Ex-vivo histopathologic examination of irrigated radiofrequency ablation utilizing half-normal saline of the human heart.

INTRODUCTION: Radiofrequency ablation (RFA) utilizing half-normal saline (HNS) irrigation is a promising intervention to circumvent commonly encountered limitations during radiofrequency ablation of deep myocardial substrate. Few studies to date have analyzed the morphologic changes in the human myocardium following HNS RFA. METHODS AND RESULTS: Three patients with symptomatic ventricular tachycardia (VT) who underwent RFA with HNS irrigation underwent pathological specimen examination at time of autopsy or following native heart explant at the time of cardiac transplantation. Gross evaluation of the heart was performed fresh and after fixation in 10% formalin. A routine examination was performed with fixation in 10% formalin. Sections of lesioned tissue were paraffin embedded and evaluated using standard hematoxylin and eosin (H&E) staining. CONCLUSION: Irrigated RF ablation with HNS irrigant produces coagulative necrosis as well as several delayed histopathological changes with a deeper field of effective ablation. Transmurality may not be obtained in the ventricular myocardium with endocardial, epicardial, or sequential unipolar HNS ablation.

Atypical atrial flutter catheter ablation in the era of high-density mapping.

BACKGROUND: Mapping and ablating atypical atrial flutters (AAFLs) have evolved greatly with advances in high-density 3D mapping systems over the last years. METHODS: The objectives are to evaluate the feasibility of AAFL catheter ablation based on high-density mapping and minimizing entrainment and to better characterize AAFL circuits. Consecutive patients who underwent AAFL ablation using the EnSite Precision™ system and HD Grid™ mapping catheter (Abbott, Chicago, IL) between 06/2018 and 1/2022 were included. Mitral isthmus-dependent and roof-dependent AAFLs were classified as conventional circuits. All other AAFL circuits were classified as non-conventional circuits and were defined based on the location of the critical isthmus. RESULTS: Sixty-two patients underwent AAFL ablation (mean age 68±11 years). A total of 95 AAFLs were mapped and 92 (97%) were successfully ablated. Fifty-three (85%) patients had a previous AF/AFL ablation. Forty-four (46%) AAFL circuits were classified as conventional and 51 (54%) as non-conventional. Conventional AAFL circuits had longer critical isthmuses (19.0±9.0 vs 10.8±6.3mm, p<0.001), a lower prevalence of slow conduction at the critical isthmus (59% vs 86%, p=0.005), and a longer radiofrequency time to AAFL termination (117±119 vs 51±66 s, p=0.002). Entrainment was attempted in 19 (20%) flutters and its use declined significantly over the study period. Procedural success rates remained high whether entrainment was used or not. Freedom of any atrial tachycardia was 65% over a follow-up of 13.8±9.0 months. CONCLUSIONS: AAFL catheter ablation can be achieved with high procedural success rate using a contemporary strategy based on high-density mapping alone. Non-conventional circuits are frequent and present unique electrophysiological characteristics.

Pharos 2023: an integrated resource for the understudied human proteome.

The Illuminating the Druggable Genome (IDG) project aims to improve our understanding of understudied proteins and our ability to study them in the context of disease biology by perturbing them with small molecules, biologics, or other therapeutic modalities. Two main products from the IDG effort are the Target Central Resource Database (TCRD) (http://juniper.health.unm.edu/tcrd/), which curates and aggregates information, and Pharos (https://pharos.nih.gov/), a web interface for fusers to extract and visualize data from TCRD. Since the 2021 release, TCRD/Pharos has focused on developing visualization and analysis tools that help reveal higher-level patterns in the underlying data. The current iterations of TCRD and Pharos enable users to perform enrichment calculations based on subsets of targets, diseases, or ligands and to create interactive heat maps and UpSet charts of many types of annotations. Using several examples, we show how to address disease biology and drug discovery questions through enrichment calculations and UpSet charts.

A multi-omic analysis of MCF10A cells provides a resource for integrative assessment of ligand-mediated molecular and phenotypic responses.

The phenotype of a cell and its underlying molecular state is strongly influenced by extracellular signals, including growth factors, hormones, and extracellular matrix proteins. While these signals are normally tightly controlled, their dysregulation leads to phenotypic and molecular states associated with diverse diseases. To develop a detailed understanding of the linkage between molecular and phenotypic changes, we generated a comprehensive dataset that catalogs the transcriptional, proteomic, epigenomic and phenotypic responses of MCF10A mammary epithelial cells after exposure to the ligands EGF, HGF, OSM, IFNG, TGFB and BMP2. Systematic assessment of the molecular and cellular phenotypes induced by these ligands comprise the LINCS Microenvironment (ME) perturbation dataset, which has been curated and made publicly available for community-wide analysis and development of novel computational methods ( synapse.org/LINCS_MCF10A ). In illustrative analyses, we demonstrate how this dataset can be used to discover functionally related molecular features linked to specific cellular phenotypes. Beyond these analyses, this dataset will serve as a resource for the broader scientific community to mine for biological insights, to compare signals carried across distinct molecular modalities, and to develop new computational methods for integrative data analysis.

Hemodynamic response and safety of vasodilator stress cardiovascular magnetic resonance in patients with permanent pacemakers or implantable cardioverter-defibrillators.

INTRODUCTION: Vasodilator stress cardiovascular magnetic resonance (CMR) is a powerful diagnostic modality, but data toward its use in patients with permanent pacemakers (PPMs) or implantable cardioverter-defibrillators (ICDs) is limited. METHODS AND RESULTS: Patients with ICDs (>1% pacing) or PPMs who underwent regadenoson single photon emission computed tomography (SPECT) and all patients with ICDs or PPMs who underwent stress CMR were retrospectively identified. SPECT tests were analyzed for hemodynamic responses and new pacing requirements; CMR studies were examined for safety, device characteristics and programming, hemodynamic responses, and image quality. Changes from baseline were evaluated with the Related-Samples Wilcoxon Signed Rank Test. Of 67 patients (median age 65 [IQR 58-72] years, 31 [46%] female, 31 [46%] Black), 47 underwent SPECT and 20 CMR. With regadenoson SPECT, 89% of patients experienced tachycardic responses above resting heart rates (+19 [13-32] beats per minute, p < .01). During stress CMR, 10 (50%) devices were asynchronously paced approximately 10 beats per minute above resting rates, and the remaining were temporarily deactivated. Those with asynchronous pacing had no changes in heart rates, whereas patients with deactivated devices had near uniform heart rate accelerations. Image quality was diagnostic in the majority of stress CMR sequences, with nonconditional ICDs contributing 40 of 57 (70%) of nondiagnostic segments. CONCLUSION: This data supports the safety of vasodilator stress CMR with promising diagnostic quality images in patients with CMR conditional ICDs and PPMs. Despite a near uniform tachycardic response to regadenoson in the SPECT environment, high rates of asynchronous pacing during vasodilator stress CMR did not result in competitive pacing or adverse arrhythmic events. Further studies are needed to validate these findings and confirm the diagnostic and prognostic performance of stress CMR in these individuals.

Left bundle branch area pacing in patients with atrioventricular conduction disease: A prospective multicenter study.

BACKGROUND: The reported success rate of His-bundle pacing (HBP) in patients with infranodal atrioventricular (AV) conduction disease is only 52%-76%. The success rate of left bundle branch area pacing (LBBAP) in this cohort is not well studied. OBJECTIVE: The purpose of this study was to evaluate the feasibility, safety, and electrophysiological characteristics of LBBAP in patients with AV conduction disease. METHODS: Patients with AV conduction disease referred for pacemaker implantation at 2 centers between February 2019 and June 2021 were considered for LBBAP. Baseline demographic characteristics, procedural success rates, electrophysiological parameters, and complications were assessed. RESULTS: LBBAP was successful in 340 of 364 patients (93%). Mean age was 72 ± 13 years, and mean follow-up was 331 ± 244 days. Pacing indications were Mobitz I in 27 patients (7%), Mobitz II or 2:1 AV block or high-grade AV block in 94 patients (26%), complete heart block in 199 patients (55%), and sick sinus syndrome with isolated bundle branch block in 44 patients (12%). Left bundle branch block and right bundle branch block were present in 57 patients (16%) and 140 patients (38%), respectively. Procedural success rates did not differ between indications (92.6%, 93.6%, 92.9%, and 95%, respectively) or between patients with narrow (<120 ms) vs wide QRS (≥120 ms). Mean LBBAP threshold was 0.77 ± 0.34 V at 0.4 ms at implant and remained stable during follow-up. There were 4 (1.2%) acute LBBAP lead dislodgments. CONCLUSION: LBBAP is safe and feasible with high success rates for patients with AV conduction disease. In contrast to HBP, LBBAP success rates remain high over the entire spectrum of AV conduction disease, and lead parameters remain stable during follow-up.

Atrioventricular junction ablation in patients with conduction system pacing leads: A comparison of His-bundle vs left bundle branch area pacing leads.

BACKGROUND: Single-center studies have shown feasibility of conduction system pacing (CSP) via His-bundle pacing (HBP) or left bundle branch area pacing (LBBAP) in atrial fibrillation (AF) patients undergoing atrioventricular junction ablation (AVJA). OBJECTIVE: The purpose of this study was to compare outcomes in patients with HBP and LBBAP leads undergoing AVJA. METHODS: Consecutive patients with CSP leads referred for AVJA between October 2014 and May 2021 were included. Pacing lead characteristics, procedural characteristics, complications, and long-term outcomes were assessed. RESULTS: One hundred five AVJA procedures (55 HBP, 50 LBBAP) were performed in 98 patients (48 HBP, 50 LBBAP). The acute success rate of the AVJA procedure was 94% vs 100% (P = .11) in HBP vs LBBAP groups. Seven (14%) redo AVJA procedures were required in the HBP group. Mean procedural time (44 ± 24 min vs 34 ± 16 min; P = .02) and mean fluoroscopy time (16 ± 18 min vs 7 ± 6 min; P <.001) were significantly longer in the HBP vs LBBAP group. An acute rise in threshold was noted in 8 cases (14.5%), and 4 (8%) developed exit block after AVJA in HBP patients. Chronic HBP threshold ≥2.5 V was seen in 23 patients (48%), and 4 (8%) HBP leads were deactivated. CSP preserved ejection fraction (EF) in the overall cohort (N = 70; 53% ± 10% vs 55% ± 10%; P = .09) and significantly improved in those with reduced EF <50% at baseline (N = 16; 37% ± 7.6% vs 46% ± 13%; P = .02). CONCLUSION: AVJA in the presence of an LBBAP lead is associated with a higher success rate and fewer acute and chronic lead-related complications. CSP with either HBP or LBBAP preserves left ventricular systolic function in patients with refractory atrial fibrillation post AVJA.

In spite of successful curative surgery for buccal mucosa carcinoma the health-related quality-of-life continues to remain poor.

BACKGROUND: In early stage buccal mucosa carcinoma, in spite of successful curative surgery, the health-related quality-of-life (HRQoL) may not improve. We aimed to study HRQoL in these patients who had undergone successful curative surgery and determined factors that influence the HRQoL. METHODS: Subjects, aged 18-70 years, who had undergone successful curative surgery for stage I and II buccal mucosa cancer, were assessed for HRQoL using the University of Washington Quality of Life Questionnaire and factors affecting HRQoL were determined. Their scores were compared with normative reference scores. RESULTS: 54 patients (stages I 54%, II 46%) aged 44 ± 11 years (87% males) were studied. They had undergone curative surgery a median of 8.5 (IQR 4-13.5) months ago. Their mean global HRQoL score was 77 ± 30, with significantly poorer scores compared to reference in domains of appearance, activity, swallowing, chewing, speech, shoulder, saliva, mood and anxiety. Anxiety, activity, and chewing were considered the most important domains by the patients. Among the factors influencing HRQoL, duration since surgery was the most important factor, and patients with recent surgery had worse performance in chewing, saliva and mood. Patients with stage II had worse performance in shoulder and anxiety compared to stage I. Post-operative radiotherapy worsened swallowing and shoulder function. CONCLUSION: In spite of successful curative surgery for buccal mucosa carcinoma, the HRQoL continues to remain sub-optimal with poor scores in most of the domains. These domains must be focused on with appropriate measures in order to improve overall HRQoL in patients after successful curative surgery.

Damsel in distress calling on her knights: Illuminating the pioneering role of E3 ubiquitin ligases in guarding the genome integrity.

The maintenance of genomic integrity is of utmost importance for the organisms to survive and to accurately inherit traits to their progenies. Any kind of DNA damage either due to defect in DNA duplication and/ or uncontrolled cell division or intracellular insults or environment radiation can result in gene mutation, chromosomal aberration and ultimately genomic instability, which may cause several diseases including cancers. Therefore, cells have evolved machineries for the surveillance of genomic integrity. Enormous exciting studies in the past indicate that ubiquitination (a posttranslational modification of proteins) plays a crucial role in maintaining the genomic integrity by diverse ways. In fact, various E3 ubiquitin ligases catalyse ubiquitination of key proteins to control their central role during cell cycle, DNA damage response (DDR) and DNA repair. Some E3 ligases promote genomic instability while others prevent it, deregulation of both of which leads to several malignancies. In this review, we consolidate the recent findings wherein the role of ubiquitination in conferring genome integrity is highlighted. We also discuss the latest discoveries on the mechanisms utilized by various E3 ligases to preserve genomic stability, with a focus on their actions during cell cycle progression and different types of DNA damage response as well as repair pathways.

Coronavirus disease 2019 and cardiovascular diseases: collateral damage?

PURPOSE OF REVIEW: Cardiovascular involvement in coronavirus disease 2019 (COVID-19) is relatively common and portends an increased risk of morbidity and mortality. Manifestations of myocardial injury may exhibit significant overlap and result in diagnostic uncertainty. This review will summarize recent literature around cardiovascular complications of COVID-19. RECENT FINDINGS: Venous thromboembolism, atrial fibrillation, and type II myocardial infarction are observed commonly in COVID-19, while severe acute respiratory syndrome coronavirus 2 viral myocarditis remains quite rare. Although infrequent, COVID-19 vaccination has been associated with myocarditis and pericarditis in young individuals. SUMMARY: Various forms of COVID-19-related myocardial injury have been associated with increased utilization of mechanical ventilation, hemodynamic deterioration, and mortality. Manifestations of myocardial injury in COVID-19 are varied, but share common drivers of illness including sequelae of sepsis, immune-mediated factors, and a prothrombotic state. Understanding the forms of myocardial injury in COVID-19 may aid in rapid diagnosis and treatment.

Autonomic Modulation for Treatment of Repolarization Alternans and Refractory Ventricular Electrical Storm.

Macroscopic T-wave alternans (TWA) is a rare finding on surface electrocardiogram and has been associated with an increased risk of impending sudden cardiac death. We highlight a case of macroscopic TWA in a patient with markedly prolonged QTc interval preceding ventricular electrical storm, which was refractory to medical management. Autonomic modulation of the stellate ganglion resulted in improvement in both TWA and QTc interval. (Level of Difficulty: Advanced.).

An Unusual Complication of Transseptal Puncture.

The interatrial septum is a structure with complex embryological development. The true atrial septum is a circumscribed structure, and transgression outside of this area during transseptal puncture may result in entry into the extracardiac space or aorta that may result in a pericardial effusion or cardiac tamponade. (Level of Difficulty: Intermediate.).

Influence of cholesterol on cancer progression and therapy.

Cholesterol is a fundamental molecule necessary for the maintenance of cell structure and is vital to various normal biological functions. It is a key factor in lifestyle-related diseases including obesity, diabetes, cardiovascular disease, and cancer. Owing to its altered serum chemistry status under pathological states, it is now being investigated to unravel the mechanism by which it triggers various health complications. Numerous clinical studies in cancer patients indicate an alteration in blood cholesterol level (either decreased or increased) in comparison to normal healthy individuals. This article elaborates on our understanding as to how cholesterol is being hijacked in the malignancy for the development, survival, stemness, progression, and metastasis of cancerous cells. Also, it provides a glimpse of how cholesterol derived entities, alters the signaling pathway towards their advantage. Moreover, deregulation of the cholesterol metabolism pathway has been often reported to hamper various treatment strategies in different cancer. In this context, attempts have been made to bring forth its relevance in being targeted, in pre-clinical and clinical studies for various treatment modalities. Thus, understanding the role of cholesterol and deciphering associated molecular mechanisms in cancer progression and therapy are of relevance towards improvement in the management of various cancers.

piNET: a versatile web platform for downstream analysis and visualization of proteomics data.

Rapid progress in proteomics and large-scale profiling of biological systems at the protein level necessitates the continued development of efficient computational tools for the analysis and interpretation of proteomics data. Here, we present the piNET server that facilitates integrated annotation, analysis and visualization of quantitative proteomics data, with emphasis on PTM networks and integration with the LINCS library of chemical and genetic perturbation signatures in order to provide further mechanistic and functional insights. The primary input for the server consists of a set of peptides or proteins, optionally with PTM sites, and their corresponding abundance values. Several interconnected workflows can be used to generate: (i) interactive graphs and tables providing comprehensive annotation and mapping between peptides and proteins with PTM sites; (ii) high resolution and interactive visualization for enzyme-substrate networks, including kinases and their phospho-peptide targets; (iii) mapping and visualization of LINCS signature connectivity for chemical inhibitors or genetic knockdown of enzymes upstream of their target PTM sites. piNET has been built using a modular Spring-Boot JAVA platform as a fast, versatile and easy to use tool. The Apache Lucene indexing is used for fast mapping of peptides into UniProt entries for the human, mouse and other commonly used model organism proteomes. PTM-centric network analyses combine PhosphoSitePlus, iPTMnet and SIGNOR databases of validated enzyme-substrate relationships, for kinase networks augmented by DeepPhos predictions and sequence-based mapping of PhosphoSitePlus consensus motifs. Concordant LINCS signatures are mapped using iLINCS. For each workflow, a RESTful API counterpart can be used to generate the results programmatically in the json format. The server is available at http://pinet-server.org, and it is free and open to all users without login requirement.

Task-specific interhemispheric hypoconnectivity in writer's cramp - An EEG study.

OBJECTIVE: Writer's cramp (WC) is a focal task-specific dystonia characterized by abnormal posturing of the hand muscles during handwriting, but not during other tasks that involve the same set of muscles and objects such as sharpening a pencil. Our objective was to investigate the pathophysiology underlying the task specificity of this disorder using EEG. We hypothesized that premotor-parietal connectivity will be lower in WC patients specifically during handwriting and motor imagery of handwriting. METHODS: We recruited 15 WC patients and 15 healthy controls. EEG was recorded while participants performed 4 tasks - writing with a pencil, sharpening a pencil, imagining writing and imagining sharpening. We determined the connectivity changes between relevant brain regions during these tasks. RESULTS: We found reduced interhemispheric alpha coherence in the sensorimotor areas in WC patients exclusively during handwriting. WC patients also showed less reduction of task-related beta spectral power and a trend for reduced premotor-parietal coherence during motor tasks. CONCLUSION: We could not confirm an abnormality in premotor-parietal connectivity specific to handwriting by this method. However, there was a task-specific reduction in interhemispheric alpha connectivity in WC patients, whose behavioral correlate remains unknown. SIGNIFICANCE: Interhemispheric alpha connectivity can be a potential interventional target in WC.

Complex nutrient channel phenotypes despite Mendelian inheritance in a Plasmodium falciparum genetic cross.

Malaria parasites activate a broad-selectivity ion channel on their host erythrocyte membrane to obtain essential nutrients from the bloodstream. This conserved channel, known as the plasmodial surface anion channel (PSAC), has been linked to parasite clag3 genes in P. falciparum, but epigenetic switching between the two copies of this gene hinders clear understanding of how the encoded protein determines PSAC activity. Here, we used linkage analysis in a P. falciparum cross where one parent carries a single clag3 gene to overcome the effects of switching and confirm a primary role of the clag3 product with high confidence. Despite Mendelian inheritance, CLAG3 conditional knockdown revealed remarkably preserved nutrient and solute uptake. Even more surprisingly, transport remained sensitive to a CLAG3 isoform-specific inhibitor despite quantitative knockdown, indicating that low doses of the CLAG3 transgene are sufficient to confer block. We then produced a complete CLAG3 knockout line and found it exhibits an incomplete loss of transport activity, in contrast to rhoph2 and rhoph3, two PSAC-associated genes that cannot be disrupted because nutrient uptake is abolished in their absence. Although the CLAG3 knockout did not incur a fitness cost under standard nutrient-rich culture conditions, this parasite could not be propagated in a modified medium that more closely resembles human plasma. These studies implicate oligomerization of CLAG paralogs encoded by various chromosomes in channel formation. They also reveal that CLAG3 is dispensable under standard in vitro conditions but required for propagation under physiological conditions.

Use of Intravenous Cangrelor as Antiplatelet Bridge Therapy in a Patient Undergoing Esophageal Dilation Procedure.

Peri-procedural management of dual antiplatelet therapy following percutaneous coronary intervention for esophagogastroduodenoscopy and intervention is not clearly defined. We describe a case of a patient with a drug-eluting stent implanted in the setting of an acute myocardial infarction six weeks earlier who was bridged with cangrelor after interruption of ticagrelor for esophageal balloon dilatation because of dysphagia. The patient tolerated the procedure well and was transitioned back to ticagrelor without any complications.

Eosinophilic Granulomatosis With Polyangiitis Presenting as an Acute Coronary Syndrome.

Eosinophilic granulomatosis with polyangiitis, formerly Churg-Strauss Syndrome, is an uncommon disorder that carries a high mortality when coronary artery disease develops. Early recognition and treatment is crucial. We highlight an unusual presentation of acute coronary syndrome not associated with atherosclerotic coronary disease. (Level of Difficulty: Intermediate.).