Incidence and predictors of persistent iatrogenic atrial septal defect following catheter ablation.

BACKGROUND: The left atrium approach for atrial fibrillation (AF) ablation requires an atrial transseptal puncture that may cause an iatrogenic atrial septal defect (iASD). This study aimed to investigate the incidence and predictors of iASD in catheter ablation, assessed by transthoracic echocardiography (TTE), a relatively non-invasive technique frequently employed in follow-up. METHODS: This retrospective study included 639 patients (489 male; 60.2±10.7years) who underwent initial catheter ablation for AF between May 2005 and June 2018. All patients underwent preprocedural transesophageal echocardiography (pre-TEE), preprocedural TTE (pre-TTE), and TTE one day after the procedure (post-TTE). iASD incidence after 6months (6M), preprocedural characteristics, and procedure methods were evaluated. RESULTS: Patent foramen ovale (PFO) was diagnosed in 42 patients (6.6%) using pre-TEE and in 11 patients using pre-TTE (26.2% of the patients with PFO in pre-TEE). Among the 597 patients without PFO, 497 underwent 6M-TTE. iASD was observed in 59.6% of patients using post-TTE and 4.6% using 6M-TTE. In the univariate logistic regression analysis, the total diameter of the sheath through the septum (odds ratio 1.15, p<0.001) or two sheaths through a single puncture (odds ratio 4.17, p=0.001) were independent risk factors on iASD incidence in 6M-TTE. iASD was also more likely to occur via cryoballoon ablation using a larger sheath than radiofrequency catheter ablation. CONCLUSIONS: iASD was not a rare complication. A larger sheath diameter or two sheaths through a single puncture were associated with the incidence of iASD.

Cardio-Ankle Vascular Index and Left Atrial Reverse Remodeling After Ablation for Atrial Fibrillation.

Arterial stiffness has been reported to cause left atrial (LA) remodeling due to increased left ventricular filling pressure, resulting in atrial fibrillation (AF). This study aimed to evaluate the association between LA reverse remodeling (LARR) after AF ablation and cardio-ankle vascular index (CAVI), an indicator of arterial stiffness.This study included 333 patients with AF (171 with paroxysmal AF and 162 with nonparoxysmal AF) and LA enlargement (LA volume index ≥ 34 mL/m2) who underwent AF ablation between December 2008 and July 2021. CAVI was evaluated preoperatively during AF (n = 155, 46.5%) or sinus rhythm (n = 178, 53.5%). Participants were divided into groups with LARR (n = 133, 39.9%) and without LARR (n = 200, 60.1%) according to whether the degree of decrease in LA volume index on transthoracic echocardiography 6 months after ablation was ≥ 15% or < 15%, respectively.Sinus rhythm was maintained in 168 (50.5%) patients within 3-6 months after the index procedure. Univariate analysis revealed that preoperative CAVI (7.80 ± 1.22 versus 8.57 ± 1.09, P < 0.001) was significantly lower, and the maintenance of sinus rhythm (61.6% versus 43.0%, P = 0.0011) was higher in the group with LARR. Multivariate logistic regression analysis revealed that preoperative CAVI was independently associated with LARR (odds ratio, 0.60, 95% confidence interval, 0.46-0.78, P < 0.001).In patients with AF and LA enlargement, CAVI is independently associated with LA reverse remodeling after catheter ablation.

Total atrial conduction time as a possible predictor of atrial fibrillation recurrence after catheter ablation for paroxysmal atrial fibrillation: relationship between electrical atrial remodeling and structural atrial remodeling time courses.

PURPOSE: Recently, the estimated total atrial conduction time measured using tissue Doppler imaging (PA-TDI duration) has been reported as a more accurate predictor of atrial fibrillation (AF) recurrence after catheter ablation than left atrial volume index (LAVI). The PA-TDI duration is considered to reflect electrical and structural remodeling in the right atrium (RA) and left atrium (LA). We sought to investigate the association between AF recurrence and PA-TDI duration after AF ablation. METHODS: We studied 209 patients who underwent radiofrequency ablation for paroxysmal AF and 75 patients who underwent second ablation for AF recurrence. We assessed the duration from the onset of the P wave on the surface electrocardiogram to the atrial electrogram in distal coronary sinus (CS) (PA-CSd duration) indicating electrical remodeling of the atrium, the PA-CS proximal duration (PA-CSp duration) representing electrical remodeling of RA, and the conduction time in CS (proximal to distal) (CSp-CSd duration) reflecting electrical remodeling of LA. We also measured LAVI as a marker of structural remodeling of LA. RESULTS: The PA-TDI duration had a positive correlation with PA-CSd duration. In the patients with AF recurrence, PA-TDI duration, PA-CSd duration, and CSp-CSd duration in the second ablation were significantly longer than those in the first (p < 0.01, respectively), whereas there was no significant difference in LAVI and PA-CSp duration between the first and second ablation sessions. CONCLUSION: A prolonged PA-TDI duration after AF ablation may indicate advanced electrical remodeling of LA, and may predict AF recurrence after ablation in patients with paroxysmal AF.

A randomized comparison of two direct oral anticoagulants for patients undergoing cardiac ablation with a contemporary warfarin control arm.

BACKGROUND: The safety and efficacy of periprocedural use of direct oral anticoagulants (DOACs) for atrial fibrillation (AF) remain unclear. We compared the incidence of asymptomatic cerebral micro-thromboembolism and hemopericardium following AF ablation among patients receiving edoxaban, rivaroxaban, and warfarin and between normal- and low-dose use of edoxaban and rivaroxaban. METHODS: This prospective randomized study included 170 consecutive AF patients. Patients taking DOACs upon admission to our hospital were randomly assigned to an edoxaban group or to a rivaroxaban group. Warfarin was continued in patients receiving warfarin at admission. All patients underwent AF ablation, and cerebral MRI was performed to evaluate asymptomatic cerebral micro-thromboembolism the day after the procedure. RESULTS: Sixty-one patients were assigned to edoxaban and 63 to rivaroxaban. Warfarin was continued in 46 patients. Although asymptomatic cerebral micro-thromboembolism was detected in 25 patients (16.3%), there were no significant differences among the groups. Hemopericardium occurred in 2 patients (one each in the rivaroxaban and warfarin groups). The incidence of asymptomatic cerebral micro-thromboembolism was higher in the low-dose group (9 patients, 25.7%) than in the normal-dose group (8 patients, 10.0%) for patients prescribed either edoxaban or rivaroxaban (p < 0.05). The proportion of males (88.0%, 69.5%, p < 0.05), history of prior AF ablation (64.0%, 42.2%, p < 0.05), and hypertension (68.0%, 46.1%, p < 0.05) were significantly higher in patients with cerebral thromboembolism. CONCLUSIONS: The incidence of asymptomatic cerebral micro-thromboembolism and hemopericardium in AF ablation was similar among patients using edoxaban, rivaroxaban, and warfarin. However, low doses of DOACs may increase the risk of asymptomatic stroke.

Dynamics of Soluble Thrombomodulin and Circulating miRNAs in Patients with Atrial Fibrillation Undergoing Radiofrequency Catheter Ablation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the world and has a high risk of thromboembolism. The most effective approach, catheter ablation, requires evaluation by electrocardiography. The aim of our study was to investigate novel clinical markers that predict restoration of sinus rhythm (SR) after catheter ablation. Seventy-eight consecutive patients with AF underwent catheter ablation and were separated into 2 groups: restored SR and recurrent AF. The levels of 4 blood proteins (serum or plasma) and 3 mature microRNAs (miRNAs) and their primary miRNAs (pri-miRNAs) in serum were measured before and after ablation, and the associations between each parameter were analyzed statistically. Soluble thrombomodulin (s-TM) and plasminogen activator inhibitor-1 (PAI-1) levels increased above baseline after ablation in both the restored SR (s-TM 11.55 [2.92] vs 13.75 [3.38], P < .001; PAI-1 25.74 [15.25] vs 37.79 [19.56], P < .001) and recurrent AF (s-TM 10.28 [2.78] vs 11.67 [3.37], P < .001; PAI-1 26.16 [15.70] vs 40.74 [22.55], P < .001) groups. Levels of C-reactive protein and asymmetric dimethylarginine were not significantly changed. Pri-miR-126 levels significantly decreased after ablation in the recurrent AF group, but the other miRNAs and pri-miRNAs did not. The measurement of s-TM and pri-miR-126 in blood was a useful tool to reflect the condition of AF patients with catheter ablation.

Evaluation of safety and efficacy of periprocedural use of rivaroxaban and apixaban in catheter ablation for atrial fibrillation.

BACKGROUND: We previously reported that dabigatran increased the risk of microthromboembolism and hemopericardium compared with warfarin. The safety of non-vitamin-K-antagonist oral anticoagulants (NOACs) in the periprocedural use of atrial fibrillation (AF) ablation is controversial. This study aimed to compare the incidence of asymptomatic cerebral microthromboembolism and hemopericardium in AF ablation among periprocedural use of rivaroxaban, apixaban, and warfarin. METHODS AND RESULTS: This study was a prospective, randomized registry. Patients taking NOACs upon visiting our hospital were randomly assigned into 2 groups; rivaroxaban and apixaban. Warfarin was continued in patients taking warfarin. Asymptomatic cerebral microthromboembolism was evaluated by magnetic resonance imaging on the day after the ablation procedure. In 176 consecutive patients (101 paroxysmal, and 75 persistent AF), rivaroxaban was used in 55, apixaban in 51, and warfarin in 70. There were no symptomatic cerebral infarctions in this study. Asymptomatic cerebral microthromboembolism was detected in 32 (18.4%) patients; nine (16.4%) with rivaroxaban, 10 (20%, p=0.80; vs. rivaroxaban) with apixaban, and 13 (18.8%, p=0.81; vs. rivaroxaban) with warfarin. Hemopericardium occurred in 5 (2.8%) patients; 2 with rivaroxaban, 1 with apixaban (p=1.0; vs. rivaroxaban), and 2 with warfarin (p=1.0; vs. rivaroxaban). In multivariate analysis, concomitant coronary angiography (p<0.05, odds ratio 5.73) was a predictor of cerebral thromboembolism. CONCLUSIONS: The incidence of asymptomatic cerebral microthromboembolism and hemopericardium in AF ablation is similar among the periprocedural use of rivaroxaban, apixaban, and warfarin.

The optimal setting of complex fractionated atrial electrogram software in substrate ablation for atrial fibrillation.

BACKGROUND: Complex fractionated atrial electrogram (CFAE)-targeted catheter ablation (CFAE ablation) requires a high rate of atrial fibrillation (AF) termination to provide good outcomes. We determined the optimal settings of CFAE software. METHODS: In our 430 consecutive patients, AF was terminated in 97 (234/242) and 79% (149/188) of patients with paroxysmal and persistent AF, respectively, by CFAE ablation combined with (31%) or without (69%) pulmonary vein isolation, occasionally with nifekalant infusion. We analyzed 109 consecutive patients who underwent CFAE ablation to determine the optimal settings for comparing subjective versus objective decisions by the CFAE software on CARTO3. We compared three settings: the default setting (0.05-0.15 mV, 50-120 ms) and two modified settings (#1: 0.05-0.30 mV, 40-70 ms, #2: 0.05-0.13 mV, 10-20 ms). We retrospectively analyzed 11,425 points during left atrial mapping before ablation and 10,306 points that were subjectively detected and ablated as CFAE points. An interval confidence level ≥6 denoted a site with CFAE. RESULTS: With the default setting, the accuracy, sensitivity, specificity, positive productive value, and negative productive values were 67, 42, 77, 48, and 73%, respectively. With modified setting #1, the values were 78, 55, 87, 74, and 77%, respectively, versus 64, 82, 60, 53, and 91%, respectively, for modified setting #2. CONCLUSION: These data suggest that setting #1 was generally superior to the default setting, whereas setting #2 was optimal for excluding areas not requiring ablation. The optimal CFAE software setting was a voltage of 0.05-0.30 mV and an interval parameter of 40-70 ms.

The incidence of asymptomatic cerebral microthromboembolism after atrial fibrillation ablation: comparison of warfarin and dabigatran.

BACKGROUND: Cerebral microthromboembolism after atrial fibrillation (AF) ablation has been reported in 4-20% with perioperative warfarin. Dabigatran is a new anticoagulant in patients with nonvalvular AF. We investigated the incidence of asymptomatic cerebral microthromboembolism after AF ablation with perioperative warfarin or dabigatran using diffusion-weighted and T2-weighted magnetic resonance imaging (MRI). METHODS AND RESULTS: Our study included 210 consecutive patients with AF (111 paroxysmal and 99 persistent) who underwent complex fractionated atrial electrogram-guided ablation (combined with pulmonary vein isolation, n = 110). Catheter irrigation was performed in all cases. Uninterrupted warfarin therapy was used in 180 patients (warfarin group) and interrupted only on the morning of the procedure with dabigatran in 30 (dabigatran group). All patients underwent cerebral MRI the day after ablation. New microthromboemboli were detected in 10.0% of the warfarin group and 26.7% of the dabigatran group (P < 0.05). The incidence of hemopericardium treated with pericardiocentesis was lower in the warfarin group than in the dabigatran group (2.5% vs 11.1%, P < 0.05). In multivariate analysis, the use of cardioversion was a predictor of new microthromboembolism development after AF ablation. CONCLUSIONS: The incidence of asymptomatic cerebral microthromboembolism and hemopericardium after AF ablation was significantly lower with perioperative warfarin therapy than with dabigatran therapy. Dabigatran may not be an effective alternative to warfarin for AF ablation, especially in patients who undergo cardioversion.

Atrial fibrillation-induced endothelial dysfunction improves after restoration of sinus rhythm.

BACKGROUND: Recent evidence suggests that atrial fibrillation (AF) adversely affects endothelial function. The goal of this study was to assess endothelial function in patients with AF before and after restoration of sinus rhythm by catheter ablation (ABL). METHODS: Reactive hyperemia peripheral arterial tonometry (RH-PAT) measurements reflecting endothelial function were conducted with Endo-PAT2000 (Itamar Medical, Caesarea, Israel) in 27 patients with persistent AF before ABL and in 21 control subjects with sinus rhythm (SR). According to cardiac rhythm on the morning after ABL, patients were divided into two groups: day 1-restored SR group (n=19) and day 1-recurred AF group (n=8). Based on the cardiac rhythm at 6 months after ABL, the restored SR group was further subdivided into the month 6-maintained SR group (n=11) and the month 6-recurred AF group (n=6). RESULTS: Loge RH-PAT index (RHI) was significantly lower in the persistent AF group than in the control (SR) group (0.52 ± 0.20; 0.69 ± 0.24, p<0.01). Multivariate logistic regression analysis revealed that persistent AF was the only independent predictor of impaired endothelial function defined as loge RHI<0.6 (odds ratio, 4.96; 95% CI, 1.2 to 21.3; p<0.05). Loge RHI was significantly higher after ABL than before ABL (0.53±0.20; 0.73 ± 0.25; p<0.01) in the day 1-restored SR group. Loge RHI of the month 6-maintained SR group was comparable to that of the day 1-restored SR group. CONCLUSIONS: These results suggest that AF is associated with impairment of endothelial dysfunction and that this impairment is reversed by restoration of sinus rhythm.

Effectiveness of esophagus detection by three-dimensional electroanatomical mapping to avoid esophageal injury during ablation of atrial fibrillation.

AIMS: Esophageal-left atrial (LA) fistula during atrial fibrillation (AF) ablation is a fatal event. We explored the relation of the esophagus-to-ablated point distance and esophageal temperature rise. METHODS: Consecutive patients (n=106) underwent complex fractionated atrial electrogram-guided AF ablation using CartoMerge; the pulmonary veins were isolated in 23 patients. Maximum radiofrequency (RF) power near the esophagus was 15 W. Ablated points with esophageal temperature rise (monitored with a probe) to ≥38.0°C were tagged; if ≥39.0°C, RF was discontinued. RESULTS: Of 1647 ablated points near the esophagus, 274 were associated with a temperature rise to 38.0-38.9°C and 241 points to ≥39.0°C. Distances (mm) from points to esophagus were 5.1 ± 0.6 (no rise), 4.2±3.1 (38.0-38.9°C), 2.9 ± 2.5 (≥39.0°C). Altogether, 15.5% of points in the upper LA posterior wall, 41.5% in the middle, and 30.2% in the lower caused rises to ≥38.0°C; 8.7%, 24.6%, and 11.0% caused rises to ≥39.0°C. The middle wall was most affected (p<0.01), as shown by multiple logistic regression analysis (both temperatures). Points causing a rise increased significantly as distance decreased (p<0.001). The odds ratio for rise to ≥38.0°C compared with <4.0 to >5.0 mm distance was 2.28 (p=0.004). The longest distance for ≥38.0°C rise was 18.5 mm. CONCLUSION: Distance is an important predictor of esophageal temperature rise. The middle LA posterior wall is most vulnerable. A dose of 15 W is too high for ablation, especially <4.0 mm from the esophagus. Points >20.0 mm away are relatively safe.

Incidence of asymptomatic cerebral microthromboembolism after atrial fibrillation ablation guided by complex fractionated atrial electrogram.

BACKGROUND: The incidence of cerebral thromboembolism after pulmonary vein isolation (PVI) ranges from 2% to 14%. This study investigated the incidence of cerebral thromboembolism after complex fractionated atrial electrogram (CFAE) ablation with or without PVI. METHODS: One hundred consecutive atrial fibrillation (AF) patients (50 paroxysmal and 50 persistent, including 10 longstanding) who underwent CFAE ablation combined with (n = 41, PVI+CFAE group) or without (n = 59, CFAE group) PVI were studied. Coronary angiography (CAG) was conducted with AF ablation in 5 cases in which coronary artery stenosis was suspected on 3D-computed tomography. PVI was performed before CFAE ablation without circular catheter during AF. After termination of AF, additional ablation was performed to complete PVI with a circular catheter. All patients underwent cerebral magnetic resonance imaging (MRI) including diffusion-weighted MRI and T2-weighted MRI the day after ablation. RESULTS: New thromboembolism was detected in 7.0%, and there was no significant difference between the 2 strategies (7.3% in PVI+CFAE group, 6.8% in CFAE group). CHADS2 score (1.6 ± 1.0 vs 0.8 ± 0.9, P < 0.05), left atrial volume (LAV; 83.8 ± 27.1 vs 67.8 ± 21.8, P < 0.05), and left ventricular ejection fraction (LVEF, 53.1 ± 9.2 vs 65.1 ± 9.7, P < 0.01) were significantly different when comparing patients with or without thromboembolism. In multivariate analysis, LVEF (odds ratio [OR], 0.92; 95% confidence interval [CI], 0.84-0.99; P < 0.05) and concomitant CAG (OR 18.82; 95% CI, 1.77-200.00; P < 0.05) were important predictors of new cerebral thromboembolism. CONCLUSIONS: The incidence of cerebral microthromboembolism after CFAE ablation was not greater than previous reports in PVI. Cautious management is required during AF ablation, especially in the patients with low LVEF.

Relationship between clinical outcomes and unintentional pulmonary vein isolation during substrate ablation of atrial fibrillation guided solely by complex fractionated atrial electrogram mapping.

BACKGROUND: Controversy exists as to whether atrial fibrillation (AF) ablation guided solely by complex fractionated atrial electrogram (CFAE) has a good outcome despite not requiring pulmonary vein isolation (PVI). OBJECTIVES: The purpose of this study was to evaluate the effectiveness of AF ablation guided solely by targeting CFAE areas, and to determine whether its clinical efficacy has any relationship with unintentionally isolating the PV. METHODS: We studied 100 consecutive patients (ages 59 ± 11 years; 54 with paroxysmal, 35 persistent, and 11 long-standing persistent AF), who underwent CFAE-ablation. PV potential (PVP) was recorded before and after ablation. After excluding 39 patients in whom sinus rhythm could not be maintained before ablation by internal cardioversion and/or who had a history of PVI(s), PVPs were analyzed. RESULTS: AF was terminated during ablation in 98% of paroxysmal, 80% of persistent, and 55% of long-standing persistent AF patients. Nifekalant (0.3-0.6 mg/kg) was administered in 30%, 57%, and 83%, respectively. The common areas of CFAE around the PVs were anterior to the right PVs, posterior to the left PVs, and at the ridge of the left atrial appendage. Among 215 PVs in 61 patients (42 paroxysmal, 19 persistent), only 17 PVs (8%) were unintentionally isolated. The atrial potential to PVP was prolonged (>30 ms) in 13% of PVs. After at least 12 months of follow-up (23 ± 5 months), 65% of paroxysmal (11% with drug), 54% of persistent (37% with drug), and 45% of long-standing (60% with drug) AF patients were free from atrial arrhythmia after one session. CONCLUSIONS: CFAE-ablation terminates AF without isolating PVs in a high percentage of patients, and yields excellent clinical outcomes.

1,5-Anhydro-D-fructose: A natural antibiotic that inhibits the growth of gram-positive bacteria and microbial biofilm formation to prevent nosocomial infection.

Nosocomial infections caused by microbial opportunistic infections or microbial biofilms may occur during hospitalization and increase patient morbidity, mortality and health care costs. Artificial antibiotic agents were initially used to prevent infection; however, the high prevalence of nosocomial infections has resulted in their excessive use, which has led to microbial resistance to these agents. The increase in microbial resistance to antibiotics and the development of antibiotic agents may be the cause of the production of other microbial resistance. Thus, natural compounds that have no adverse side effects would be a preferred treatment modality. Recently, the monosaccharide 1,5-anhydro-D-fructose (1,5-AF), a natural plant compound derived from starch, has been found to have multifunctional properties, including antioxidant, antiplatelet aggregation by thrombin and anti-inflammatory activities. The results of the present study demonstrate that 1,5-AF suppressed the growth of coagulase-negative staphylococci on the hands as well as the growth of Staphylococcus epidermidis, which is a cause of opportunistic infections. Furthermore, 1,5-AF suppressed biofilm formation by the methicillin-resistant Staphylococcus aureus. In conclusion, 1,5-AF is a natural compound that may be effective in preventing nosocomial infections, without causing adverse side effects.

Potential of edaravone for neuroprotection in neurologic diseases that do not involve cerebral infarction.

Edaravone was originally developed as a potent free radical scavenger and has been widely used to treat cerebral infarction in Japan since 2001. Several free radical scavengers have been developed and some of them have progressed to clinical trials for the treatment of cerebral infarction. One such scavenger, edaravone, has been approved by the regulatory authority in Japan for the treatment of patients with cerebral infarction. Of particular interest is the ability of edaravone to diffuse into the central nervous system in various neurologic diseases. Aside from its hydroxyl radical scavenging effect, edaravone has been found to have beneficial effects on inflammation, matrix metalloproteinases, nitric oxide production and apoptotic cell death. Concordantly, edaravone has been found to have neuroprotective effects in a number of animal models of disease, including stroke, spinal cord injury, traumatic brain injury, neurodegenerative diseases and brain tumors. The proven safety of edaravone following 9 years of use as a free radical scavenger suggests that it may have potential for development into an effective treatment of multiple neurologic conditions in humans.

Edaravone: a new therapeutic approach for the treatment of acute stroke.

Acute stroke, including acute ischemic stroke (AIS) and acute hemorrhagic stroke, (AHS) is a common medical problem with particular relevance to the demographic changes in industrialized societies. In recent years, treatments for AIS have emerged, including thrombolysis with tissue plasminogen activator (t-PA). Although t-PA is the most effective currently available therapy, it is limited by a narrow therapeutic time window and side effects, and only 3% of all AIS patients receive thrombolysis. Edaravone was originally developed as a potent free radical scavenger and, since 2001, has been widely used to treat AIS in Japan. It was shown that edaravone extended the narrow therapeutic time window of t-PA in rats. The therapeutic time window is very important for the treatment of AIS, and early edaravone treatment is more effective. Thus, more AIS patients might be rescued by administering edaravone with t-PA. Meanwhile, edaravone attenuates AHS-induced brain edema, neurologic deficits and oxidative injury in rats. Although edaravone treatment is currently only indicated for AIS, it does offer neuroprotective effects against AHS in rats. Therefore, we hypothesize that early administration of edaravone can rescue AHS patients as well as AIS patients. Taken together, our findings suggest that edaravone should be immediately administered on suspicion of acute stroke, including AIS and AHS.

The diagnostic value of endothelial function as a potential sensor of fatigue in health.

PURPOSE: Many epidemiological research studies have shown that vital exhaustion and psychosocial factors are associated with the occurrence of cerebrocardiovascular disease (CCVD). Fatigue is thought to induce endothelial dysfunction and may be linked to the occurrence of CCVD; however, no studies have investigated this potential link. We studied to determine the effect of fatigue on endothelial function in healthy subjects with no traditional CCVD risk factors or potential confounding factors to be controlled. SUBJECTS AND METHODS: Peripheral arterial tonometry (PAT) was used to evaluate endothelial function. The influence of the following parameters on endothelial function was analyzed in 74 office workers without traditional CCVD risk factors at health check-ups: endothelial function before and after work, subjective fatigue, lifestyle factors such as sleeping time, and psychosocial factors such as depression and social support. RESULTS: Twenty-five subjects (33.8%) had low endothelial function; reactive hyperemia (RH)-PAT index <1.67, even though no abnormalities were reported in the health check-ups. There was no significant difference in endothelial function before versus after labor. Of note, endothelial function was associated with the individual's level of subjective fatigue (t = 2.98, P = 0.008) and showed a daily fluctuation, sometimes to a pathological degree (<1.67). CONCLUSION: We showed that, even in healthy people, endothelial function fluctuates diurnally, with an interaction between the individual's cognitive fatigue and the environment, sometimes to a pathological degree. Based on these findings, we suggest that endothelial function is an objective assessment tool of fatigue in healthy individuals.

HMGB1: A new marker for estimation of the postmortem interval.

Estimation of the postmortem interval (PMI) is one of the most important tasks in forensic medicine. Numerous methods have been proposed for the determination of the time since death by chemical means. High mobility group box-1 (HMGB1), a nonhistone DNA-binding protein is released by eukaryotic cells upon necrosis. Postmortem serum levels of HMGB1 of 90 male Wistar rats stored at 4, 14 and 24°C since death were measured by enzyme-linked immunosorbent assay. The serum HMGB1 level showed a time-dependent increase up to seven days at 4°C. At 14°C, the HMGB1 level peaked at day 3, decreased at day 4, and then plateaued. At 24°C, the HMGB1 level peaked at day 2, decreased at day 3, and then plateaued. Our findings suggest that HMGB1 is related to the PMI in rats.

Edaravone attenuates cerebral ischemic injury by suppressing aquaporin-4.

Aquaporin-4 (AQP4) plays a role in the generation of post-ischemic edema. Pharmacological modulation of AQP4 function may thus provide a novel therapeutic strategy for the treatment of stroke, tumor-associated edema, epilepsy, traumatic brain injury, and other disorders of the central nervous system (CNS) associated with altered brain water balance. Edaravone, a free radical scavenger, is used for the treatment of acute ischemic stroke (AIS) in Japan. In this study, edaravone significantly reduced the infarct area and improved the neurological deficit scores at 24h after reperfusion in a rat transient focal ischemia model. Furthermore, edaravone markedly reduced AQP4 immunoreactivity and protein levels in the cerebral infarct area. In light of observations that edaravone specifically inhibited AQP4 in a rat transient focal ischemia model, we propose that edaravone might reduce cerebral edema through the inhibition of AQP4 expression following cerebral infarction.

Minocycline attenuates both OGD-induced HMGB1 release and HMGB1-induced cell death in ischemic neuronal injury in PC12 cells.

High mobility group box-1 (HMGB1), a non-histone DNA-binding protein, is massively released into the extracellular space from neuronal cells after ischemic insult and exacerbates brain tissue damage in rats. Minocycline is a semisynthetic second-generation tetracycline antibiotic which has recently been shown to be a promising neuroprotective agent. In this study, we found that minocycline inhibited HMGB1 release in oxygen-glucose deprivation (OGD)-treated PC12 cells and triggered the activation of p38mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases (ERK1/2). The ERK kinase (MEK)1/2 inhibitor U-0126 and p38MAPK inhibitor SB203580 blocked HMGB1 release in response to OGD. Furthermore, HMGB1 triggered cell death in a dose-dependent fashion. Minocycline significantly rescued HMGB1-induced cell death in a dose-dependent manner. In light of recent observations as well as the good safety profile of minocycline in humans, we propose that minocycline might play a potent neuroprotective role through the inhibition of HMGB1-induced neuronal cell death in cerebral infarction.