Single-cell transcriptomics reveals granzyme K-expressing cytotoxic Tfh cells in tertiary lymphoid structures in IgG4-RD.

BACKGROUND: Germinal center (GC) responses controlled by T follicular helper (Tfh) and T follicular regulatory (Tfr) cells are crucial for the generation of high-affinity antibodies. Acquired immune responses to tissue-released antigens might be mainly induced in tertiary lymphoid organs (TLOs) with GCs in affected tissues. IgG4-related disease (IgG4-RD) demonstrates polarized isotype switching and TLOs in affected tissues. We performed single-cell transcriptomics of tissue-infiltrating T cells from these TLOs to obtain a comprehensive, unbiased view of tissue-infiltrating GC-Tfh cells. OBJECTIVE: To identify GC-Tfh-cell subsets in TLOs in patients with IgG4-RD using single-cell transcriptomics. METHODS: Single-cell RNA sequencing of sorted CD3+ T cells and multicolor immunofluorescence analysis were used to investigate CD4+CXCR5+Bcl6+ GC-Tfh cells in affected lesions from patients with IgG4-RD. RESULTS: Infiltrating CD4+CXCR5+Bcl6+ Tfh cells were divided into 5 main clusters. We detected HLA+ granzyme K+ (GZMK+) Tfh cells with cytotoxicity-associated features in patients with IgG4-RD. We also observed abundant infiltrating Tfr cells with suppressor-associated features in patients with IgG4-RD. These GZMK+ Tfh cells and Tfr cells clustered together in affected tissues from patients with IgG4-RD. CONCLUSIONS: This single-cell data set revealed a novel subset of HLA+GZMK+ cytotoxic Tfh cells infiltrating affected organs in patients with IgG4-RD, suggesting that infiltrating Tfr cells might suppress cytotoxic Tfh cells.

Granzyme K- and amphiregulin-expressing cytotoxic T cells and activated extrafollicular B cells are potential drivers of IgG4-related disease.

BACKGROUND: IgG4-related disease (IgG4-RD), an example of a type I immune disease, is an immune-mediated fibrotic disorder characterized by dysregulated resolution of severe inflammation and wound healing. However, truly dominant or pathognomonic autoantibodies related to IgG4-RD are not identified. OBJECTIVE: We sought to perform single-cell RNA sequencing and T-cell receptor and B-cell receptor sequencing to obtain a comprehensive, unbiased view of tissue-infiltrating T and B cells. METHODS: We performed unbiased single-cell RNA-sequencing analysis for the transcriptome and T-cell receptor sequencing and B-cell receptor sequencing on sorted CD3+ T or CD19+ B cells from affected tissues of patients with IgG4-RD. We also conducted quantitative analyses of CD3+ T-cell and CD19+ B-cell subsets in 68 patients with IgG4-RD and 30 patients with Sjögren syndrome. RESULTS: Almost all clonally expanded T cells in these lesions were either Granzyme K (GZMK)-expressing CD4+ cytotoxic T cells or GZMK+CD8+ T cells. These GZMK-expressing cytotoxic T cells also expressed amphiregulin and TGF-ß but did not express immune checkpoints, and the tissue-infiltrating CD8+ T cells were phenotypically heterogeneous. MKI67+ B cells and IgD-CD27-CD11c-CXCR5- double-negative 3 B cells were clonally expanded and infiltrated affected tissue lesions. GZMK+CD4+ cytotoxic T cells colocalized with MKI67+ B cells in the extrafollicular area from affected tissue sites. CONCLUSIONS: The above-mentioned cells likely participate in T-B collaborative events, suggesting possible avenues for targeted therapies. Our findings were validated using orthogonal approaches, including multicolor immunofluorescence and the use of comparator disease groups, to support the central role of cytotoxic CD4+ and CD8+ T cells expressing GZMK, amphiregulin, and TGF-ß in the pathogenesis of inflammatory fibrotic disorders.

Distinct disease-specific Tfh cell populations in 2 different fibrotic diseases: IgG4-related disease and Kimura disease.

BACKGROUND: How T follicular (Tfh) cells contribute to many different B-cell class-switching events during T-cell-dependent immune responses has been unclear. Diseases with polarized isotype switching offer a unique opportunity for the exploration of Tfh subsets. Secondary and tertiary lymphoid organs in patients with elevated tissue expression levels of IgE (Kimura disease, KD) and those of IgG4 (IgG4-related disease, IgG4-RD) can provide important insights regarding cytokine expression by Tfh cells. OBJECTIVE: We sought to identify disease-specific Tfh cell subsets in secondary and tertiary lymphoid organs expressing IL-10 or IL-13 and thus identify different cellular drivers of class switching in 2 distinct types of fibrotic disorders: allergic fibrosis (driven by type 2 immune cells) and inflammatory fibrosis (driven by cytotoxic T lymphocytes). METHODS: Single-cell RNA sequencing, in situ sequencing, and multicolor immunofluorescence analysis were used to investigate B cells, Tfh cells, and infiltrating type 2 cells in lesion tissues from patients with KD or IgG4-RD. RESULTS: Infiltrating Tfh cells in tertiary lymphoid organs from IgG4-RD were divided into 6 main clusters. We encountered abundant infiltrating IL-10-expressing LAG3+ Tfh cells in patients with IgG4-RD. Furthermore, we found that infiltrating AICDA+CD19+ B cells expressing IL-4, IL-10, and IL-21 receptors correlated with IgG4 expression. In contrast, we found that infiltrating IL-13-expressing Tfh cells were abundant in affected tissues from patients with KD. Moreover, we observed few infiltrating IL-13-expressing Tfh cells in tissues from patients with IgG4-RD, despite high serum levels of IgE (but low IgE in the disease lesions). Cytotoxic T cells were abundant in IgG4-RD; in contrast, type 2 immune cells were abundant in KD. CONCLUSIONS: Our analysis revealed a novel subset of IL-10+LAG3+ Tfh cells infiltrating the affected organs of IgG4-RD patients. In contrast, IL-13+ Tfh cells and type 2 immune cells infiltrated those of KD patients.

Identification of hub molecules of FUS-ALS by Bayesian gene regulatory network analysis of iPSC model: iBRN.

Fused in sarcoma/translated in liposarcoma (FUS) is a causative gene of amyotrophic lateral sclerosis (ALS). Mutated FUS causes accumulation of DNA damage and cytosolic stress granule (SG) formation, thereby motor neuron (MN) death. However, key molecular aetiology remains unclear. Here, we applied a novel platform technology, iBRN, "Non- biased" Bayesian gene regulatory network analysis based on induced pluripotent stem cell (iPSC)-derived cell model, to elucidate the molecular aetiology using transcriptome of iPSC-derived MNs harboring FUSH517D. iBRN revealed "hub molecules", which strongly influenced transcriptome network, such as miR-125b-5p-TIMELESS axis and PRKDC for the molecular aetiology. Next, we confirmed miR-125b-5p-TIMELESS axis in FUSH517D MNs such that miR-125b-5p regulated several DNA repair-related genes including TIMELESS. In addition, we validated both introduction of miR-125b-5p and knocking down of TIMELESS caused DNA damage in the cell culture model. Furthermore, PRKDC was strongly associated with FUS mis-localization into SGs by DNA damage under impaired DNA-PK activity. Collectively, our iBRN strategy provides the first compelling evidence to elucidate molecular aetiology in neurodegenerative diseases.

Animal models of chronic pain increase spontaneous glutamatergic transmission in adult rat spinal dorsal horn in vitro and in vivo.

The ability to detect noxious stimulation is essential to an organism's survival and wellbeing. Chronic pain is characterized by abnormal sensitivity to normal stimulation coupled with a feeling of unpleasantness. This condition afflicts people worldwide and severely impacts their quality of life and has become an escalating health problem. The spinal cord dorsal horn is critically involved in nociception and chronic pain. Especially, the substantia gelatinosa (SG) neurons of lamina II, which receives nociceptive inputs from primary afferents. Two major models are used to study chronic pain in animals, including nerve injury and the injection of a complete Freund's adjuvant (CFA) into the hind paw. However, how these models induce glutamatergic synaptic plasticity in the spinal cord is not fully understood. Here, we studied synaptic plasticity on excitatory transmissions in the adult rat SG neurons. Using in vitro and in vivo whole-cell patch-clamp recording methods, we analyzed spontaneous excitatory postsynaptic currents (sEPSCs) 2 weeks following nerve injury and 1 week following CFA injection. In the spinal slice preparation, these models increased both the frequency and amplitude of sEPSCs in SG neurons. The frequency and amplitude of sEPSCs in the nerve injury and the CFA group were reduced by the presence of tetrodotoxin (TTX). By contrast, TTX did not reduce the sEPSCs compared with miniature EPSCs in naïve rats. Next, we analyzed the active electrophysiological properties of neurons, which included; resting membrane potentials (RMPs) and the generation of action potentials (APs) in vitro. Interestingly, about 20% of recorded SG neurons in this group elicited spontaneous APs (sAPs) without changing the RMPs. Furthermore, we performed in vivo whole-cell patch-clamp recording in SG neurons to analyze active electrophysiological properties under physiological conditions. Importantly, in vivo SG neurons generated sAPs without affecting RMP in the nerve injury and the CFA group. Our study describes how animal models of chronic pain influence both passive and active electrophysiological properties of spinal SG neurons.

Prognostic value of high-sensitive troponin T for predicting cardiovascular events after atrial fibrillation ablation.

BACKGROUND AND OBJECTIVES: This study aimed to evaluate the utility of high-sensitive troponin T (hs-TnT) for predicting AF recurrence and major adverse cardiovascular events (MACE) after AF ablation. METHODS AND RESULTS: A total of 227 consecutive patients with AF (mean age, 66 ± 10 years; persistent AF, n = 98) who underwent an initial ablation were enrolled. We measured hs-TnT before AF ablation and divided the patients into three groups according to the hs-TnT level: low, lesser than or equal to 0.005 µg/L (n = 54); medium, 0.006-0.013 µg/L (n = 127); and high, greater than or equal to0.014 µg/L (n = 46). We evaluated the composite endpoint of AF recurrence or MACE (including death, stroke, acute coronary syndrome, and heart failure hospitalization) after the ablation. The median hs-TnT level was 0.008 µg/L. The values of chronic kidney disease prevalence, CHA2 DS2 -VASc score, B-type natriuretic peptide level, and left atrial diameter were the highest in the high hs-TnT group among the three groups. During a mean follow-up of 15 ± 8 months, AF recurrence and MACE occurred in 56 (25%) and 9 (4%) patients, respectively. The high hs-TnT group had the highest incidence of AF recurrence and MACE among the three groups (high: 39% and 15%, medium: 22% and 2%, and low: 19% and 0%, respectively; log-rank P < .05). In multivariate analysis, hs-TnT greater than or equal to 0.014 µg/L and persistent AF were independent predictors of the composite endpoint. CONCLUSION: Hs-TnT may be a useful marker for predicting AF recurrence or MACE after AF ablation.

Diagnostic value of electrocardiographic P-wave characteristics in atrial fibrillation recurrence and tachycardia-induced cardiomyopathy after catheter ablation.

Abnormal P-wave characteristics were reportedly associated with left ventricular interstitial fibrosis as defined by cardiac magnetic resonance images. The objective of this study is to investigate the utility of P-wave characteristics to predict atrial fibrillation (AF) recurrence and the recovery of left ventricular systolic dysfunction (LVSD) after catheter ablation (CA) for AF. Two hundred and five AF patients (109 paroxysmal and 96 persistent) who underwent CA were enrolled. We measured maximum P-wave duration (max PWD) and P-wave terminal force in lead V1 (PTFV1) calculated as a product of P-wave terminal amplitude (PTaV1) and duration (PTdV1) in lead V1 during sinus rhythm. AF recurrence was noted in 50 patients at 12 months after CA. Patients with AF recurrence had a higher prevalence of persistent AF, a larger left atrial volume, and a longer max PWD than those without. We divided the patients into 2 groups: 156 patients with left ventricular ejection fraction (LVEF) > 45% and 49 patients with LVEF ≤ 45% (Low-EF group). In Low-EF group, tachycardia-induced cardiomyopathy (TIC) was defined as improvement in LVEF ≥ 15% or LVEF ≥ 50% at 5 months after CA. TIC and non-TIC groups consisted of 37 and 12 patients, respectively. Max PWD, PTFV1, PTdV1, and PTaV1 were significantly greater in non-TIC-group than in TIC-group. PTFV1 had the highest diagnostic accuracy to discriminate between TIC and no-TIC-groups; cut-off value for PTFV1 was determined as 56.7 mV ms (area under the ROC curve = 0.80; 75% sensitivity; and 76% specificity). Max PWD was a useful predictor of AF recurrence and the complete recovery of LVSD after CA. PTFV1 had the highest diagnostic accuracy to discriminate between TIC and no-TIC-groups.

Impact of simple electrocardiographic markers as predictors for deterioration of left ventricular function in patients with frequent right ventricular apical pacing.

Several trials demonstrated that frequent right ventricular apical pacing (RVAP) was associated with cardiac dysfunction and an increased rate of heart failure hospitalization. However, there are few reports about the 12-lead electrocardiogram (12-ECG) parameters at the time of device implantation to predict deterioration of LVEF in patients with frequent RVAP. We retrospectively studied 115 consecutive patients undergoing pacemaker or implantable cardioverter-defibrillator implantation with RVAP, with rate of ventricular pacing ≥ 40% and LVEF ≥ 50% at the time of implantation. We compared the 12-ECG characteristics at the time of device implantation between patients with deterioration of LVEF (≥ 10% reduction) and those without. Twenty-nine patients (25%) had deteriorated LVEF with a decrease in mean LVEF from 59 to 40% during a median follow-up period of 8.9 [4.6-13.7] years. Multivariate logistic regression analysis showed that cumulative % of ventricular pacing [odds ratio (OR) 1.04 per 1% increase, 95% confidence interval (CI) 1.01-1.09, p = 0.04], notching of baseline paced QRS in limb leads (OR 5.04, 95% CI 1.59-19.6, p = 0.005) and the QS pattern in all precordial leads (OR 3.56, 95% CI 1.21-10.8, p = 0.02) were independently associated with deterioration of LVEF. The QS pattern of baseline paced QRS in all precordial leads had 58% sensitivity, 93% specificity for the RV lead position at the tip of RV apex. In conclusion, considering OR by multivariate analysis, notching of baseline paced QRS in limb leads and the QS pattern in all precordial leads at device implantation may be simple and useful predictors to identify patients who are at risk for deterioration of cardiac function during long-term RVAP. 12-ECG monitoring at device implantation and avoidance of the RVAP site showing a QS pattern may be important to prevent deterioration of cardiac function in patients with frequent RVAP.

Alterations of Hepatic Metabolism in Chronic Kidney Disease via D-box-binding Protein Aggravate the Renal Dysfunction.

Chronic kidney disease (CKD) is associated with an increase in serum retinol; however, the underlying mechanisms of this disorder are poorly characterized. Here, we found that the alteration of hepatic metabolism induced the accumulation of serum retinol in 5/6 nephrectomy (5/6Nx) mice. The liver is the major organ responsible for retinol metabolism; accordingly, microarray analysis revealed that the hepatic expression of most CYP genes was changed in 5/6Nx mice. In addition, D-box-binding protein (DBP), which controls the expression of several CYP genes, was significantly decreased in these mice. Cyp3a11 and Cyp26a1, encoding key proteins in retinol metabolism, showed the greatest decrease in expression in 5/6Nx mice, a process mediated by the decreased expression of DBP. Furthermore, an increase of plasma transforming growth factor-ß1 (TGF-ß1) in 5/6Nx mice led to the decreased expression of the Dbp gene. Consistent with these findings, the alterations of retinol metabolism and renal dysfunction in 5/6Nx mice were ameliorated by administration of an anti-TGF-ß1 antibody. We also show that the accumulation of serum retinol induced renal apoptosis in 5/6Nx mice fed a normal diet, whereas renal dysfunction was reduced in mice fed a retinol-free diet. These findings indicate that constitutive Dbp expression plays an important role in mediating hepatic dysfunction under CKD. Thus, the aggravation of renal dysfunction in patients with CKD might be prevented by a recovery of hepatic function, potentially through therapies targeting DBP and retinol.

Saturated two-photon excitation fluorescence microscopy with core-ring illumination.

We demonstrated resolution improvement in two-photon excitation microscopy by combining saturated excitation (SAX) of fluorescence and pupil manipulation. We theoretically estimated the resolution improvement and the sidelobe effect in the point spread function with various pupil designs and found that the combination of SAX and core-ring illumination can effectively enhance the spatial resolution in 3D and suppress sidelobe artifacts. The experimental demonstration shows that the proposed technique is effective for observation with a depth of 100 µm in a tissue phantom and can be applied to 3D observations of tissue samples with higher spatial resolution than conventional two-photon excitation microscopy.

Utility of 12-lead and signal-averaged Holter electrocardiograms after pilsicainide provocation for risk stratification in Brugada syndrome.

Non-invasive risk stratification for ventricular fibrillation (VF) in Brugada syndrome (BrS) has not been fully evaluated. The aim of this study was to assess the utility of signal-averaged Holter electrocardiogram (Holter SAECG) and 12-lead Holter electrocardiogram (Holter ECG) after a pilsicainide provocation test for non-invasive risk stratification in BrS. We enrolled 30 consecutive patients with BrS [divided into 2 groups: the VF group, those with a previous history of VF (n = 10); and the non-VF group, those without a history of VF (n = 20)] and 10 control subjects without type 1 ECG. We evaluated late potentials [LP: filtered QRS (f-QRS), RMS40, and LAS40] on the Holter SAECG for 4 h after the pilsicainide provocation and in the same patients on another day without performing the pilsicainide provocation. Furthermore, we measured QRS duration and QTc interval in leads V2 and V5, and J amplitude in lead V2 on the Holter ECG after the pilsicainide provocation. On the Holter SAECG, the f-QRS at 1 h and LAS40 at 3 h after the pilsicainide provocation were significantly larger in the VF group than in the non-VF group (f-QRS at 1 h: 113.9 ± 8.9 vs. 104.9 ± 8 ms; p = 0.01, LAS40 at 3 h: 45.4 ± 5.9 vs. 35.5 ± 7.4 ms; p < 0.001). The receiver-operating characteristic curve analysis for a single parameter of VF occurrence was determined [f-QRS at 1 h: area under the curve (AUC) 0.8, with sensitivity 80% and specificity 80%; and LAS40 at 3 h: AUC 0.87, with sensitivity 90% and specificity 75%]. On the Holter ECG, there were no significant differences in these parameters between the VF and non-VF groups. In conclusion, the LP after the pilsicainide provocation using Holter SAECG may be useful for risk stratification of VF episodes in patients with BrS.

The utility of T-wave alternans during the morning in the summer for the risk stratification of patients with Brugada syndrome.

The prognostic value of the seasonal variations of T-wave alternans (TWA) and heart rate variability (HRV), and the seasonal distribution of ventricular fibrillation (VF) in Brugada syndrome (Br-S) is unknown. We assessed the utility of seasonal variations in TWA and HRV for risk stratification in Br-S using a 24-h multichannel Holter electrocardiogram (24-M-ECG). We enrolled 81 patients with Br-S (grouped according to their history of VF, n = 12; syncope, n = 8; no symptoms, n = 61) who underwent 24-M-ECG in all four seasons. Precordial electrodes were attached to the third (3L-V2) and fourth (4L-V2, 4L-V5) intercostal spaces. We determined the maximum TWA (max-TWA) values and calculated HRV during night and morning time periods for all seasons. During a follow-up period of 5.8 ± 2.8 years, 11 patients experienced new VF episodes and there was a peak in new VF episodes in the summer. The VF group had the greatest 3L-V2 max-TWA value during morning time in the summer among the three groups and showed higher 3L-V2 max-TWA value than in the other seasons. The cutoff value for the 3L-V2 max-TWA during morning time in the summer was determined to be 42 µV using ROC analysis (82 % sensitivity, 74 % specificity; p = 0.0006). Multivariate analysis revealed that a 3L-V2 max-TWA value ≥42 µV during morning time in the summer and previous VF episodes were predictors of future VF episodes. The 3L-V2 max-TWA value during morning time in the summer may be a useful predictor of future VF episodes in Br-S.

Incidence and predictors of silent cerebral thromboembolic lesions after catheter ablation for atrial fibrillation in patients treated with direct oral anticoagulants.

There are few reports about the incidence and predictors of silent cerebral thromboembolic lesions (SCLs) after atrial fibrillation (AF) ablation in patients treated with direct oral anticoagulants (DOACs). The purpose of this study is to evaluate the incidence and predictors of SCLs after AF ablation with cerebral magnetic resonance imaging (C-MRI) in patients treated with DOACs. We enrolled 117 consecutive patients who underwent first AF ablation and received DOACs, including apixaban, dabigatran, edoxaban, and rivaroxaban. DOACs were discontinued after administration 24 h before the procedure, and restarted 6 h after the procedure. During the procedure, activated clotting time (ACT) was measured every 15 min, and intravenous heparin infusion was performed to maintain ACT at 300-350 s. All patients underwent C-MRI the day after the procedure. SCLs were detected in 28 patients (24%) after AF ablation. Age, female sex, the presence of persistent AF, left atrial volume, procedure time, radiofrequency energy, electrical cardioversion, and mean ACT showed no correlations with the incidence of SCLs. Multivariate analysis revealed independent predictors of SCLs were CHA2DS2VASc scores ≥3, left atrial appendage (LAA) emptying velocity ≤39 cm/s, and minimum ACT ≤260 s. Patients with both CHA2DS2VASc scores ≥3 and LAA flow velocity ≤39 cm/s had the highest incidence of SCLs 15 of 26 patients (58%). In patients treated with DOACs, CHA2DS2VASc score ≥3, minimum ACT ≤260 s, and LAA emptying velocity ≤39 cm/s were independent risk factors for the SCLs after AF ablation.

Administration of tolvaptan with reduction of loop diuretics ameliorates congestion with improving renal dysfunction in patients with congestive heart failure and renal dysfunction.

In patients with congestive heart failure and renal dysfunction, high dose of diuretics are necessary to improve congestion, which may progress to renal dysfunction. We examined the efficacy of tolvaptan with reduction of loop diuretics to improve renal function in patients with congestive heart failure and renal dysfunction. We conducted a multicenter, prospective, randomized study in 44 patients with congestive heart failure and renal dysfunction (serum creatinine concentration ≥1.1 mg/dl) treated with conventional diuretics. Patients were randomly divided into two groups: tolvaptan (15 mg) with a fixed dose of diuretics or with reducing to a half-dose of diuretics for 7-14 consecutive days. We examined the change of urine volume, body weight, serum creatinine and electrolyte concentrations in each group. Both groups demonstrated significant urine volume increase (724 ± 176 ml/day in the fixed-dose group and 736 ± 114 ml/day in the half-dose group) and body weight reduction (1.6 ± 1.5 kg and 1.6 ± 1.9 kg, respectively) from baseline, with no differences between the two groups. Serum creatinine concentration was significantly increased in the fixed-dose group (from 1.60 ± 0.47 to 1.74 ± 0.66 mg/dl, p = 0.03) and decreased in the half-dose group (from 1.98 ± 0.91 to 1.91 ± 0.97 mg/dl, p = 0.10). So the mean changes in serum creatinine concentration from baseline significantly differed between the two groups (0.14 ± 0.08 mg/dl in the fixed-dose group and -0.07 ± 0.19 mg/dl in the half-dose group, p = 0.006). The administration of tolvaptan with reduction of loop diuretics was clinically effective to ameliorate congestion with improving renal function in patients with congestive heart failure and renal dysfunction.

Safety and efficacy of high-rate cutoff and long detection interval ICD programming in secondary prevention patients.

Several trials demonstrated that a long detection interval and a high-rate cutoff reduced implantable cardioverter-defibrillator (ICD) therapy in primary prevention patients. However, only a few data are available for secondary prevention (SP) patients. The aim of this study was to evaluate whether these ICD programming would be effective in reducing ICD therapies in SP patients. We enrolled 65 SP patients under ICD or cardiac resynchronization therapy with the defibrillator programmed with the same setting (conventional setting). During follow-up, we changed detection rates in each zone; cycle length (CL) ≤400 to ≤370 ms for ventricular tachycardia (VT) zone, CL ≤350 to ≤320 ms for fast VT zone, CL ≤300 to ≤270 ms for ventricular fibrillation (VF) zone, and number of intervals to detect ventricular tachyarrhythmia in VF zone: 12-24. We retrospectively compared the incidences of ICD therapies, syncope, and hospitalization due to slow VT under the detection rate between both settings. Median follow-up periods were 5.0 (interquartile range 2.5-7.8) and 2.5 years (interquartile range 2.3-2.7) in conventional and strategic settings, respectively. The incidence of appropriate ATP and shock significantly decreased in strategic setting (conventional and strategic settings: 21.2 and 4.8 ATPs per year, respectively, OR 0.18, 95 % CI 0.06-0.54, p = 0.002, 26.1 and 7.8 shocks per year, respectively, OR 0.29, 95 % CI 0.09-0.88, p = 0.03). The incidence of overall inappropriate therapy significantly decreased (conventional and strategic settings: 17.6 and 2.8 therapies per year, respectively, OR 0.14, 95 % CI 0.05-0.44, p = 0.01). The incidence of syncope and slow VT was not significantly different between both settings. In conclusion, ICD programming-combined long detection interval with high-rate cutoff was effective in reducing appropriate shock and inappropriate therapy without increasing the incidence of syncope and slow VT in SP patients.

Persistent tachycardia within isolated pulmonary veins during atrial fibrillation ablation.

During circumferential pulmonary vein (PV) isolation for ongoing atrial fibrillation (AF), distinguishing passive conduction to the pulmonary vein (PV) from rapid PV arrhythmia in the isolated PV is difficult. Hence, the purpose of this study is to investigate both the feasibility of distinguishing the PV tachycardia after circumferential PV isolation and the electrophysiological characteristics of these tachycardia. Among 178 consecutive patients who underwent circumferential PV isolation during ongoing AF, fibrillatory PV converted to a regular cycle length PV tachycardia independent of the atrial rhythm (=independent PV tachycardia) in 13 PVs among 12 (7%) patients. We classified independent PV tachycardia according to 3 different atrial rhythms: sinus rhythm (type 1, n = 2), atrial tachycardia (type 2, n = 4), and AF (type 3, n = 6). independent PV tachycardia was observed in 3 right PV and 10 left PV (P = 0.0864). There were 10 mappable independent PV tachycardia, in which 8 were focal and 2 were macroreentrant tachycardia. i-PVT can be diagnosed in a small number of patients who underwent circumferential PV isolation during AF. The main mechanism or independent PV tachycardia was focal tachycardia mainly in the left PV.

Utility of T-wave alternans during night time as a predictor for ventricular fibrillation in patients with Brugada syndrome.

The prognostic value of T-wave alternans (TWA) during the night time in patients with Brugada syndrome (Br-S) remains unknown. We assessed TWA for risk stratification using 24-h multichannel Holter electrocardiogram (24-M-ECG) in Br-S. We enrolled 129 patients with Br-S [grouped according to histories of ventricular fibrillation (VF), n = 16; syncope, n = 10; or no symptoms (asymptomatic), n = 103] and 11 controls. Precordial electrodes were attached to the third (3L-V1, 3L-V2) and fourth (4L-V1, 4L-V2 and 4L-V5) intercostal spaces. We measured the values of maximum TWA (max-TWA) during the night time (12 a.m.-6 a.m.) and the day time (12 p.m.-6 p.m.) and calculated parameters of heart rate variability. Compared to the asymptomatic and control groups, the VF and syncope groups showed significantly greater 3L-V2 max-TWA during the night time. The cutoff value for the 3L-V2 max-TWA during the night time was determined as 20 µV (sensitivity 94 % and specificity 48 %; p = 0.01). Multivariate analysis revealed that 3L-V2 max-TWA during the night time ≥20 µV and previous VF episodes were independent predictors of future VF episodes. During a mean follow-up period of 68 ± 37 months, 16 patients experienced VF episodes. The incidence of VF episodes was the highest during the night time (p < 0.001). The 3L-V2 max-TWA during the night time may be a useful predictor for VF episodes in patients with Br-S.