Synaptotagmin-11 mediates a vesicle trafficking pathway that is essential for development and synaptic plasticity.

Synaptotagmin-11 (Syt11) is a Synaptotagmin isoform that lacks an apparent ability to bind calcium, phospholipids, or SNARE proteins. While human genetic studies have linked mutations in the Syt11 gene to schizophrenia and Parkinson's disease, the localization or physiological role of Syt11 remain unclear. We found that in neurons, Syt11 resides on abundant vesicles that differ from synaptic vesicles and resemble trafficking endosomes. These vesicles recycle via the plasma membrane in an activity-dependent manner, but their exocytosis is slow and desynchronized. Constitutive knockout mice lacking Syt11 died shortly after birth, suggesting Syt11-mediated membrane transport is required for survival. In contrast, selective ablation of Syt11 in excitatory forebrain neurons using a conditional knockout did not affect life span but impaired synaptic plasticity and memory. Syt11-deficient neurons displayed normal secretion of fast neurotransmitters and peptides but exhibited a reduction of long-term synaptic potentiation. Hence, Syt11 is an essential component of a neuronal vesicular trafficking pathway that differs from the well-characterized synaptic vesicle trafficking pathway but is also essential for life.

A genetically targeted reporter for PET imaging of deep neuronal circuits in mammalian brains.

Positron emission tomography (PET) allows biomolecular tracking but PET monitoring of brain networks has been hampered by a lack of suitable reporters. Here, we take advantage of bacterial dihydrofolate reductase, ecDHFR, and its unique antagonist, TMP, to facilitate in vivo imaging in the brain. Peripheral administration of radiofluorinated and fluorescent TMP analogs enabled PET and intravital microscopy, respectively, of neuronal ecDHFR expression in mice. This technique can be used to the visualize neuronal circuit activity elicited by chemogenetic manipulation in the mouse hippocampus. Notably, ecDHFR-PET allows mapping of neuronal projections in non-human primate brains, demonstrating the applicability of ecDHFR-based tracking technologies for network monitoring. Finally, we demonstrate the utility of TMP analogs for PET studies of turnover and self-assembly of proteins tagged with ecDHFR mutants. These results establish opportunities for a broad spectrum of previously unattainable PET analyses of mammalian brain circuits at the molecular level.

Clinical outcomes and predictors of delayed echocardiographic response to cardiac resynchronization therapy.

INTRODUCTION: The clinical outcomes and mechanisms of delayed responses to cardiac resynchronization therapy (CRT) remain unclear. We aimed to investigate the differences in outcomes and gain insight into the mechanisms of early and delayed responses to CRT. METHODS: This retrospective study included 110 patients who underwent CRT implantation. Positive response to CRT was defined as ≥15% reduction of left ventricular (LV) end-systolic volume on echocardiography at 1 year (early phase) and 3 years (delayed phase) after implantation. The latest mechanical activation site (LMAS) of the LV was identified using two-dimensional speckle-tracking radial strain analysis. RESULTS: Seventy-eight (71%) patients exhibited an early response 1 year after CRT implantation. Of 32 non-responders in the early phase, 12 (38%) demonstrated a delayed response, and 20 (62%) were classified as non-responders after 3 years. During the follow-up time of 10.3 ± 0.5 years, the delayed and early responders had a similar prognosis of mortality and heart failure (HF) hospitalization. In contrast, non-responders had a worse prognosis. Multivariate analysis revealed that a longer duration (months) between initial HF hospitalization and CRT (odds ratio [OR]: 1.126; 95% confidence interval [CI]: 1.036-1.222; p = .005), non-exact concordance of LV lead location with LMAS (OR: 32.744; 95% CI: 1.101-973.518; p = .044), and pre-QRS duration (OR: 0.901; 95% CI: 0.827-0.981; p = .016) were independent predictors of delayed response to CRT compared with early response. CONCLUSION: The prognoses were similar regardless of the response time after CRT. A longer history of HF, suboptimal LV lead position, and shorter pre-QRS duration were related to delayed response than early response.

Comparison of novel intrinsic versus conventional antitachycardia pacing for ventricular tachycardia among implantable cardioverter-defibrillator recipients.

INTRODUCTION: Intrinsic antitachycardia pacing (iATP) is a novel automated antitachycardia pacing (ATP) that provides individual treatment to terminate ventricular tachycardia (VT). However, the clinical efficacy of iATP in comparison with conventional ATP is unknown. We aim to compare the termination rate of VT between iATP and conventional ATP in patients with implantable cardioverter-defibrillators using a unique setting of different sequential orders of both ATP algorisms. METHODS: Patients with the iATP algorithm were assigned to iATP-first and conventional ATP-first groups sequentially. In the iATP-first group, a maximum of seven iATP sequences were delivered, followed by conventional burst and ramp pacing. In contrast, in the conventional ATP-first group, two bursts and ramp pacing were initially programmed, followed by iATP sequences. We compared the success rates of VT termination in the first and secondary programmed ATP zones between the two groups. RESULTS: Fifty-eight and 56 patients were enrolled in the iATP-first and conventional ATP-first groups, and 67 and 44 VTs were analyzed in each group, respectively. At the first single ATP therapy, success rates were 64% and 70% in the iATP and conventional groups, respectively. At the end of the first iATP treatment zone, the success rate increased from 64% to 85%. Moreover, secondary iATP therapy following the failure of conventional ATPs increased the success rate from 80% to 93%. There was a significant benefit of alternative iATP for VT termination compared to secondary conventional ATP (100% vs. 33%, p = .028). CONCLUSIONS: iATP may be beneficial as a secondary therapy after failure of conventional ATP to terminate VT.

A novel practical algorithm using machine learning to differentiate outflow tract ventricular arrhythmia origins.

INTRODUCTION: Diagnosis of outflow tract ventricular arrhythmia (OTVA) localization by an electrocardiographic complex is key to successful catheter ablation for OTVA. However, diagnosing the origin of OTVA with a precordial transition in lead V3 (V3TZ) is challenging. This study aimed to create the best practical electrocardiogram algorithm to differentiate the left ventricular outflow tract (LVOT) from the right ventricular outflow tract (RVOT) of OTVA origin with V3TZ using machine learning. METHODS: Of 498 consecutive patients undergoing catheter ablation for OTVA, we included 104 patients who underwent ablation for OTVA with V3TZ and identified the origin of LVOT (n = 62) and RVOT (n = 42) from the results. We analyzed the standard 12-lead electrocardiogram preoperatively and measured 128 elements in each case. The study population was randomly divided into training group (70%) and testing group (30%), and decision tree analysis was performed using the measured elements as features. The performance of the algorithm created in the training group was verified in the testing group. RESULTS: Four measurements were identified as important features: the aVF/II R-wave ratio, the V2S/V3R index, the QRS amplitude in lead V3, and the R-wave deflection slope in lead V3. Among them, the aVF/II R-wave ratio and the V2S/V3R index had a particularly strong influence on the algorithm. The performance of this algorithm was extremely high, with an accuracy of 94.4%, precision of 91.5%, recall of 100%, and an F1-score of 0.96. CONCLUSIONS: The novel algorithm created using machine learning is useful in diagnosing the origin of OTVA with V3TZ.

A rare case of delayed complete lead dislodgement after deep septal pacing: A hidden risk of the specific procedure.

Deep septal ventricular pacing is a recently developed physiological pacing modality with good efficacy; however, it has a potential risk of unusual complications. Here, we report a patient with pacing failure and spontaneous, complete lead dislodgement after >2 years of deep septal pacing, possibly caused by systemic bacterial infection and specific lead behavior in the septal myocardium. This case report may implicate a hidden risk of unusual complications in deep septal pacing.

Characteristics of successful reactive atrial-based antitachycardia pacing in patients with cardiac implantable electronic devices: History of catheter ablation of atrial fibrillation as a predictor of high treatment efficacy.

INTRODUCTION: Reactive atrial-based antitachycardia pacing (rATP) in patients with cardiac implantable electronic devices (CIEDs) suppresses the progression of atrial fibrillation (AF) to the persistent form. However, the clinical factors associated with successful reactive atrial-based antitachycardia pacing (rATP) treatment are unknown. This study aimed to examine the predictors of high rATP efficacy in patients with CIEDs. METHODS: The data of 101,325 rATP-treated atrial tachyarrhythmia (AT/AF) episodes in 51 patients, obtained through remote monitoring and device interrogation, were analyzed. The study population was divided into the high and low efficacy groups based on the overall median success rate of rATP. Clinical characteristics were compared between the two groups. RESULTS: During a follow-up period of 28.6 ± 8.6 months, the median success rate was 43.7% (31.5%-64.9%). The prevalence of a history of catheter ablation of AF was significantly higher in the high efficacy group than in the low efficacy group (73.0% vs. 44.0%, p = .048) and was the only independent predictor of high rATP efficacy (odds ratio, 3.45; p = .038). The rATP success rate in patients with (n = 30) and without (n = 21) a history of catheter ablation was 53.9% (40.0%-67.5%) and 36.4% (22.2%-47.7%), respectively (p = .012). The effect of rATP after ablation was more pronounced in patients with long cycle length episodes (≥75% of AT/AF sequences having a cycle length of 200-449 ms) (67.3% [46.0%-73.6%] vs. 30.6% [18.1%-60.3%], p = .027). The high efficacy group had a significantly lower incidence of AT/AF lasting ≥1, ≥7, and ≥30 days than the low efficacy group. CONCLUSION: rATP combined with catheter ablation therapy is effective in suppressing AT/AF.

A quantitative in vivo imaging platform for tracking pathological tau depositions and resultant neuronal death in a mouse model.

PURPOSE: Depositions of tau fibrils are implicated in diverse neurodegenerative disorders, including Alzheimer's disease, and precise assessments of tau pathologies and their impacts on neuronal survival are crucial for pursuing the neurodegenerative tau pathogenesis with and without potential therapies. We aimed to establish an in vivo imaging system to quantify tau accumulations with positron emission tomography (PET) and brain atrophy with volumetric MRI in rTg4510 transgenic mice modeling neurodegenerative tauopathies. METHODS: A total of 91 rTg4510 and non-transgenic control mice underwent PET with a tau radiotracer, 18F-PM-PBB3, and MRI at various ages (1.8-12.3 months). Using the cerebellum as reference, the radiotracer binding in target regions was estimated as standardized uptake value ratio (SUVR) and distribution volume ratio (DVR). Histopathological staining of brain sections derived from scanned animals was also conducted to investigate the imaging-neuropathology correlations. RESULTS: 18F-PM-PBB3 SUVR at 40-60 min in the neocortex, hippocampus, and striatum of rTg4510 mice agreed with DVR, became significantly different from control values around 4-5 months of age, and progressively and negatively correlated with age and local volumes, respectively. Neocortical SUVR also correlated with the abundance of tau inclusions labeled with PM-PBB3 fluorescence, Gallyas-Braak silver impregnation, and anti-phospho-tau antibodies in postmortem assays. The in vivo and ex vivo 18F-PM-PBB3 binding was blocked by non-radioactive PM-PBB3. 18F-PM-PBB3 yielded a 1.6-fold greater dynamic range for tau imaging than its ancestor, 11C-PBB3. CONCLUSION: Our imaging platform has enabled the quantification of tau depositions and consequent neuronal loss and is potentially applicable to the evaluation of candidate anti-tau and neuroprotective drugs.

Identification of high priority focal activations in persistent atrial fibrillation using a novel mapping strategy.

Focal activation is believed to be an atrial fibrillation (AF) driver; however, little is known about whether all focal activations are necessary for AF persistence. The purpose of this study was to assess the electrical nature of focal activation and identify high-priority focal activations using a novel mapping system (CARTOFINDER). Thirty-five patients with persistent AF who underwent catheter ablation were assessed. Cycle length (CL) and CL standard deviation (CLSD) on unipolar recordings and voltage amplitude and electrogram morphologies on bipolar recordings were evaluated at all points of interest. The most frequent CL at each mapping site was defined as the dominant CL. We identified dominant focal activations (DFAs) that had a shorter dominant CL on the integrated CARTOFINDER map. The effect of elimination of DFAs on AF maintenance was assessed by the composite endpoint (termination to sinus rhythm, organization of the rhythm to atrial tachycardia, and AF CL slowing). In all, 450 focal activations were identified among 10,868 points, and 50.4% of focal activations were DFAs. Focal activations showed relatively long CL and regularity with short CLSD. Most focal activations showed an isoelectric baseline and were located outside of the fractionated electrogram area. Both DFAs and non-DFAs were typically observed in the normal voltage range. Elimination of DFAs was achieved in 19 (54.3%) patients, with a remarkable impact on AF maintenance (68.4% vs. 25.0%, p = 0.018). In conclusion, DFAs may play an important role in AF maintenance and could be an attractive therapeutic target for AF.

Depolarization and repolarization dynamics after His-bundle pacing: Comparison with right ventricular pacing and native ventricular conduction.

BACKGROUND: The current study aimed to evaluate changes in electrical depolarization and repolarization parameters after His-bundle pacing (HBP) compared with right ventricular pacing (RVP) and its association with ventricular arrhythmia (VA). METHODS: Forty-one patients (13 with HBP, 14 with RVP, and 14 controls [AAI mode]) were evaluated. After continuous pacing algorithm, QRS duration, QT interval, QTc, JT interval, T-peak to T-end (Tpe), and Tpe/QT ratio were measured on electrocardiography at baseline and 1 week, 1 month, and 6 months postoperatively. We investigated VA occurrence and adverse events after implantation. RESULTS: At 6 months, QRS duration was significantly shorter in the HBP (121.6 ± 15.6 ms) than in the RVP (150.1 ± 14.9 ms) group. The QT intervals were lower in the HBP (424.0 ± 40.9 ms) and control (405.9 ± 23.0 ms) groups than in the RVP (453.0 ± 40.2 ms) group. The Tpe and Tpe/QT ratios at 6 months differed significantly between the HBP and RVP groups (Tpe, 69.8 ± 19.7 ms vs 87.4 ± 11.9 ms and Tpe/QT, 0.16 ± 0.03 vs 0.19 ± 0.02, respectively). The Tpe and Tpe/QT ratios were similarly shortened in the HBP and control groups. VA occurred less frequently in the HBP (15%) and control (7.1%) groups than in the RVP (50%) group (p = 0.020). The non-RVP group showed significantly lower rates of VA and major adverse events than the RVP group. Patients with VA demonstrated significantly longer QRS duration, QT interval, Tpe, and Tpe/QT at 6 months than those without VA. CONCLUSION: HBP showed better depolarization and repolarization stability than RVP.

Evaluation of the Novel Automated Anti-Tachycardia Pacing Algorithm Successfully Terminating Sustained Monomorphic Ventricular Tachycardia in an Electrophysiology Study.

We report the usefulness of novel automated anti-tachycardia pacing (ATP) for ventricular tachycardia (VT) termination evaluated in an electrophysiology study. This intrinsic, automated ATP with an implanted cardiac resynchronization therapy-defibrillator successfully terminated the sustained VT, which had not been suppressed by repetitive burst pacing from the electrode catheter. The reproduction of programed pacing of the automated ATP by a right ventricular electrode catheter was effective in terminating VT, and this termination was absolute and reproducible. Further detailed assessment in an electrophysiology study could highlight the algorithm of the automated ATP and its possible benefit in terminating the reentrant VT.

Selective Disruption of Inhibitory Synapses Leading to Neuronal Hyperexcitability at an Early Stage of Tau Pathogenesis in a Mouse Model.

Synaptic dysfunction provoking dysregulated cortical neural circuits is currently hypothesized as a key pathophysiological process underlying clinical manifestations in Alzheimer's disease and related neurodegenerative tauopathies. Here, we conducted PET along with postmortem assays to investigate time course changes of excitatory and inhibitory synaptic constituents in an rTg4510 mouse model of tauopathy, which develops tau pathologies leading to noticeable brain atrophy at 5-6 months of age. Both male and female mice were analyzed in this study. We observed that radiosignals derived from [11C]flumazenil, a tracer for benzodiazepine receptor, in rTg4510 mice were significantly lower than the levels in nontransgenic littermates at 2-3 months of age. In contrast, retentions of (E)-[11C]ABP688, a tracer for mGluR5, were unaltered relative to controls at 2 months of age but then gradually declined with aging in parallel with progressive brain atrophy. Biochemical and immunohistochemical assessment of postmortem brain tissues demonstrated that inhibitory, but not excitatory, synaptic constituents selectively diminished without overt loss of somas of GABAergic interneurons in the neocortex and hippocampus of rTg4510 mice at 2 months of age, which was concurrent with enhanced immunoreactivity of cFos, a well-characterized immediate early gene, suggesting that impaired inhibitory neurotransmission may cause hyperexcitability of cortical circuits. Our findings indicate that tau-induced disruption of the inhibitory synapse may be a critical trigger of progressive neurodegeneration, resulting in massive neuronal loss, and PET assessments of inhibitory versus excitatory synapses potentially offer in vivo indices for hyperexcitability and excitotoxicity early in the etiologic pathway of neurodegenerative tauopathies.SIGNIFICANCE STATEMENT In this study, we examined the in vivo status of excitatory and inhibitory synapses in the brain of the rTg4510 tauopathy mouse model by PET imaging with (E)-[11C]ABP688 and [11C]flumazenil, respectively. We identified inhibitory synapse as being significantly dysregulated before brain atrophy at 2 months of age, while excitatory synapse stayed relatively intact at this stage. In line with this observation, postmortem assessment of brain tissues demonstrated selective attenuation of inhibitory synaptic constituents accompanied by the upregulation of cFos before the formation of tau pathology in the forebrain at young ages. Our findings indicate that selective degeneration of inhibitory synapse with hyperexcitability in the cortical circuit constitutes the critical early pathophysiology of tauopathy.

Prognostic value of leucine/phenylalanine ratio as an amino acid profile of heart failure.

Heart failure (HF) causes a hypercatabolic state that enhances the catabolic activity of branched-chain amino acids (BCAA; leucine, isoleucine, and valine) in the heart and skeletal muscles and reduces protein synthesis in the liver. Consequently, free plasma aromatic amino acids (AAA, tyrosine and phenylalanine) are increased. To date, we have reported the prognostic value of the BCAA/AAA ratio (Fischer's ratio) in patients with HF. However, the leucine/phenylalanine ratio, which is a simpler index than the Fischer's ratio, has not been examined. Therefore, the prognostic value of the leucine/phenylalanine ratio in patients with HF was investigated. Overall 157 consecutive patients hospitalized for worsening HF (81 men, median age 78 years) were enrolled in the study. Plasma amino acid levels were measured when the patients were stabilized at discharge. Cardiac events were defined as a composite of cardiac death and hospitalization for worsening HF. A total of 46 cardiac events occurred during the median follow-up period of 238 (interquartile range 93-365) days. The median leucine/phenylalanine ratio was significantly lower in patients with cardiac events than in those without cardiac events (1.4 vs. 1.8, P < 0.001). The best cutoff value of the leucine/phenylalanine ratio was determined as 1.7 in the receiver operating characteristic (ROC) curve for cardiac events. Following a Kaplan-Meier survival analysis, the low group (leucine/phenylalanine ratio < 1.7, n = 72) had more cardiac events than the high group (leucine/phenylalanine ratio ≥ 1.7, n = 85) (log-rank, P < 0.001). Multivariate Cox proportional hazards regression analysis showed that the leucine/phenylalanine ratio was an independent predictor of cardiac events. Furthermore, on comparing the prognostic values for cardiac events based on ROC curves of leucine levels, BCAA levels, Fischer's ratio, and leucine/phenylalanine ratio, the leucine/phenylalanine ratio was the most accurate in predicting future cardiac events (area under the curve 0.763,; sensitivity 0.783,; specificity 0.676,; P < 0.001). The leucine/phenylalanine ratio could be a useful predictor of future cardiac events in patients with HF, reflecting an imbalance in amino acid metabolism.

Mechanisms of torsades de pointes: an update.

Torsades de Pointes (TdP) refers to a polymorphic ventricular tachycardia (VT) with undulating QRS axis that occurs in long QT syndrome (LQTS), although the term has been used to describe polymorphic ventricular tachyarrhythmias in which QT intervals are not prolonged, such as short-coupled variant of TdP currently known as short-coupled ventricular fibrillation (VF) and Brugada syndrome. Extensive works on LQTS-related TdP over more than 50 years since it was first recognized by Dessertennes who coined the French term meaning "twisting of the points", have led to current understanding of the electrophysiological mechanism that TdP is initiated by triggered activity due to early afterdepolarization (EAD) and maintained by reentry within a substrate of inhomogeneous repolarization. While a recently emerging notion that steep voltage gradients rather than EADs are crucial to generate premature ventricular contractions provides additions to the initiation mode, the research to elucidate the maintenance mechanism hasn't made much progress. The reentrant activity that produces the specific form of VT is not well characterized. We have conducted optical mapping in a rabbit model of electrical storm by electrical remodeling (QT prolongation) due to chronic complete atrioventricular block and demonstrated that a tissue-island with prolonged refractoriness due to enhanced late Na+ current (INa-L) contributes to the generation of drifting rotors in a unique manner, which may explain the ECG characteristic of TdP. Moreover, we have proposed that the neural Na+ channel NaV1.8-mediated INa-L may be a new player to form the substrate for TdP. Here we discuss TdP mechanisms by comparing the findings in electrical storm rabbits with recently published studies by others in simulation models and human and animal models of LQTS.

Feasibility and efficacy of real-time ultrasound-guided venous closure with suture-mediated vascular closure device.

BACKGROUND: Venous vascular access complications are usually nonfatal but are the most common complications after transvenous catheter intervention. Vascular closure devices (VCDs) have recently become available for venous closure. OBJECTIVE: This study aimed to evaluate the feasibility and efficacy of real-time ultrasound-guided venous closure with suture-mediated VCDs in patients who underwent catheter ablation. METHODS: This single-center observational study enrolled 226 consecutive patients who underwent elective catheter ablation with femoral venipuncture. For hemostasis, vessel closure by VCD was performed with real-time ultrasound guidance after 2022 (n = 123) and without ultrasound guidance in 2021 (n = 103). The occurrence of venous access site-related complications (major, minor, or other) was compared. RESULTS: The rate of device failure was significantly lower in patients with ultrasound guidance than in those without (1.6% vs 6.3%; P = .048). The occurrence of all venous access site-related complications was significantly lower in patients with ultrasound guidance than in those without (4.9% vs 18.4%; P = .001). Time to ambulation was shorter in patients with ultrasound guidance than in those without (2.0 ± 0.1 hours vs 2.2 ± 0.6 hours; P < .001). CONCLUSION: Real-time ultrasound guidance can reduce device failure, access site-related complications, and time to ambulation in performing venous closure with a VCD.

Distributions and number of drivers on real-time phase mapping associated with successful atrial fibrillation termination during catheter ablation for non-paroxysmal atrial fibrillation.

BACKGROUND: Real-time phase mapping (ExTRa™) is useful in determining the strategy of catheter ablation for non-paroxysmal atrial fibrillation (AF). This study aimed to investigate the features of drivers of AF associated with its termination during ablation. METHODS: Thirty-six patients who underwent catheter ablation for non-paroxysmal AF using online real-time phase mapping (ExTRa™) were enrolled. A significant AF driver was defined as an area with a non-passively activated ratio of ≥ 50% on mapping analysis in the left atrium (LA). All drivers were simultaneously evaluated using a low-voltage area, complex fractionated atrial electrogram (CFAE), and rotational activity by unipolar electrogram analysis. The electrical characteristics of drivers were compared between patients with and without AF termination during the procedure. RESULTS: Twelve patients achieved AF termination during the procedure. The total number of drivers detected on the mapping was significantly lower (4.4 ± 1.6 vs. 7.4 ± 3.8, p = 0.007), and the drivers were more concentrated in limited LA regions (2.8 ± 0.9 vs. 3.9 ± 1.4, p = 0.009) in the termination group than in the non-termination group. The presence of drivers 2-6 with limited (≤ 3) LA regions showed a tenfold increase in the likelihood of AF termination, with 83% specificity and 67% sensitivity. Among 231 AF drivers, the drivers related to termination exhibited a greater overlap of CFAE (56.8 ± 34.1% vs. 39.5 ± 30.4%, p = 0.004) than the non-related drivers. The termination group showed a trend toward a lower recurrence rate after ablation (p = 0.163). CONCLUSIONS: Rotors responsible for AF maintenance may be characterized in cases with concentrated regions and fewer drivers on mapping.

Selective dysfunction of fast-spiking inhibitory interneurons and disruption of perineuronal nets in a tauopathy mouse model.

In Alzheimer's disease (AD), network hyperexcitability is frequently observed and associated with subsequent cognitive impairment. Dysfunction of inhibitory interneurons (INs) is thought to be one of the key biological mechanisms of hyperexcitability. However, it is still unknown how INs are functionally affected in tau pathology, which is a major pathology in AD. To clarify this, we evaluated the neuronal activity of cortical INs in 6-month-old rTg4510 mice, a model of tauopathy. Calcium imaging with mDlx enhancer-driven labeling revealed that neuronal activity in INs was decreased in rTg4510 mice. In the patch clamp recording, the firing properties of fast-spiking INs were altered so as to reduce their activity in rTg4510 mice. In parallel with microglial activation, perineuronal nets around parvalbumin-positive INs were partially disrupted in rTg4510 mice. Taken together, our data indicate that the excitability of cortical fast-spiking INs is decreased, possibly because of the disruption of perineuronal nets.

Different time course effect of autonomic nervous modulation after cryoballoon and hotballoon catheter ablations for paroxysmal atrial fibrillation.

BACKGROUND: Few studies have reported on the quantitative evaluation of autonomic nerve modification after balloon ablation. Therefore, this study aimed to evaluate the effects of cryoballoon and hotballoon ablations on the autonomic nervous system (ANS) and their relationship with prognosis. METHODS: We included 234 patients who underwent cryoballoon ablation (n = 190) or hotballoon ablation (n = 44) for paroxysmal atrial fibrillation. Heart rate variability (HRV) analysis was performed on all patients using a 3-min electrocardiogram at baseline, 1, 3, 6, and 12 months after ablation. HRV parameters and prognoses were compared between the two balloon systems. RESULTS: Ln low-frequency (LF), Ln high-frequency (HF), standard deviation of the R-R intervals (SDNN), and RR intervals significantly decreased after 1 month in both groups, but the changes were more pronounced in the cryoballoon group than in the hotballoon group. In contrast, HRV indices in the hotballoon ablation group decreased gradually and reached their lowest point 3-to-6 months after the procedure, which was later than in the cryoballoon ablation group. The recurrence rate did not differ between the two groups. HRV parameters changed similarly in the cryoballoon group, regardless of recurrence. However, patients with recurrence had significantly higher SDNN and Ln LF at 12 months than those without recurrence in the hotballoon group (41.2 ± 39.3 ms vs. 18.5 ± 12.6 ms, p = 0.006, and 2.2 ± 0.7 ms2 vs. 1.5 ± 0.7 ms2, p = 0.003, respectively). CONCLUSIONS: The time course of HRV changes differed between cryoballoon and hotballoon ablations. Hence, the two balloon systems may have distinct effects on the ANS and its role in prognosis.

Stereotactic radiotherapy for ventricular tachycardia: A study protocol.

Background: Currently, the standard curative treatment for ventricular tachycardia (VT) and ventricular fibrillation (VF) is radiofrequency catheter ablation. However, when the VT circuit is deep in the myocardium, the catheter may not be delivered, and a new, minimally invasive treatment using different energies is desired. Methods: This is a protocol paper for a feasibility study designed to provide stereotactic radiotherapy for refractory VT not cured by catheter ablation after at least one catheter ablation. The primary end point is to evaluate the short-term safety of this treatment and the secondary endpoint is to evaluate its efficacy as assessed by the reduction in VT episode. Cyberknife M6 radiosurgery system will be used for treatment, and the prescribed dose to the target will be 25Gy in one fraction. The study will be conducted on three patients. Conclusion: Since catheter ablation is the only treatment option for VT that is covered by insurance in Japan, there is currently no other treatment for VT/VF that cannot be cured by catheter ablation. We hope that this feasibility study will provide hope for patients who are currently under the stress of ICD activation. Trial registration: The study has been registered in the Japan Registry of Clinical Trials (jRCTs042230030).

Impact of synchronized left ventricular pacing rate on risk for ventricular tachyarrhythmias after cardiac resynchronization therapy in patients with heart failure.

BACKGROUND: The adaptive cardiac resynchronization therapy (aCRT) algorithm automatically produces synchronized left ventricular pacing (sLVP) with intrinsic atrioventricular conduction to improve clinical outcomes. However, relationship between sLVP percentage and risk for ventricular tachyarrhythmia (VT/VF) remains unclear. This study aimed to evaluate the clinical impact of sLVP rate on VT/VF occurrence. METHODS: In total, 1,419 device interrogation data from 42 consecutive patients who underwent new aCRT device implantation were retrospectively analyzed. The primary endpoint was the first time VT/VF episode after aCRT device implantation. RESULTS: During a median follow-up of 34 months, 15 patients had VT/VF episodes. Patients were divided into a high sLVP (the average sLVP percentage of ≥ 51.5%, n = 27) or low sLVP group (< 51.5%, n = 15). The high sLVP group had a significantly lower VT/VF incidence (22% vs. 60%; p = 0.014) and an independent predictor for VT/VF occurrence on multivariate analysis (hazard ratio 0.21; p = 0.007). LV ejection fraction improvements after 6 months (12.3 ± 8.7% vs. 2.8 ± 10.3%; p = 0.004) and 12 months (13.8 ± 9.3% vs. 6.2 ± 11.1%; p = 0.030) were significantly greater in the high sLVP group than in the low sLVP group. Age, PR interval, and left atrial diameter were significantly associated with the sLVP rate after aCRT. CONCLUSIONS: Patients with high sLVP percentage after aCRT had lower long-term risk of VT/VF incidence with a favorable response to CRT. A synchronized pacing algorithm using intrinsic conduction may prevent malignant arrhythmias, as well as recover cardiac functions.