Edoxaban eliminates hypercoagulability evoked by transient temperature changes in human whole blood.

Background: Thrombosis is a common critical complication relating to radiofrequency catheter ablation and cryoablation. There is a possibility that high-temperature stimulation during radiofrequency ablation or low-temperature stimulation during cryoablation may affect the coagulability of blood. In this study, we aimed to determine the impacts of transient temperature stimulations on the coagulability of whole blood and to clarify if edoxaban suppressed the hypercoagulability. Methods: Citrated blood samples were drawn from 41 healthy subjects. Some blood samples were mixed with tissue factor (TF) and several concentrations of edoxaban (50, 100, and 200 ng/mL). Blood samples were exposed to several temperature stimulations for 1 min: heat stimulation (50°C) or cryostimulation (-20°C), and compared with control (37°C). Repeated cryostimulations or sequential cryo- and heat stimulation were also applied. Coagulability of whole blood was measured using a dielectric blood coagulometry. As an index of coagulability, the end of acceleration time (EAT) was used. Results: Both heat- and cryostimulations significantly shortened the EAT compared to the control, indicating that hypercoagulability was induced by temperature stimulations. Application of TF enhanced and extended the hypercoagulability after the temperature stimulations. Sequential application of cryo- followed by heat stimulation further enhanced the hypercoagulability of blood. Application of edoxaban increased the EAT in a concentration-dependent manner in control condition. Edoxaban at 100 or 200 ng/mL completely suppressed the shortening of EAT evoked by these temperature stimulations. Conclusion: Transient temperature stimulations evoked hypercoagulability regardless of cryo- or heat stimulation. Edoxaban with 100 ng/mL or more eliminated this temperature-stimulated hypercoagulability.

Author Correction: Differential Assessment of Factor Xa Activity and Global Blood Coagulability Utilizing Novel Dielectric Coagulometry.

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Differential Assessment of Factor Xa Activity and Global Blood Coagulability Utilizing Novel Dielectric Coagulometry.

An easy-to-use assessment for activated factor X (FXa) is lacking despite its pivotal role in the coagulation. Dielectric blood coagulometry (DBCM) was recently invented as a novel assessment tool for determining the whole blood coagulability by measuring the temporal change in the permittivity of blood. We previously reported that it could evaluate the global blood coagulability. This study aimed to apply the DBCM for assessing FXa activity and its inhibition by anticoagulants. We performed the DBCM analysis along with measurement of the FXa activity by a fluorometric assay in samples from healthy subjects, and identified a new index named maximum acceleration time (MAT) that had a correlation to the FXa activity. Next the DBCM analysis was performed using blood samples mixed with anticoagulants (unfractionated heparin, dalteparin, and edoxaban). Blood samples with three anticoagulants had different profiles of the temporal change in the permittivity, reflecting their different selectivity for FXa. We compared the MAT with the anti-FXa activity assay, and found that the prolongation of MAT was similarly correlated with the anti-FXa activity regardless of the type of anticoagulants. In conclusion, the DBCM has the possibility for evaluating the innate FXa activity and effect of anticoagulants focusing on their FXa inhibition.

Combined Analysis of Human and Experimental Murine Samples Identified Novel Circulating MicroRNAs as Biomarkers for Atrial Fibrillation.

BACKGROUND: Recent experimental studies have demonstrated that several microRNAs (miRNAs) expressed in atrial tissue promote a substrate of atrial fibrillation (AF). However, because it has not been fully elucidated whether these experimental data contribute to identifying circulating miRNAs as biomarkers for AF, we used a combined analysis of human serum and murine atrial samples with the aim of identifying these biomarkers for predicting AF.Methods and Results:Comprehensive analyses were performed to screen 733 miRNAs in serum from 10 AF patients and 5 controls, and 672 miRNAs in atrial tissue from 6 inducible atrial tachycardia model mice and 3 controls. We selected miRNAs for which expression was detected in both analyses, and their expression levels were changed in the human analyses, the murine analyses, or both. This screening identified 11 candidate miRNAs. Next, we quantified the selected miRNAs using a quantitative RT-PCR in 50 AF and 50 non-AF subjects. The individual assessment revealed that 4 miRNAs (miR-99a-5p, miR-192-5p, miR-214-3p, and miR-342-5p) were significantly upregulated in AF patients. A receiver-operating characteristics curve indicated that miR-214-3p and miR-342-5p had the highest accuracy. The combination of the 4 miRNAs modestly improved the predictive accuracy for AF (76% sensitivity, 80% specificity). CONCLUSIONS: Novel circulating miRNAs were upregulated in the serum of AF patients and might be potential biomarkers of AF.

Assessment of vascular autonomic function using peripheral arterial tonometry.

Peripheral autonomic function is impaired in diabetic polyneuropathy. However, it is difficult to evaluate it due to the lack of non-invasive quantitative assessment. We aimed to establish a novel index to evaluate vascular autonomic function using reactive hyperemia peripheral arterial tonometry (RH-PAT), a widely performed endothelial function test. Sixty-five subjects were enrolled, including healthy subjects, cases with sympathetic nerve blockers, and diabetic patients. RH-PAT was performed with 5-min blood flow occlusion in unilateral arm. We calculated the reduction ratio of the post-occlusion pulse amplitude to the baseline in the non-occluded arm (RPN), with 1-min sliding window. In healthy subjects, RPN gradually increased with time-dependent manner. However, this phenomenon was eliminated in cases with sympathetic nerve blockers. Plasma concentration of norepinephrine was measured before and after the blood flow occlusion, which showed a significant increase. We then compared RPNs with the change in heart rate variability (HRV) parameters. RPN calculated at 5 min after the reperfusion had the highest correlation with the change in sympathetic HRV parameter, and thus, we named sympathetic hypoemia index (SHI). Finally, we studied the relationship between SHI and diabetes. SHI was significantly lower in diabetic patients than matched controls. SHI, a novel index derived from RH-PAT, represented the peripheral sympathetic activity. SHI may be useful for assessing the vascular autonomic activity in diabetic patients.