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Aims: Direct oral anticoagulant (DOAC) is widely used for the prevention of embolic stroke in non-valvular atrial fibrillation (NVAF) patients. However, the gastrointestinal bleeding risk in several DOAC regimens was higher than warfarin, especially in once-daily regimens. Methods and results: We conducted a single-center prospective registry of patients with NVAF treated with DOACs: the DIRECT registry (N = 2216; follow-up duration 650 [IQR 103–1574] days, UMIN000033283). All patients were divided into 2 groups: the twice-daily (BID) regimen group (dabigatran and apixaban) versus the once-daily (QD) regimen group (rivaroxaban and edoxaban). Out of 2216 patients, we successfully matched 904 patients in the QD group and 904 patients in the BID group using propensity score. The primary endpoint was gastrointestinal bleeding defined as any bleeding in the gastrointestinal tract that was identified through medical records regardless of bleeding site or severity. The BID group showed a significantly lower gastrointestinal bleeding rate than the QD group (3.5/100 person-year vs. 6.2/100 person-year, log-rank P

Background Newer implantable cardioverter defibrillators can monitor intracardiac ECGs , but their ability to detect ischemia is unclear. This study investigated the usefulness of implantable cardioverter defibrillators with an ST‐monitoring function in coronary artery disease patients. Methods and Results We conducted a prospective study of implantable cardioverter defibrillator patients with the ST‐monitoring function. One hundred seventy‐three patients who received implantable cardioverter defibrillators for primary or secondary prevention of sudden cardiac death. All patients underwent medical examinations at least every 6 months, with standard 12‐lead ECGs and device checks that included analysis of the ST‐monitoring function. Myocardial perfusion imaging or coronary angiography was performed during the follow‐up. The mean follow‐up duration was 23.3±7.7 months. Significant ST changes occurred in 15 patients (8.7%), of whom 14 were asymptomatic. The incidence of angina pectoris was significantly higher in the ST change (+) group than that in the ST change (−) group (28.6% versus 7.2%, P=0.03). In the patients who underwent myocardial perfusion imaging, the sensitivity, specificity, and negative predictive value of the ST‐monitoring feature to detect ischemia were 75.0%, 72.5%, and 93.5%, respectively. The sensitivity, specificity, and negative predictive value of the ST‐monitoring feature to predict residual stenosis evaluated using coronary angiography were 76.9%, 83.5%, and 97.5%, respectively. The percentage of patients with a septal right ventricular lead was significantly lower in the ST change (+) group than in the ST change (−) group (13.5% versus 33.5%, P=0.01). Conclusions If intracardiac ECGs ST changes are detected, it is necessary to use additional modalities even in asymptomatic patients. Clinical Trial Registration URL: upload.umin.ac.jp. Unique identifier: UMIN000011824.

A 78-year-old man was implanted with a cardiac resynchronization therapy defibrillator. One month later, chest X-ray and electrocardiography suggested left ventricular (LV) lead dislodgement. However, the LV lead pacing threshold obtained by a programmer was unchanged because anodal capture had developed, which made it difficult to confirm the LV lead dislodgement. Radiographs obtained in the catheterization laboratory revealed that the tip of the LV lead had dislodged into the right atrium. The LV lead was relocated into another lateral coronary vein. Electrocardiography showed the QRS duration to be shorter than prior to this revision.

Neocortex network activity changes from a deactivated state during quiescence to an activated state during arousal and vigilance. In urethane-anesthetized rats, cortical activation is readily produced by either stimulating the brainstem reticular formation or by application of cholinergic agonists into the thalamus. We studied the effects of cortical activation on spontaneous activity and sensory responses in the barrel cortex. Cortical activation leads to a suppression of low-frequency sensory responses and to a reduction in their variability due to the abolishment of up and down membrane potential fluctuations in cortical cells. Overall, sensory responses become sharper and more reliable during cortical activation. [ABSTRACT FROM AUTHOR]

Influence of subcortical inhibition on barrel cortex receptive fields. By the time neural responses driven by vibrissa stimuli reach the barrel cortex, they have undergone significant spatial and temporal transformations within subcortical relays. A major regulator of these transformations is thought to be subcortical GABA-mediated inhibition, but the actual degree of this influence is unknown. We used disinhibition produced by GABA receptor antagonists to unmask the excitatory sensory responses that are normally suppressed by inhibition in the main subcortical sensory relays to barrel cortex; principal trigeminal (Pr5) and primary thalamic (VPM) nuclei. We found that, within subcortical relays, inhibition only slightly suppresses short-latency receptive field responses, but robustly suppresses long-latency center and surround receptive field responses. However, the long-latency subcortical effects of inhibition are mostly not reflected in the barrel cortex. The most robust effect of subcortical inhibition on barrel cortex responses is to transiently suppress the receptive field responses of high-frequency sensory stimuli. This transient adaptation caused by subcortical inhibition recovers within a few stimuli and gives way to a steady-state adaptation that is independent of subcortical inhibition. [ABSTRACT FROM AUTHOR]

In the barrel cortex of rodents, cells respond to a principal whisker (PW) and more weakly to several adjacent whiskers (AWs). Here we show that compared with PW responses, simultaneous wide-field stimulation of the PW and several AWs enhances short-latency responses and suppresses long-latency responses. Multiwhisker enhancement and suppression is first seen at the level of the cortex in layer 4 and not in the ventroposterior medial thalamus. Within the cortex, enhancement is manifested as a reduction in spike latency in layer 4 but also as an increase in spike probability in layer 2/3. Intracellular recordings revealed that multiwhisker enhancement of short-latency responses is caused by synaptic summation that can be explained by synaptic cooperativity (i.e., convergence of synaptic inputs activated by different whiskers). Conversely, multiwhisker suppression of long-latency responses is due to increased recruitment of inhibition in cortical cells. Interestingly, the ability to differentiate multiwhisker and PW responses is lost during rapid sensory adaptation caused by high-frequency whisker stimulation. The results reveal that simultaneous and temporally dispersed wide-field sensory inputs are discriminated at the level of single cells in barrel cortex with high temporal resolution, but the ability to compute this difference is highly dynamic and dependent on the level of adaptation in the thalamocortical network. [ABSTRACT FROM AUTHOR]

Aldosterone promotes cardiovascular inflammation and remodeling, both of which are characteristic changes in hypertensive and failing hearts. Since chronic inhibition of nitric oxide (NO) synthase with Nω-nitro-L-arginine methyl ester (L-NAME) induces systemic hypertension associated with cardiovascular inflammation and remodeling, we examined the potential role of aldosterone in this process using eplerenone, a selective aldosterone receptor antagonist. Ten-week-old male Wistar-Kyoto rats were randomly divided into 3 groups: the control group (no treatment), the L-NAME group (received L-NAME 1 g/L in drinking water), and the L-NAME+Eplerenone group (L-NAME plus eplerenone at 100 mg/kg/day). After 8 weeks of the treatment, the L-NAME group showed significantly higher systolic blood pressure than the control group (198 ± 7 vs. 141 ± 3 mmHg, P < 0.05). Eplerenone did not affect the increase in blood pressure caused by L-NAME (189 ± 12 mmHg). Chronic inhibition of NO synthesis increased the plasma aldosterone concentration and CYP11B2 mRNA in adrenal glands. Cardiac inflammation and fibrosis were detected in the L-NAME group, while both changes were completely prevented by eplerenone. Cardiac hypertrophy was induced in L-NAME group, but was partially prevented by eplerenone. In the L-NAME group, left ventricular fractional shortening (LVFS: 27 ± 2 vs. 38 ± 1%) and E/A ratio (1.7 ± 0.1 vs. 2.1 ± 0.1) were significantly lower and LV end-diastolic pressure (LVEDP) was higher (4.9 ± 0.6 vs. 13.9 ± 0.5 mmHg) without LV enlargement, compared with those in the control group (P < 0.05). Eplerenone completely normalized LVFS (36 ± 2%), E/A ratio (2.2 ± 0.1), and LVEDP (6.2 ± 0.7 mmHg). These results suggest that chronic inhibition of NO synthesis induces cardiac inflammation and dysfunction via an aldosterone receptor-dependent mechanism. [ABSTRACT FROM AUTHOR]

Thalamocortical synapses may be able to undergo activity-dependent long-term changes in efficacy, such as long-term potentiation. Indeed, studies conducted in vivo have found that theta-burst stimulation (TBS) of the thalamus induces a long-term enhancement (LTE) of field potential responses evoked in the neocortex of adult rodents. Because the thalamus and neocortex form a complex interconnected network that is highly active in vivo, it is possible that a change in thalamic excitability would be reflected in the neocortex. To test this possibility, we recorded from barrel neocortex and applied TBS to the thalamic radiation while the somatosensory thalamus was inactivated with muscimol. Thalamocortical LTE was absent when the thalamus was inactivated, suggesting that changes in thalamic excitability are involved. Single-unit recordings from thalamocortical cells revealed that TBS causes a significant reduction in the spontaneous firing rate of thalamocortical cells. Reducing the spontaneous firing of thalamocortical cells directly enhances the efficacy of the thalamocortical pathway because it relieves the tonic depression of the thalamocortical connection caused by thalamocortical activity. Because these changes in thalamic excitability are triggered by corticothalamic activity, this may be a useful top-down mechanism to regulate afferent sensory input to the neocortex during behavior as a function of experience. [ABSTRACT FROM AUTHOR]

Abstract Although recent studies suggest that erythropoietin (EPO) may reduce multiple features of the myocardial ischemia/reperfusion injury, the cellular mechanisms and the clinical implications of EPO-induced cardioprotection are still unclear. Thus, in this study, we clarified dose-dependent effects of EPO administered just before reperfusion on infarct size and the incidence of ventricular fibrillation and evaluated the involvement of the phosphatidylinositol-3 (PI3) kinase in the in vivo canine model. The canine left anterior descending coronary artery was occluded for 90 min followed by 6 h of reperfusion. A single intravenous administration of EPO just before reperfusion significantly reduced infarct size (high dose (1,000 IU/kg): 7.7 1.6%, low dose (100 IU/kg): 22.1 2.4%, control: 40.0 3.6%) in a dose-dependent manner. Furthermore, the high, but not low, dose of EPO administered as a single injection significantly reduced the incidence of ventricular fibrillation during reperfusion (high dose: 0%, low dose: 40.0%, control: 50.0%). An intracoronary administration of a PI3 kinase inhibitor, wortmannin, blunted the infarct size-limiting and anti-arrhythmic effects of EPO. Low and high doses of EPO equally induced Akt phosphorylation and decreased the equivalent number of TUNEL-positive cells in the ischemic myocardium of dogs. These effects of EPO were abolished by the treatment with wortmannin. In conclusion, EPO administered just before reperfusion reduced infarct size and the incidence of ventricular fibrillation via the PI3 kinase-dependent pathway in canine hearts. EPO administration can be a realistic strategy for the treatment of acute myocardial infarction. [ABSTRACT FROM AUTHOR]