day of CA significantly predicted periprocedural bleeding events (AUC 0.859, 95% CI 0.766-0.951; P<0.001). The cutoff AR10-AUC30 level was 1648 for identification of periprocedural bleeding events. CONCLUSIONS: These results suggested that the AR10-AUC30 level determined by T-TAS is a potentially useful marker for prediction of bleeding events in atrial fibrillation patients undergoing CA.