Transient pacing in pigs with complete heart block via myocardial injection of mRNA coding for the T-box transcription factor 18.

The adenovirus-mediated somatic transfer of the embryonic T-box transcription factor 18 (TBX18) gene can convert chamber cardiomyocytes into induced pacemaker cells. However, the translation of therapeutic TBX18-induced cardiac pacing faces safety challenges. Here we show that the myocardial expression of synthetic TBX18 mRNA in animals generates de novo pacing and limits innate and inflammatory immune responses. In rats, intramyocardially injected mRNA remained localized, whereas direct myocardial injection of an adenovirus carrying a reporter gene resulted in diffuse expression and in substantial spillover to the liver, spleen and lungs. Transient expression of TBX18 mRNA in rats led to de novo automaticity and pacemaker properties and, compared with the injection of adenovirus, to substantial reductions in the expression of inflammatory genes and in activated macrophage populations. In rodent and clinically relevant porcine models of complete heart block, intramyocardially injected TBX18 mRNA provided rate-adaptive cardiac pacing for one month that strongly correlated with the animal's sinus rhythm and physical activity. TBX18 mRNA may aid the development of biological pacemakers.

Case Report: Comprehensive evaluation of ECG phenotypes and genotypes in a family with Brugada syndrome carrying SCN5A-R376H.

Background: Brugada syndrome (BrS) is a channelopathy that can lead to sudden cardiac death in the absence of structural heart disease. Patients with BrS can be asymptomatic or present with symptoms secondary to polymorphic ventricular tachycardia or ventricular fibrillation. Even though BrS can exhibit autosomal dominant inheritance, it is not easy to identify the phenotype and genotype in a family thoroughly. Case: We report the case of a 20-year-old man with variants in SCN5A and RyR2 genes who was resuscitated from sudden cardiac death during sleep due to a ventricular fibrillation. The patient did not have underlying diseases. The routine laboratory results, imaging study, coronary angiogram, and echocardiogram (ECG) were normal. A type 1 BrS pattern was identified in one resting ECG. Furthermore, prominent J wave accentuation with PR interval prolongation was identified during therapeutic hypothermia. Therefore, we were easily able to diagnose BrS. For secondary prevention, the patient underwent implantable cardioverter defibrillator implantation. Before discharge, a genetic study was performed using next-generation sequencing. Genotyping was performed in the first-degree relatives, and ECG evaluations of almost all maternal and paternal family members were conducted. The proband and his mother showed SCN5A-R376H and RyR2-D4038Y variants. However, his mother did not show the BrS phenotype on an ECG. One maternal aunt and uncle showed BrS phenotypes. Conclusion: Genetics alone cannotdiagnose BrS. However, genetics could supply evidence or direction for evaluating ECG phenotypes in family groups. This case report shows how family evaluation using ECGs along with a genetic study can be used in BrS diagnosis.

Lung endothelium exploits susceptible tumor cell states to instruct metastatic latency.

In metastasis, cancer cells travel around the circulation to colonize distant sites. Due to the rarity of these events, the immediate fates of metastasizing tumor cells (mTCs) are poorly understood while the role of the endothelium as a dissemination interface remains elusive. Using a newly developed combinatorial mTC enrichment approach, we provide a transcriptional blueprint of the early colonization process. Following their arrest at the metastatic site, mTCs were found to either proliferate intravascularly or extravasate, thereby establishing metastatic latency. Endothelial-derived angiocrine Wnt factors drive this bifurcation, instructing mTCs to follow the extravasation-latency route. Surprisingly, mTC responsiveness towards niche-derived Wnt was established at the epigenetic level, which predetermined tumor cell behavior. Whereas hypomethylation enabled high Wnt activity leading to metastatic latency, methylated mTCs exhibited low activity and proliferated intravascularly. Collectively the data identify the predetermined methylation status of disseminated tumor cells as a key regulator of mTC behavior in the metastatic niche.

Identification of Atrial Fibrillation With Single-Lead Mobile ECG During Normal Sinus Rhythm Using Deep Learning.

BACKGROUND: The acquisition of single-lead electrocardiogram (ECG) from mobile devices offers a more practical approach to arrhythmia detection. Using artificial intelligence for atrial fibrillation (AF) identification enhances screening efficiency. However, the potential of single-lead ECG for AF identification during normal sinus rhythm (NSR) remains under-explored. This study introduces a method to identify AF using single-lead mobile ECG during NSR. METHODS: We employed three deep learning models: recurrent neural network (RNN), long short-term memory (LSTM), and residual neural networks (ResNet50). From a dataset comprising 13,509 ECGs from 6,719 patients, 10,287 NSR ECGs from 5,170 patients were selected. Single-lead mobile ECGs underwent noise filtering and segmentation into 10-second intervals. A random under-sampling was applied to reduce bias from data imbalance. The final analysis involved 31,767 ECG segments, including 15,157 labeled as masked AF and 16,610 as Healthy. RESULTS: ResNet50 outperformed the other models, achieving a recall of 79.3%, precision of 65.8%, F1-score of 71.9%, accuracy of 70.5%, and an area under the receiver operating characteristic curve (AUC) of 0.79 in identifying AF from NSR ECGs. Comparative performance scores for RNN and LSTM were 0.75 and 0.74, respectively. In an external validation set, ResNet50 attained an F1-score of 64.1%, recall of 68.9%, precision of 60.0%, accuracy of 63.4%, and AUC of 0.68. CONCLUSION: The deep learning model using single-lead mobile ECG during NSR effectively identified AF at risk in future. However, further research is needed to enhance the performance of deep learning models for clinical application.

Modified application of SAMe-TT2R2 scoring system in Asian patients with atrial fibrillation for the selection of oral anticoagulants.

BACKGROUND/AIMS: The SAMe-TT2R2 score is used for assessing anticoagulation control (AC) quality with warfarin. However, it is hard to apply SAMe-TT2R2 score in Asian patients with atrial fibrillation (AF), because it has not been proven in those populations. This study aimed to validate the SAMe-TT2R2 score in Asian patients with AF and suggest a modified SAMe- TT2R2 score for this population. METHODS: We analyzed 710 Korean patients with AF who were using warfarin. The AC quality was assessed as the mean time in therapeutic range (TTR). Each component of SAMe-TT2R2 score was evaluated for the relationship with AC. Further clinical factors that predict AC were analyzed. Identified factors were re-assorted and constructed as SA2Me-TTR scoring system. RESULTS: Of the components of the SAMe-TT2R2 score, female, age, and rhythm control were associated with AC. Heart failure and renal insufficiency were newly identified factors associated with AC. The modified SA2Me-TTR score was reconstructed with the relevant risk factors (S, female gender, 1 point; A, age < 60 yr, 2 points; Me, medical history of heart failure, 1 point; T, treatment for rhythm control, 1 point; T, history of stroke or transient ischemic attack, 1 point; R, renal insufficiency, 1 point). The modified SA2Me-TTR score demonstrated an excellent relationship with the grading of AC. The modified SA2Me-TTR score ≤ 1 identified patients with good AC (hazard ratio 2.46, 95% CI 1.75-3.47). CONCLUSION: The modified SA2Me-TTR score was useful for guiding oral anticoagulants selection in Asian patients with AF.

Low-dose non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.

In the last decade, non-vitamin K antagonist oral anticoagulants (NOACs), a new generation of OACs, were introduced to prevent thromboembolism in patients with atrial fibrillation. Although vitamin K-dependent anticoagulants have long been used as OACs, their inherent disadvantage of considerable bleeding complications has limited their use. NOACs demonstrate similar or superior clinical outcomes to those of warfarin. Although strict dose reduction criteria are recommended for NOACs, low-dose NOACs are frequently utilized, especially in Asian patients. Low-dose NOACs have shown clinical outcomes similar to those of warfarin in randomized controlled trials (RCTs) and real-world studies. However, off-label low-dose NOACs have shown inconsistent results compared with standard-dose NOACs and warfarin. Therefore, strict dose reduction criteria for NOACs should be followed until RCTs confirm the issues associated with NOAC underdosing.

Net clinical benefit of oral anticoagulants in Korean atrial fibrillation patients with low to intermediate stroke risk: A report from the Clinical Survey on Stroke Prevention in patients with Atrial Fibrillation (CS-SPAF).

Background: The balance of stroke risk reduction and potential bleeding risk associated with antithrombotic treatment (ATT) remains unclear in atrial fibrillation (AF) at non-gender CHA2DS2-VASc scores 0-1. A net clinical benefit (NCB) analysis of ATT may guide stroke prevention strategies in AF with non-gender CHA2DS2-VASc scores 0-1. Methods: This multi-center cohort study evaluated the clinical outcomes of treatment with a single antiplatelet (SAPT), vitamin K antagonist (VKA), and non-VKA oral anticoagulant (NOAC) in non-gender CHA2DS2-VASc score 0-1 and further stratified by biomarker-based ABCD score (Age [≥60 years], B-type natriuretic peptide [BNP] or N-terminal pro-BNP [≥300 pg/mL], creatinine clearance [<50 mL/min], and dimension of the left atrium [≥45 mm]). The primary outcome was the NCB of ATT, including composite thrombotic events (ischemic stroke, systemic embolism, and myocardial infarction) and major bleeding events. Results: We included 2465 patients (age 56.2 ± 9.5 years; female 27.0%) followed-up for 4.0 ± 2.8 years, of whom 661 (26.8%) were treated with SAPT; 423 (17.2%) with VKA; and 1040 (42.2%) with NOAC. With detailed risk stratification using the ABCD score, NOAC showed a significant positive NCB compared with the other ATTs (SAPT vs. NOAC, NCB 2.01, 95% confidence interval [CI] 0.37-4.66; VKA vs. NOAC, NCB 2.38, 95% CI 0.56-5.40) in ABCD score ≥1. ATT failed to show a positive NCB in patients with truly low stroke risk (ABCD score = 0). Conclusions: In the Korean AF cohort at non-gender CHA2DS2-VASc scores 0-1, NOAC showed significant NCB advantages over VKA or SAPT with ABCD score ≥1.

Emergent N=4 Supersymmetry from N=1.

We discover a four-dimensional N=1 supersymmetric field theory that is dual to the N=4 super Yang-Mills theory with gauge group SU(2n+1) for each n. The dual theory is constructed through the diagonal gauging of the SU(2n+1) flavor symmetry of three copies of a strongly coupled superconformal field theory (SCFT) of Argyres-Douglas type. We find that this theory flows in the infrared to a strongly coupled N=1 SCFT that lies on the same conformal manifold as N=4 super Yang-Mills with gauge group SU(2n+1). Our construction provides a hint on why certain N=1, 2 SCFTs have identical central charges (a=c).

Antiarrhythmic Effect of Artemisinin in an Ex-vivo Model of Brugada Syndrome Induced by NS5806.

BACKGROUND AND OBJECTIVES: Brugada syndrome (BrS) is an inherited arrhythmia syndrome that presents as sudden cardiac death (SCD) without structural heart disease. One of the mechanisms of SCD has been suggested to be related to the uneven dispersion of transient outward potassium current (Ito) channels between the epicardium and endocardium, thus inducing ventricular tachyarrhythmia. Artemisinin is widely used as an antimalarial drug. Its antiarrhythmic effect, which includes suppression of Ito channels, has been previously reported. We investigated the effect of artemisinin on the suppression of electrocardiographic manifestations in a canine experimental model of BrS. METHODS: Transmural pseudo-electrocardiograms and epicardial/endocardial transmembrane action potentials (APs) were recorded from coronary-perfused canine right ventricular wedge preparations (n=8). To mimic the BrS phenotypes, acetylcholine (3 µM), calcium channel blocker verapamil (1 µM), and Ito agonist NS5806 (6-10 µM) were used. Artemisinin (100-150 µM) was then perfused to ameliorate the ventricular tachyarrhythmia in the BrS models. RESULTS: The provocation agents induced prominent J waves in all the models on the pseudo-electrocardiograms. The epicardial AP dome was attenuated. Ventricular tachyarrhythmia was induced in six out of 8 preparations. Artemisinin suppressed ventricular tachyarrhythmia in all 6 of these preparations and recovered the AP dome of the right ventricular epicardium in all preparations (n=8). J wave areas and epicardial notch indexes were also significantly decreased after artemisinin perfusion. CONCLUSIONS: Our findings suggest that artemisinin has an antiarrhythmic effect on wedge preparation models of BrS. It might work by inhibition of potassium channels including Ito channels, subsequently suppressing ventricular tachycardia/ventricular fibrillation.

Standard-Intensity Versus Low-Intensity Anticoagulation with Warfarin in Asian Patients with Atrial Fibrillation: A Multi-Center, Randomized Controlled Trial.

Anticoagulation with warfarin in Asian patients with atrial fibrillation (AF) often has been decreased as an international normalized ratio (INR) of prothrombin time 1.6-2.6 due to fear of bleeding, although universal criteria recommend an INR of 2.0-3.0. In this randomized, open-label trial, low-intensity anticoagulation (INR 1.6-2.6) was compared with standard-intensity anticoagulation (INR 2.0-3.0) with warfarin. A total 616 patients with AF and at least 1 risk factor for stroke were randomized to low-intensity anticoagulation (n = 308) and standard-intensity anticoagulation (n = 308) groups. The intention-to-treat analysis was performed to determine differences. The baseline characteristics of the two groups were comparable. New-onset stroke occurred in 2 patients (0.44% per year) in the low-intensity group and 5 patients (1.05% per year) in the standard-intensity group (HR 0.42, 95% CI 0.08-2.15). Major bleeding occurred in 4 patients (0.89% per year) in the low-intensity group and 5 patients (1.06% per year) in the standard-intensity group (HR 0.84, 95% CI 0.22-3.11). The rate of the net clinical outcome (composite of stroke, systemic embolism, major bleeding, and death) was 1.33% per year in the low-intensity group compared with 2.12% per year in the standard-intensity group (HR 0.63, 95% CI 0.23-1.72). In Asian patients with AF, clinical outcomes were not different between low-intensity and standard-intensity anticoagulation with warfarin.

Validation of Biomarker-Based ABCD Score in Atrial Fibrillation Patients with a Non-Gender CHA2DS2-VASc Score 0-1: A Korean Multi-Center Cohort.

PURPOSE: Atrial fibrillation (AF) patients with low to intermediate risk, defined as non-gender CHA2DS2-VASc score of 0-1, are still at risk of stroke. This study verified the usefulness of ABCD score [age (≥60 years), B-type natriuretic peptide (BNP) or N-terminal pro-BNP (≥300 pg/mL), creatinine clearance (<50 mL/min/1.73 m²), and dimension of the left atrium (≥45 mm)] for stroke risk stratification in non-gender CHA2DS2-VASc score 0-1. MATERIALS AND METHODS: This multi-center cohort study retrospectively analyzed AF patients with non-gender CHA2DS2-VASc score 0-1. The primary endpoint was the incidence of stroke with or without antithrombotic therapy (ATT). An ABCD score was validated. RESULTS: Overall, 2694 patients [56.3±9.5 years; female, 726 (26.9%)] were followed-up for 4.0±2.8 years. The overall stroke rate was 0.84/100 person-years (P-Y), stratified as follows: 0.46/100 P-Y for an ABCD score of 0; 1.02/100 P-Y for an ABCD score ≥1. The ABCD score was superior to non-gender CHA2DS2-VASc score in the stroke risk stratification (C-index=0.618, p=0.015; net reclassification improvement=0.576, p=0.040; integrated differential improvement=0.033, p=0.066). ATT was prescribed in 2353 patients (86.5%), and the stroke rate was significantly lower in patients receiving non-vitamin K antagonist oral anticoagulant (NOAC) therapy and an ABCD score ≥1 than in those without ATT (0.44/100 P-Y vs. 1.55/100 P-Y; hazard ratio=0.26, 95% confidence interval 0.11-0.63, p=0.003). CONCLUSION: The biomarker-based ABCD score demonstrated improved stroke risk stratification in AF patients with non-gender CHA2DS2-VASc score 0-1. Furthermore, NOAC with an ABCD score ≥1 was associated with significantly lower stroke rate in AF patients with non-gender CHA2DS2-VASc score 0-1.

Tie2 Receptor in Tumor-Infiltrating Macrophages Is Dispensable for Tumor Angiogenesis and Tumor Relapse after Chemotherapy.

Tumor relapse after chemotherapy relies on the reconstruction of damaged tumor vasculature. In this context, proangiogenic Tie2-expressing macrophages have been suggested to serve as crucial instructors of tumor revascularization by secreting angiogenic factors while being closely associated with the vessel wall. Although the proangiogenic nature of Tie2+ macrophages is well described, the functional contribution of macrophage Tie2 expression remains elusive. Here, we employed a Cre-loxP system to specifically delete Tie2 in macrophages. In multiple syngeneic solid tumor models and two distinct chemotherapeutic treatment regimens, macrophage-expressed Tie2 did not contribute to primary tumor growth, tumor revascularization after chemotherapy, tumor recurrence, or metastasis. Exposing cultured murine macrophage cell lines and bone marrow-derived macrophages to hypoxia or stimulating them with Ang2 did not induce expression of Tie2 at the RNA or protein level. Furthermore, a comprehensive meta-analysis of publicly available single cell RNA sequencing datasets of human and murine tumor-infiltrating CD11b+ myeloid cells did not reveal a transcriptionally distinct macrophage population marked by the expression of Tie2. Collectively, these data question the previously reported critical role of Tie2-expressing macrophages for tumor angiogenesis and tumor relapse after chemotherapy. Moreover, lack of Tie2 inducibility and absence of Tie2-positive macrophages in multiple recently published tumor studies refute a possible prognostic value of macrophage-expressed Tie2. SIGNIFICANCE: Multiple preclinical tumor models, cell stimulation experiments, and meta-analysis of published tumor single cell RNA sequencing data challenge the reported role of Tie2-positive macrophages for tumor angiogenesis, metastasis, and relapse after chemotherapy. See related commentary by Zhang and Brekken, p. 1172.

Ambulatory blood pressure response to S-amlodipine in Korean adult patients with uncontrolled essential hypertension: A prospective, observational study.

Although amlodipine is recommended as the first-line therapy for the treatment of hypertension, its use is limited by its potential side effects. S-amlodipine is expected to be able to minimize side effects of amlodipine with a similar antihypertensive effect by removing the malicious R-chiral form. However, sustainable blood pressure control with S-amlodipine has not been well established yet. The purpose of the current study was to evaluate ambulatory blood pressure (ABP) profiles before and after a 12-week treatment of S-amlodipine. Patients received once-daily S-amlodipine 2.5 or 5 mg. ABP during 24 hr and office blood pressure were measured at baseline and after the 12-week treatment. Primary endpoints were changes of systolic and diastolic 24 hr ABP. After 12-week S-amlodipine treatment, mean systolic ABP (-15.1 ± 16.2 mmHg, p < .001) and diastolic ABP (-8.9 ± 9.8 mmHg, p < .001) were decreased significantly. Both daytime and night-time mean systolic BP and diastolic BP were also significantly decreased after the 12-week treatment. Global trough-to-peak ratio and smoothness index after 12-week S-amlodipine treatment were .75 and .79 for SBP and .65 and .61 for DBP, respectively. Age ≥65 years (hazard ratio [HR]: 3.13; 95% confidence interval [CI]: 1.67-14.3) and nonalcohol drinking (HR: 3.09; 95% CI: 1.34-7.17) were independent clinical factors for target ABP achievement. Adverse drug reactions (ADR) were developed in 16 (6.4%) patients, including two (.8%) cases of peripheral edema. In conclusion, this study demonstrated the efficacy and safety of S-amlodipine in patients with uncontrolled essential hypertension.

Clinical outcomes in patients with atrioventricular block undergoing pacemaker: 3-year follow-up.

PURPOSE: Left ventricular function can be affected by chronic ventricular pacing. Different right ventricular (RV) pacing sites have shown heterogeneous clinical outcomes. We investigated these factors in patients receiving permanent pacemaker (PPM) implants. METHODS: This multicenter, retrospective analysis of PPM use in South Korea, included all patients undergoing de novo transvenous PPM implantation for atrioventricular block from 2017 to 2019. Clinical characteristics, 12-lead electrocardiograms, echocardiography, and laboratory parameters were evaluated. Composite outcomes are defined by two coprimary endpoints: (1) hospitalizations and (2) cardiac death by heart failure during follow-up period. RESULTS: There were 167 patients (66 males; overall mean age 75.3 ± 11.9 years), divided into two groups according to the pacing site: 83 apical RV (RVA) vs. 84 septal RV (RVS). There were no significant baseline differences. Paced QRS duration (pQRSd) increased with RVA (168.5 ± 20.1 vs. 159.1 ± 16.3 ms; p < 0.001). Over a median 31-month follow-up, there were 15 hospitalizations and 2 deaths. More patients with RVA were hospitalized or died (16% vs. 5%, respectively; p = 0.049). In Cox proportional regression analysis, pQRSd (hazard ratio [HR] 1.046; 95% confidence interval [CI] 1.004-1.091; p = 0.033), and diastolic dysfunction (HR 7.343; 95% CI 2.035-26.494; p = 0.002) were independent predictors of composite clinical outcomes. CONCLUSIONS: RVS placement shortened the pQRSd and improved clinical outcomes. However, the determinants of these were pQRSd and diastolic dysfunction. Therefore, clinicians should try to shorten the pQRSd when implanting a PPM, and patients with diastolic dysfunction should be monitored intensively.

Post-operative Atrial Fibrillation Impacts on Outcomes in Transcatheter and Surgical Aortic Valve Replacement.

Background: Atrial fibrillation (AF) in severe aortic stenosis (AS) has poor outcomes after transcatheter and surgical aortic valve replacement (TAVR and SAVR, respectively). We compared the incidence of AF after aortic valve replacement (AVR) according to the treatment method and the impact of AF on outcomes. Methods: We investigated the incidence of AF and clinical outcomes of AVR according to whether AF occurred after TAVR and SAVR after propensity score (PS)-matching for 1 year follow-up. Clinical outcomes were defined as death, stroke, and admission due to heart failure. The composite outcome comprised death, stroke, and admission due to heart failure. Results: A total of 221 patients with severe AS were enrolled consecutively, 100 of whom underwent TAVR and 121 underwent SAVR. The incidence of newly detected AF was significantly higher in the SAVR group before PS-matching (6.0 vs. 40.5%, P < 0.001) and after PS-matching (7.5 vs. 35.6%, P = 0.001). TAVR and SAVR showed no significant differences in outcomes except in terms of stroke. In the TAVR group, AF history did not affect the outcomes; however, in the SAVR group, AF history affected death (log rank P = 0.038). Post-AVR AF had a worse impact on admission due to heart failure (log rank P = 0.049) and composite outcomes in the SAVR group. Post-AVR AF had a worse impact on admission due to heart failure (log rank P = 0.008) and composite outcome in the TAVR group. Conclusion: Post-AVR AF could be considered as a predictor of the outcomes of AVR. TAVR might be a favorable treatment option for patients with severe symptomatic AS who are at high-risk for AF development or who have a history of AF because the occurrence of AF was more frequent in the SAVR group.

What is Standard Dose of Rivaroxaban in Elderly Asian Patients with Atrial Fibrillation: 20ms versus. 15mg?

Although there is no age criterion for rivaroxaban dose reduction, elderly patients with atrial fibrillation (AF) are often prescribed an off-label reduced dose. We aimed to evaluate whether age is a necessary criterion for rivaroxaban dose reduction in Korean patients with AF. Among 2208 patients who prescribed warfarin or rivaroxaban, 552 patients over 75 years without renal dysfunction (creatinine clearance >50 mL/min) were compared based on propensity score matching. The rivaroxaban group was further divided into a 20 mg (R20; on-label) and a 15 mg (R15; off-label). Primary net clinical benefit (NCB) was defined as the composite of stroke, systemic embolism, major bleeding, and all-cause mortality. Secondary NCB was defined as the composite of stroke, systemic embolism, and major bleeding. Patients were followed for 1 year, or until the first outcome occurrence. Both rivaroxaban groups had comparable efficacy compared with warfarin. However, both R20 (0.9% vs 7.4%, p = .014) and R15 (2.3% vs 7.4%, p = .018) had a significant reduction in major bleeding. There were no differences in efficacy or safety outcomes between R20 and R15. R20 had significantly reduced primary (hazard ratio [HR] 0.33, 95% confidence interval [CI]: 0.12-0.93) and secondary (HR 0.31, 95% CI: 0.10-0.93) NCBs compared with warfarin. However, primary and secondary NCBs were not reduced in R15. In real-world practice with elderly patients with AF, off-label rivaroxaban dose reduction to 15 mg conferred no benefits. Therefore, guideline-adherent rivaroxaban 20 mg is favorable in elderly Korean patients with AF.

A spatial vascular transcriptomic, proteomic, and phosphoproteomic atlas unveils an angiocrine Tie-Wnt signaling axis in the liver.

Single-cell transcriptomics (scRNA-seq) has revolutionized the understanding of the spatial architecture of tissue structure and function. Advancing the "transcript-centric" view of scRNA-seq analyses is presently restricted by the limited resolution of proteomics and genome-wide techniques to analyze post-translational modifications. Here, by combining spatial cell sorting with transcriptomics and quantitative proteomics/phosphoproteomics, we established the spatially resolved proteome landscape of the liver endothelium, yielding deep mechanistic insight into zonated vascular signaling mechanisms. Phosphorylation of receptor tyrosine kinases was detected preferentially in the central vein area, resulting in an atypical enrichment of tyrosine phosphorylation. Prototypic biological validation identified Tie receptor signaling as a selective and specific regulator of vascular Wnt activity orchestrating angiocrine signaling, thereby controlling hepatocyte function during liver regeneration. Taken together, the study has yielded fundamental insight into the spatial organization of liver endothelial cell signaling. Spatial sorting may be employed as a universally adaptable strategy for multiomic analyses of scRNA-seq-defined cellular (sub)-populations.

Right Ventricular Longitudinal Conduction Delay in Patients with Brugada Syndrome.

BACKGROUND: The mechanism of Brugada syndrome (BrS) is still unclear, with different researchers favoring either the repolarization or depolarization hypothesis. Prolonged longitudinal activation time has been verified in only a small number of human right ventricles (RVs). The purpose of the present study was to demonstrate RV conduction delays in BrS. METHODS: The RV outflow tract (RVOT)-to-RV apex (RVA) and RVA-to-RVOT conduction times were measured by endocardial stimulation and mapping in 7 patients with BrS and 14 controls. RESULTS: Patients with BrS had a longer PR interval (180 ± 12.6 vs. 142 ± 6.7 ms, P = 0.016). The RVA-to-RVOT conduction time was longer in the patients with BrS than in controls (stimulation at 600 ms, 107 ± 9.9 vs. 73 ± 3.4 ms, P = 0.001; stimulation at 500 ms, 104 ± 12.3 vs. 74 ± 4.2 ms, P = 0.037; stimulation at 400 ms, 107 ±12.2 vs. 73 ± 5.1 ms, P = 0.014). The RVOT-to-RVA conduction time was longer in the patients with BrS than in controls (stimulation at 500 ms, 95 ± 10.3 vs. 62 ± 4.1 ms, P = 0.007; stimulation at 400 ms, 94 ±11.2 vs. 64 ± 4.6 ms, P = 0.027). The difference in longitudinal conduction time was not significant when isoproterenol was administered. CONCLUSION: The patients with BrS showed an RV longitudinal conduction delay obviously. These findings suggest that RV conduction delay might contribute to generate the BrS phenotype.

Angiodiversity and organotypic functions of sinusoidal endothelial cells.

'Angiodiversity' refers to the structural and functional heterogeneity of endothelial cells (EC) along the segments of the vascular tree and especially within the microvascular beds of different organs. Organotypically differentiated EC ranging from continuous, barrier-forming endothelium to discontinuous, fenestrated endothelium perform organ-specific functions such as the maintenance of the tightly sealed blood-brain barrier or the clearance of macromolecular waste products from the peripheral blood by liver EC-expressed scavenger receptors. The microvascular bed of the liver, composed of discontinuous, fenestrated liver sinusoidal endothelial cells (LSEC), is a prime example of organ-specific angiodiversity. Anatomy and development of LSEC have been extensively studied by electron microscopy as well as linage-tracing experiments. Recent advances in cell isolation and bulk transcriptomics or single-cell RNA sequencing techniques allowed the identification of distinct LSEC molecular programs and have led to the identification of LSEC subpopulations. LSEC execute homeostatic functions such as fine tuning the vascular tone, clearing noxious substances from the circulation, and modulating immunoregulatory mechanisms. In recent years, the identification and functional analysis of LSEC-derived angiocrine signals, which control liver homeostasis and disease pathogenesis in an instructive manner, marks a major change of paradigm in the understanding of liver function in health and disease. This review summarizes recent advances in the understanding of liver vascular angiodiversity and the functional consequences resulting thereof.

Defibrillation threshold testing during implantable cardioverter defibrillator implantation: 5-year follow-up.

PURPOSE: Defibrillation threshold (DFT) testing is a routine practice in some Asian countries for patients receiving an implantable cardioverter defibrillator (ICD). However, there are few long-term data about the necessity of intraoperative DFT testing in an Asian population. We investigated the safety of DFT testing and the long-term clinical outcomes in Asian patients undergoing ICD implantation. METHODS: All patients undergoing de novo transvenous ICD implantation were randomized to undergo periprocedural DFT testing. The study included 67 patients (50 males; 51.5 ± 16.9 years) who underwent ICD implantation with (n = 33) or without (n = 34) intraoperative DFT testing between March 2012 and February 2014. We compared first-shock success, composite safety end points (the sum of complications recorded at 30 days), arrhythmic death, and all-cause mortality. RESULTS: The baseline clinical characteristics and the procedural-related adverse event rate (3.0% with DFT vs. 0% with non-DFT, p = 0.214) did not differ between groups. The programmed output of the first shock was lower in the DFT testing group (22.9 ± 4.4 J vs. 25.3 ± 5.4 J, p = 0.007). However, there were no significant differences between groups for all-cause mortality (12.1% vs. 17.6%, p = 0.526) or first-shock success rate for ventricular arrhythmia (100% vs. 88.2%, p = 0.471). CONCLUSIONS: There were no between-group differences in periprocedural safety, complications, and long-term clinical outcomes. Our results suggest that DFT testing in Asian patients allows reduction of the programmed output of the first shock, but does not affect long-term clinical outcomes.