Effect of Direct Slow Pathway Capture Mapping-Guided Ablation on Typical Atrioventricular Nodal Re-Entrant Tachycardia.

BACKGROUND: Direct slow pathway capture (DSPC) mapping is a novel electrophysiological technique for detecting antegrade slow pathway input sites. However, the effect of DSPC mapping-guided ablation on atrioventricular nodal re-entrant tachycardia (AVNRT) is unknown. OBJECTIVES: This study aimed to evaluate the efficacy and safety of DSPC mapping-guided ablation in typical AVNRT patients. METHODS: A multicenter retrospective study was conducted in 301 consecutive typical AVNRT patients. The outcomes in patients who underwent DSPC mapping-guided ablation (DSPC group) and those who underwent conventional anatomical ablation (conventional group) were compared. The conventional group was established before introducing DSPC mapping-guided ablation. Positive DSPC sites were defined as sites with a return cycle atrioventricular prolongation of ≥20 ms with high-output (10-20 V) pacing during tachycardia or the last paced beat of the atrial extrastimulation. RESULTS: Among 116 patients in the DSPC group, 102 (88%) had positive DSPC sites, and 86 (74%) had a successful ablation at that site. Of the remaining 30 patients, 27 had a successful anatomical ablation. The DSPC group had a significantly lower frequency of radiofrequency applications and shorter total application time than the conventional group (median: 5.5 [IQR: 3-11] times vs 9 [IQR: 5-15] times, and 168 [IQR: 108-266] seconds vs 244 [IQR: 158-391] seconds, respectively; P < 0.01). Moreover, the DSPC group had a numerically lower incidence of permanent pacemaker implantations and AVNRT recurrences than the conventional group (0% vs 1.6%; P = 0.17, and 1.7% vs 3.2%; P = 0.43, respectively). CONCLUSIONS: DSPC mapping-guided ablation was associated with a lower operative time, which can reduce the risk of AV conduction injury in typical AVNRT.

Rationale and study design of the GOREISAN for heart failure (GOREISAN-HF) trial: A randomized clinical trial.

BACKGROUND: The decongestion strategy using loop diuretics is essential for improving signs and symptoms of heart failure (HF). However, chronic use of loop diuretics in HF has been linked to worsening renal function and adverse clinical outcomes in a dose-dependent manner. Goreisan, a traditional Japanese herbal medicine, has a long history of use in Japan for regulating body fluid homeostasis and has been recognized as causing less adverse outcomes such as dehydration in contrast to loop diuretics in clinical practice. Therefore, we designed the GOREISAN-HF trial to evaluate the long-term effects of a new decongestion strategy adding Goreisan to usual care in patients with HF and volume overload. METHODS: The GOREISAN-HF trial is an investigator-initiated, multicenter, pragmatic, randomized, comparative effectiveness trial in which we will enroll 2,192 patients hospitalized for HF at 68 hospitals in Japan. All study participants will be randomly assigned to either a decongestion strategy that adds Goreisan at a dose of 7.5 g daily on top of usual care or usual care alone. Investigators have the flexibility to change the existing diuretic regimen in both groups. The primary end point is the improvement rate of cardiac edema at 12-month follow-up, and the co-primary end point is a composite of all-cause death or hospitalization up to the end of the planned follow-up period. Secondary end points include longitudinal changes in patient-reported outcomes, loop diuretics dose, and renal function. CONCLUSIONS: The GOREISAN-HF is the first large-scale randomized pragmatic trial to assess the efficacy and safety of a new congestion control strategy adding Goreisan to usual care in patients with HF and volume overload. REGISTRATION NUMBER: NCT04691700.

The clinical practice of high-flow nasal cannula oxygen therapy in adults: A Japanese cross-sectional multicenter survey.

BACKGROUND: High-flow nasal cannula oxygen therapy (HFNC) is widely used mainly in the acute care setting, but limited data are available on real-world practice in adults. The objective of this study was to describe HFNC practices in Japanese adults. METHODS: A retrospective cross-sectional multicenter survey of adult patients receiving HFNC from January through March 2015 was conducted in 33 participating hospitals in Japan. RESULTS: We obtained information on 321 patients (median age, 76; 218 men, 103 women; median estimated PaO2/FIO2, 178 mm Hg) from 22 hospitals. Do-not-intubate status was determined in 37.4% of patients. Prior to HFNC, 57.9% of patients received conventional oxygen therapy; 25.9%, noninvasive ventilation; and 15.0%, invasive mechanical ventilation. The common indications for HFNC were acute hypoxemic respiratory failure (ARF) (65.4%), postoperative respiratory support (15.9%), and post-extubation respiratory support (11.2%). The underlying etiology of ARF included interstitial lung disease, pneumonia, and cardiogenic pulmonary edema. HFNC was administered mostly in intensive care units or intermittent care units (60.7%) and general wards (36.1%). Median duration of HFNC was 4 days; median total flow rate, 40 L/min; and median FIO2, 50%. HFNC significantly improved PaO2, PaCO2, SpO2 and respiratory rate from baseline. Two-thirds of patients finally survived to be discharged or transferred. CONCLUSIONS: We documented patient demographics, clinical indications, and settings of HFNC use in the real world. We also demonstrated positive effects of HFNC on respiratory parameters. Further studies are urgently needed regarding the efficacy and safety of HFNC in populations outside of previous clinical trials.

Surgical feasibility and biocompatibility of wide-field dual-array suprachoroidal-transretinal stimulation prosthesis in middle-sized animals.

PURPOSE: To investigate the safety and efficacy of a newly-developed wide-field dual-array suprachoroidal-transretinal stimulation (STS) prosthesis in middle-sized animals. METHODS: The prosthesis consisted of two arrays with 50 to 74 electrodes. To test the feasibility of implanting the prosthesis and its efficacy, the prosthesis was implanted for 14 days into two rabbits. Optical coherence tomography (OCT) and ophthalmoscopy were performed 7 and 14 days after the implantation. Then the rabbits were euthanized, eyes were enucleated, and the posterior segment of the eye was examined histologically. In a second experiment, the arrays were implanted into two cats, and their ability to elicit neural responses was determined by electrically evoked potentials (EEPs) at the chiasm and by optical imaging of the retina. RESULTS: All arrays were successfully implanted, and no major complications occurred during the surgery or during the 2-week postoperative period. Neither OCT nor ophthalmoscopy showed any major complications or instability of the arrays. Histological evaluations showed only mild cellular infiltration and overall good retinal preservation. Stimulation of the retina by the arrays evoked EEPs recorded from the chiasm. Retinal imaging showed that the electrical pulses from the arrays altered the retinal images indicating an activation of retinal neurons. The thresholds were as low as 100 µA for a chiasm response and 300 µA for the retinal imaging. CONCLUSION: Implantation of a newly-developed dual-array STS prosthesis for 2 weeks in rabbits was feasible surgically, and safe. The results of retinal imaging showed that the dual-array system was able to activate retinal neurons. We conclude that the dual-array design can be implanted without complication and is able to activate retinal neurons and optic nerve axons.

Comparative efficacy and safety of novel oral anticoagulants in patients with atrial fibrillation: A network meta-analysis with the adjustment for the possible bias from open label studies.

BACKGROUND: This study was designed to compare efficacy and safety among novel oral anticoagulants (NOACs), which have not been directly compared in randomized control trials to date. METHOD: We performed network meta-analyses of randomized control trials in preventing thromboembolic events and major bleeding in patients with atrial fibrillation. PubMed, Embase, and the Cochrane Database of Systematic Reviews for published studies and various registries of clinical trials for unpublished studies were searched for 2002-2013. All phase III randomized controlled trials (RCTs) of NOACs (apixaban, edoxaban, dabigatran, rivaroxaban), idraparinux, and ximelagatran were reviewed. RESULTS: A systematic literature search identified nine phase III RCTs for primary analyses. The efficacy of each NOAC was similar with respect to our primary composite endpoint following adjustment for open label designs [odds ratios (ORs) versus vitamin K antagonists: apixaban 0.79; dabigatran 150mg 0.77; edoxaban 60mg 0.87; rivaroxaban 0.86] except for dabigatran 110mg and edoxaban 30mg. Apixaban and edoxaban 30mg and 60mg had significantly fewer major bleeding events than dabigatran 150mg, ricvaroxaban, and vitamin K antagonists. All NOACs were similar in reducing secondary endpoints with the exception of dabigatran 110mg and 150mg which were associated with a significantly greater incidence of myocardial infarction compared to apixaban, edoxaban 60mg, and rivaroxaban. CONCLUSIONS: Our indirect comparison with adjustment for study design suggests that the efficacy of the examined NOACs is similar across drugs, but that some differences in safety and risk of myocardial infarction exist, and that open label study designs appear to overestimate safety and treatment efficacy. Differences in study design should be taken into account in the interpretation of results from RCTs of NOACs.

Role of electrical activity of neurons for neuroprotection.

Neurons of the central nervous system (CNS) of adult mammals can be damaged in a variety of ways. Most neurons rapidly die after injury. Even if the injured CNS neurons do not die in a short time, the neurons eventually die because they are not able to regenerate their axons to reconnect with their normal targets. In addition, neurons are normally not replaced. Therefore, much work has been directed toward understanding of the molecular regulation of the CNS degeneration following injury, and different experimental strategies are being used to try to protect the damaged neurons. Following axonal lesion, the neurons not only need to survive but also to reconnect to be functionally relevant, and efforts are directed toward not only survival but also axonal regeneration and proper rewiring of injured neurons. Recent experimental data suggest that electrical activity, endogenous or exogenous, can enhance neuronal survival and regeneration in vitro and in vivo. This chapter reviews the evidence that have been obtained on the role of neuronal electrical activity on neuroprotection. We will develop perspectives toward neuroprotection and regeneration of adult lesioned CNS neurons based on electrical activity-dependent cell survival that may be applicable to various diseases of the CNS.

Optimal parameters of transcorneal electrical stimulation (TES) to be neuroprotective of axotomized RGCs in adult rats.

We previously showed that transcorneal electrical stimulation (TES) promoted the survival of axotomized retinal ganglion cells (RGCs) of rats. However the relationship between the parameters of TES and the neuroprotective effect of TES on axotomized RGCs was unclear. In the present study, we determined whether the neuroprotective effect of TES is affected by the parameters of TES. Adult male Wistar rats received TES just after transection of the left optic nerve (ON). The pulse duration, current intensity, frequency, waveform, and numbers of sessions of the TES were changed systematically. The alterations of the retina were examined histologically seven days or fourteen days after the ON transection. The optimal neuroprotective parameters were pulse duration of 1 and 2 ms/phase (P < 0.001, each), current intensity of 100 and 200 muA (P < 0.05, each), and stimulation frequency of 1, 5, and 20 Hz (P < 0.001, respectively). More than 30 min of TES was necessary to have a neuroprotective effect (P < 0.001). Symmetric pulses without an inter-pulse interval were most effective (P < 0.001). Repeated TES was more neuroprotective than a single TES at 14 days after ON transection (P < 0.001). Our results indicate that there is a range of optimal neuroprotective parameters of TES for axotomized RGCs of rats. These values will provide a guideline for the use of TES in patients with different retinal and optic nerve diseases.

Axonal regeneration induced by repetitive electrical stimulation of crushed optic nerve in adult rats.

PURPOSE: To investigate whether electrical stimulation promoted axonal regeneration of retinal ganglion cells (RGCs) after optic nerve (ON) crush in adult rats. METHODS: Transcorneal electrical stimulation (TES), which stimulates the retina with current from a corneal contact lens electrode, was used to stimulate the eye. TES was applied for 1 h immediately after ON crush. Axonal regeneration was determined by anterograde labeling of RGC axons. To examine whether the axonal regeneration was mediated by insulin-like growth factor 1 (IGF-1) receptors, an IGF-1 receptor antagonist, JB3, was injected intraperitoneally before each TES application. Immunostaining for IGF-1 was performed to examine the effects of TES. To test the survival-promoting effects of TES applied daily, the mean density of retrogradely labeled RGCs was determined on day 12 after ON crush. RESULTS: Compared with sham stimulation, the mean number of regenerating axons significantly increased at 250 microm distal from the lesion and increased IGF-1 immunoreactivity was observed in retinas treated daily with TES. Preinjection of an IGF-1 receptor antagonist significantly blocked axonal regeneration by TES applied daily. TES applied daily also markedly enhanced the survival of RGCs 12 days after ON crush. CONCLUSION: TES applied daily promotes both axonal regeneration and survival of RGCs after ON crush.

Parameters of optic nerve electrical stimulation affecting neuroprotection of axotomized retinal ganglion cells in adult rats.

We previously showed the enhancement of survival of retinal ganglion cells (RGCs) by electrical stimulation (ES) of the optic nerve (ON) stump in adult rats. To elucidate the mechanisms underlying the survival enhancement, we determined whether the neuroprotective effect of ES is affected by the following parameters: stimulation time, frequency of current pulses and starting of ES. ES for 10min immediately after ON transection was not effective in increasing the number of surviving RGCs 7 days after the transection, but that for 30min was effective. ES at 20Hz was the most effective, when applied just after axotomy. When the starting of ES to the ON was shifted either 3h after or 4h before the axotomy, the neuroprotective effect of ES was not observed. These results suggest that the electrical activation of RGCs and/or the transected ON interfere with early events after axotomy that leads to RGC death.

Transcorneal electrical stimulation promotes the survival of photoreceptors and preserves retinal function in royal college of surgeons rats.

PURPOSE: To determine whether transcorneal electrical stimulation (TES) has neuroprotective effects on photoreceptors and preserves retinal function in Royal College of Surgeons (RCS) rats. METHODS: Three-week-old RCS rats received TES through a contact lens electrode on the left eye weekly for 2 to 6 weeks. The right eyes received sham stimulation on the same days. Electroretinograms (ERGs) were recorded from the rats at 3 weeks (before TES), and at 5, 7, and 9 weeks of age. After the ERG recordings, the rats were killed for morphologic analyses of the retina. RESULTS: Morphologic analyses showed that the mean thickness of the outer nuclear layer (ONL) at each time point was significantly thicker in eyes treated with TES of 100 muA than in eyes with sham stimulation (TES 100 muA versus sham: 5, 7, and 9 weeks of age; P < 0.001). ERG studies showed that TES also significantly preserved retinal function up to 7 weeks of age, but did not preserve retinal function at 9 weeks of age. CONCLUSIONS: TES prolongs the survival of photoreceptors and delays the decrease of retinal function in RCS rats. Although further investigations are necessary before using TES on patients, these findings indicate that TES may be a therapeutic treatment for some patients with diseases of the photoreceptors such as retinitis pigmentosa.

Evaluation of phosphenes elicited by extraocular stimulation in normals and by suprachoroidal-transretinal stimulation in patients with retinitis pigmentosa.

BACKGROUND: To determine the efficient parameters to evoke electrical phosphenes is essential for the development of a retinal prosthesis. We studied the efficient parameters in normal subjects and investigated if suprachoroidal-transretinal stimulation (STS) is effective in patients with advanced retinitis pigmentosa (RP) using these efficient parameters. METHODS: The amplitude of pupillary reflex (PR) evoked by transcorneal electrical stimulation (TcES) was determined at different frequencies in eight normal subjects. The relationship between localized phosphenes elicited by transscleral electrical stimulation (TsES) and the pulse parameters was also examined in six normal subjects. The phosphenes evoked by STS were examined in two patients with RP with bare light perception. Biphasic pulses (cathodic first, duration: 0.5 or 1.0 ms, frequency: 20 Hz) were applied through selected channel(s). The size and shape of the phosphenes perceived by the patients were recorded. RESULTS: The maximum PR was evoked by TcES with a frequency of 20 Hz. The brightest phosphene was elicited by TsES with a pulse train of more than 10 pulses, duration of 0.5-1.0 ms and a frequency of 20 to 50 Hz. In RP patients, localized phosphenes were elicited with a current of 0.3-0.5 mA (0.5 ms) in patient 1 and 0.4 mA (1.0 ms) in patient 2. Two isolated or dumbbell-shaped phosphenes were perceived when the stimulus was delivered through two adjacent channels. CONCLUSION: Biphasic pulse trains (> or =10 pulses) with a duration of 0.5-1.0 ms and a frequency of 20-50 Hz were efficient for evoking phosphenes by localized extraocular stimulation in normal subjects. With these parameters, STS is a feasible method to use with a retinal prosthesis even in advanced stages of RPs.

Effect of transcorneal electrical stimulation in patients with nonarteritic ischemic optic neuropathy or traumatic optic neuropathy.

PURPOSE: To determine whether transcorneal electrical stimulation (TES) can improve the visual function of patients with nonarteritic ischemic optic neuropathy (NAION) or traumatic optic neuropathy (TON). METHODS: Eight consecutive patients at the Osaka University Hospital were studied. TES (600-800 microA, 20 Hz, 30 min) was applied once each to three eyes with NAION and to five eyes with TON, using a contact lens-type stimulating electrode. The primary outcome measurement was the change in visual acuity at 1 to 3 months after TES. An improvement in visual acuity was defined as a change of > or =0.3 log (minimum angle of resolution) (logMAR) units. The side effects of TES were also investigated. RESULTS: After TES application, the visual acuity improved in two patients with NAION and in four patients with TON. Visual acuity did not worsen in any of the eyes. Only a mild superficial punctuate keratopathy was observed in all eyes immediately after TES, and it healed by the next day. CONCLUSIONS: Visual acuity can be improved after TES without major complications in some patients with NAION or TON. These results suggest that TES should be considered as a new treatment for eyes with optic neuropathy.

Transcorneal electrical stimulation rescues axotomized retinal ganglion cells by activating endogenous retinal IGF-1 system.

PURPOSE: To investigate the effect of transcorneal electrical stimulation (TES) on the survival of axotomized RGCs and the mechanism underlying the TES-induced neuroprotection in vivo. METHODS: Adult male Wistar rats received TES after optic nerve (ON) transection. Seven days after the ON transection, the density of the surviving RGCs was determined, to evaluate the neuroprotective effect of TES. The levels of the mRNA and protein of insulin-like growth factor (IGF)-1 in the retina after TES were determined by RT-PCR and Northern and Western blot analyses. The localization of IGF-1 protein in the retina was examined by immunohistochemistry. RESULTS: TES after ON transection increased the survival of axotomized RGCs in vivo, and the degree of rescue depended on the strength of the electric charge. RT-PCR and Northern and Western blot analyses revealed a gradual upregulation of intrinsic IGF-1 in the retina after TES. Immunohistochemical analysis showed that IGF-1 immunoreactivity was localized initially in the endfeet of Muller cells and then diffused into the inner retina. CONCLUSIONS: TES can rescue the axotomized RGCs by increasing the level of IGF-1 production by Muller cells. These findings provide a new therapeutic approach to prevent or delay the degeneration of retinal neurons without the administration of exogenous neurotrophic factors.

Electrophysiological studies of the feasibility of suprachoroidal-transretinal stimulation for artificial vision in normal and RCS rats.

PURPOSE: Assessment of a novel method of retinal stimulation, known as suprachoroidal-transretinal stimulation (STS), which was designed to minimize insult to the retina by implantation of stimulating electrodes for artificial vision. METHODS: In 17 normal hooded rats and 12 Royal College of Surgeons (RCS) rats, a small area of the retina was focally stimulated with electric currents through an anode placed on the fenestrated sclera and a cathode inserted into the vitreous chamber. Evoked potentials (EPs) in response to STS were recorded from the surface of the superior colliculus (SC) with a silver-ball electrode, and their physiological properties and localization were studied. RESULTS: In both normal and RCS rats, STS elicited triphasic EPs that were vastly diminished by changing polarity of stimulating electrodes and abolished by transecting the optic nerve. The threshold intensity (C) of the EP response to STS was approximately 7.2 +/- 2.8 nC in normal and 12.9 +/- 7.7 nC in RCS rats. The responses to minimal STS were localized in an area on the SC surface measuring 0.12 +/- 0.07 mm(2) in normal rats and 0.24 +/- 0.12 mm(2) in RCS rats. The responsive area corresponded retinotopically to the retinal region immediately beneath the anodic stimulating electrode. CONCLUSIONS: STS is less invasive in the retina than stimulation through epiretinal or subretinal implants. STS can generate focal excitation in retinal ganglion cells in normal animals and in those with degenerated photoreceptors, which suggests that this method of retinal stimulation is suitable for artificial vision.