Targeting Wavefront Discontinuity Lines for Scar-Related Ventricular Tachycardia Ablation: A Novel Functional Substrate Ablation Approach.

BACKGROUND: The boundaries of critical isthmuses for re-entrant ventricular tachycardia (VT) are formed by wave-front discontinuities (fixed lines of block, slow propagation, and rotational propagation) seen during baseline rhythm. It is unknown whether wavefront discontinuities can be automatically identified and targeted for ablation using electroanatomic mapping systems. OBJECTIVES: The purpose of this study was to assess the electrophysiologic characteristics of automatically projected wavefront discontinuity lines (WADLs) and outcomes of an ablation strategy targeting WADLs in a mixed cohort of VT patients. METHODS: Late activation substrate maps were analyzed from 1 or more baseline rhythm wavefronts. WADLs were identified using the Carto Extended Early Meets Late module. Number, total length, and distance to critical VT sites were measured. VT recurrence and VT-free survival were followed. RESULTS: In total, 49 patients underwent 52 ablations with 71 unique substrate maps analyzed (18.8% epicardial; 62.0% right ventricular paced, 28.2% sinus rhythm, 9.9% left ventricular paced). A total of 28 VT critical sites were identified in 24 patients. WADLs were present in 49 of 71 (69.0%) maps. WADLs were present regardless of cardiomyopathy etiology, mapping wavefront, or surface. At a WADL threshold of 30%, 73.9% of critical VT sites were in close proximity (≤15 mm) to a WADL. VT-free survival was 62% at 1 year, with a competing risk model estimating a 1-year risk of VT recurrence of 23%. CONCLUSIONS: WADLs can be automatically projected in a majority of patients in a mixed cohort of cardiomyopathy etiology, mapped wavefronts, and myocardial surfaces mapped. Targeting WADLs results in low rate of VT recurrence at 1 year.

The Spatial Ventricular Gradient Is Associated With Inducibility of Ventricular Arrhythmias During Electrophysiology Study.

BACKGROUND: Myocardial electrical heterogeneity is critical for normal cardiac electromechanical function, but abnormal or excessive electrical heterogeneity is proarrhythmic. The spatial ventricular gradient (SVG), a vectorcardiographic measure of electrical heterogeneity, has been associated with arrhythmic events during long-term follow-up, but its relationship with short-term inducibility of ventricular arrhythmias (VAs) is unclear. OBJECTIVE: This study was designed to determine associations between SVG and inducible VAs during electrophysiology study. METHODS: A retrospective study was conducted of adults without prior sustained VA, cardiac arrest, or implantable cardioverter-defibrillator who underwent ventricular stimulation for evaluation of syncope and nonsustained ventricular tachycardia or for risk stratification before primary prevention implantable cardioverter-defibrillator implantation. The 12-lead electrocardiograms were converted into vectorcardiograms, and SVG magnitude (SVGmag) and direction (azimuth and elevation) were calculated. Odds of inducible VA were regressed by logistic models. RESULTS: Of 143 patients (median age, 69 years; 80% male; median left ventricular ejection fraction [LVEF], 47%; 52% myocardial infarction), 34 (23.8%) had inducible VAs. Inducible patients had lower median LVEF (38% vs 50%; P < .0001), smaller SVGmag (29.5 vs 39.4 mV·ms; P = .0099), and smaller cosine SVG azimuth (cosSVGaz; 0.64 vs 0.89; P = .0007). When LVEF, SVGmag, and cosSVGaz were dichotomized at their medians, there was a 39-fold increase in adjusted odds (P = .002) between patients with all low LVEF, SVGmag, and cosSVGaz (65% inducible) compared with patients with all high LVEF, SVGmag, and cosSVGaz (4% [n = 1] inducible). After multivariable adjustment, SVGmag, cosSVGaz, and sex but not LVEF or other characteristics remained associated with inducible VAs. CONCLUSION: Assessment of electrical heterogeneity by SVG, which reflects abnormal electrophysiologic substrate, adds to LVEF and identifies patients at high and low risk of inducible VA at electrophysiology study.

A Dynamic Marketplace for Distributing Anesthesia Call: A Quality Improvement Initiative.

Anesthesiologists have a significant responsibility to provide care at all hours of the day, including nights, weekends, and holidays. This call burden carries a significant lifestyle constraint that can impact relationships, affect provider wellbeing, and has been associated with provider burnout. This quality improvement study analyzes the effects of a dynamic call marketplace, which allows anesthesiologists to specify how much call they would like to take across a spectrum of hypothetical compensation levels, from very low to very high. The system then determines the market equilibrium price such that every anesthesiologist gets exactly the amount of desired call. A retrospective analysis compared percentage participation in adjusting call burden both pre- and post-implementation of a dynamic marketplace during the years of 2017 to 2023. Additionally, a 2023 post-implementation survey was sent out assessing various aspects of anesthesiologist perception of the new system including work-life balance and job satisfaction. The dynamic call marketplace in this study enabled a more effective platform for adjusting call levels, as there was a statistically significant increase in the percentage of anesthesiologists participating in call exchanged during post- compared to pre-implementation (p < 0.0001). The satisfaction survey suggested agreement among anesthesiologists that the dynamic call marketplace positively affected professional satisfaction and work-life balance. Further, the level of agreement with these statements was most prevalent among middle career stage anesthesiologists (11-20 years as attending physician). The present system may target elements with the capacity to increase satisfaction, particularly among physicians most at risk of burnout within the anesthesia workforce.

Residual Neuromuscular Block Remains a Safety Concern for Perioperative Healthcare Professionals: A Comprehensive Review.

Residual neuromuscular block (RNMB) remains a significant safety concern for patients throughout the perioperative period and is still widely under-recognized by perioperative healthcare professionals. Current literature suggests an association between RNMB and an increased risk of postoperative pulmonary complications, a prolonged length of stay in the post anesthesia care unit (PACU), and decreased patient satisfaction. The 2023 American Society of Anesthesiologists Practice Guidelines for Monitoring and Antagonism of Neuromuscular Blockade provide guidance for the use of quantitative neuromuscular monitoring coupled with neuromuscular reversal to recognize and reduce the incidence of RNMB. Using sugammadex for the reversal of neuromuscular block as well as quantitative neuromuscular monitoring to quantify the degree of neuromuscular block may significantly reduce the risk of RNMB among patients undergoing general anesthesia. Studies are forthcoming to investigate how using neuromuscular blocking agent reversal with quantitative monitoring of the neuromuscular block may further improve perioperative patient safety.

The role of RNF138 in DNA end resection is regulated by ubiquitylation and CDK phosphorylation.

Double-strand breaks (DSBs) are DNA lesions that pose a significant threat to genomic stability. The repair of DSBs by the homologous recombination (HR) pathway is preceded by DNA end resection, the 5' to 3' nucleolytic degradation of DNA away from the DSB. We and others previously identified a role for RNF138, a really interesting new gene finger E3 ubiquitin ligase, in stimulating DNA end resection and HR. Yet, little is known about how RNF138's function is regulated in the context of DSB repair. Here, we show that RNF138 is phosphorylated at residue T27 by cyclin-dependent kinase (CDK) activity during the S and G2 phases of the cell cycle. We also observe that RNF138 is ubiquitylated constitutively, with ubiquitylation occurring in part on residue K158 and rising during the S/G2 phases. Interestingly, RNF138 ubiquitylation decreases upon genotoxic stress. By mutating RNF138 at residues T27, K158, and the previously identified S124 ataxia telangiectasia mutated phosphorylation site (Han et al., 2016, ref. 22), we find that post-translational modifications at all three positions mediate DSB repair. Cells expressing the T27A, K158R, and S124A variants of RNF138 are impaired in DNA end resection, HR activity, and are more sensitive to ionizing radiation compared to those expressing wildtype RNF138. Our findings shed more light on how RNF138 activity is controlled by the cell during HR.

Liposomal bupivacaine interscalene blocks demonstrate a greater proportion of total shoulder arthroplasty patients with clinically tolerable pain: a retrospective quality improvement study of 491 patients.

OBJECTIVE: To evaluate the effects of liposomal bupivacaine use for interscalene blocks on postoperative analgesia in total shoulder arthroplasty patients. METHODS: De-identified total or reverse total shoulder arthroplasty patients between 2018 and 2021 were analyzed. Patients were grouped into single shot interscalene block with liposomal bupivacaine (LB) with plain bupivacaine, other block (OB) with other local anesthetics (mepivacaine, ropivacaine, or plain bupivacaine), or no block (NB). The primary outcome was the proportion of patients with clinically tolerable pain scores (mean VAS ≤4) from 0 to 24 â€‹h in each group. Secondary outcomes included averaged visual analog pain scores (VAS) and opioid consumption measured in morphine milligram equivalents (MMEs) from 0 to 24 â€‹h. We also analyzed the proportion of patients with clinically tolerable pain, mean VAS, and opioid consumption from 0 to 72 â€‹h in those patients with at least a 3-day hospital length of stay. RESULTS: A total of 491 de-identified total shoulder arthroplasty patients, 285 liposomal bupivacaine group (LB), 178 other block group (OB), and 28 no block group (NB), were analyzed. The primary outcome showed a statistically significant different proportion of patients with clinically tolerable pain from 0 to 24 â€‹h in the LB group (69 â€‹%) vs. OB group (39 â€‹%) vs. NB group (11 â€‹%) (<0.001). Secondary outcomes included statistically significant differences in VAS (LB median â€‹= â€‹3.35, OB median â€‹= â€‹4.38, NB median â€‹= â€‹5.25 (p â€‹< â€‹0.001, <0.001)) and total MME opioid consumption (LB median â€‹= â€‹40, OB median â€‹= â€‹60, NB median â€‹= â€‹88 (p â€‹< â€‹0.001, 0.001)) between groups from 0 to 24 â€‹h. For patients who had hospital stays of at least 3 days, a significant association was found with having achieved clinically tolerable pain 0-72 â€‹h and the LB group (51 â€‹%) vs. OB group (21 â€‹%) vs. NB group (11 â€‹%) (P â€‹= â€‹0.006). However, there was no statistical difference in mean VAS or opioid consumption between these groups. CONCLUSION: A greater proportion of total shoulder arthroplasty patients that received liposomal bupivacaine in interscalene block have clinically tolerable pain scores from 0 to 24 â€‹h, lower VAS, and lower MME consumption in patients following total shoulder arthroplasty. LEVEL OF EVIDENCE: Level III - Clinical Study.

Correlation Between Functional Substrate Mapping and Cardiac Computed Tomography-Derived Wall Thinning for Ventricular Tachycardia Ablation.

BACKGROUND: Functional substrate mapping during baseline rhythm can identify arrhythmogenic tissue during ventricular tachycardia (VT) ablation. Wall thinning and wall thickness channels (WTCs) derived from computed tomography angiography have been shown to correlate with low voltage and VT isthmuses. The correlation between functional substrate mapping, wall thinning, and WTCs in patients with infarct- or non-infarct-related cardiomyopathies (ICM and NICM, respectively) has not been previously described. OBJECTIVES: The purpose of this study was to correlate cardiac CTA-derived myocardial wall thinning with functional VT substrate mapping using isochronal late activation mapping. METHODS: In 34 patients with ICM or NICM undergoing VT ablation who had a preprocedure computed tomography angiography, myocardial wall thinning was segmented in layers of 1 to 5 mm. Areas of wall thinning and WTCs were then spatially correlated with deceleration zones (DZs) from registered left ventricular endocardial isochronal late activation maps. RESULTS: In 21 ICM patients and 13 NICM patients, ICM patients had greater surfaces areas of wall thinning (P < 0.001). In ICM patients, 94.1% of primary DZs were located on areas of wall thinning, compared to 20% of DZs in NICM patients overall but 50% if there was any wall thinning present. Fifty-nine percent of DZs in ICM patients and 56% of DZs in NICM patients were located near WTCs. The positive predictive value for WTC in localizing DZs was 22.5% and 37.8% in ICM and NICM patients, respectively. CONCLUSIONS: Wall thinning is highly sensitive for functional substrate in ICM patients. WTCs had modest sensitivity for functional substrate but low positive predictive value for identifying DZs in ICM and NICM patients. These findings suggest that wall thinning may facilitate more efficient mapping in ICM patients, but WTCs are insufficient to localize wavefront discontinuities.

Incidence, Treatment, and Outcomes of Symptomatic Device Lead-Related Venous Obstruction.

BACKGROUND: The incidence and clinical impact of lead-related venous obstruction (LRVO) among patients with cardiovascular implantable electronic devices (CIEDs) is poorly defined. OBJECTIVES: The objectives of this study were to determine the incidence of symptomatic LRVO after CIED implant; describe patterns in CIED extraction and revascularization; and quantify LRVO-related health care utilization based on each type of intervention. METHODS: LRVO status was defined among Medicare beneficiaries after CIED implant from October 1, 2015, to December 31, 2020. Cumulative incidence functions of LRVO were estimated by Fine-Gray methods. LRVO predictors were identified using Cox regression. Incidence rates for LRVO-related health care visits were calculated with Poisson models. RESULTS: Among 649,524 patients who underwent CIED implant, 28,214 developed LRVO, with 5.0% cumulative incidence at maximum follow-up of 5.2 years. Independent predictors of LRVO included CIEDs with >1 lead (HR: 1.09; 95% CI: 1.07-1.15), chronic kidney disease (HR: 1.17; 95% CI: 1.14-1.20), and malignancies (HR: 1.23; 95% CI: 1.20-1.27). Most patients with LRVO (85.2%) were managed conservatively. Among 4,186 (14.8%) patients undergoing intervention, 74.0% underwent CIED extraction and 26.0% percutaneous revascularization. Notably, 90% of the patients did not receive another CIED after extraction, with low use (2.2%) of leadless pacemakers. In adjusted models, extraction was associated with significant reductions in LRVO-related health care utilization (adjusted rate ratio: 0.58; 95% CI: 0.52-0.66) compared with conservative management. CONCLUSIONS: In a large nationwide sample, the incidence of LRVO was substantial, affecting 1 of every 20 patients with CIEDs. Device extraction was the most common intervention and was associated with long-term reduction in recurrent health care utilization.

Quantification of protein enrichment at site-specific DNA double-strand breaks by chromatin immunoprecipitation in cultured human cells.

Here, we present a chromatin-immunoprecipitation-based protocol to quantify the recruitment of proteins adjacent to site-specific DNA double-strand breaks (DSBs), such as proteins involved in DSB repair. We describe steps to induce DSBs in U2OS osteosarcoma cells stably expressing the restriction endonucleases FokI or AsiSI. We then detail the procedures of chromatin isolation and immunoprecipitation, followed by protein elution and quantitative-PCR-based quantification of DNA. This protocol cannot be used on DSBs generated at random loci by DNA damaging agents. For complete details on the use and execution of this protocol, please refer to Fitieh et al. (2022).1.

BMI-1 regulates DNA end resection and homologous recombination repair.

BMI-1 is an essential regulator of transcriptional silencing during development. Recently, the role of BMI-1 in the DNA damage response has gained much attention, but the exact mechanism of how BMI-1 participates in the process is unclear. Here, we establish a role for BMI-1 in the repair of DNA double-strand breaks by homologous recombination (HR), where it promotes DNA end resection. Mechanistically, BMI-1 mediates DNA end resection by facilitating the recruitment of CtIP, thus allowing RPA and RAD51 accumulation at DNA damage sites. Interestingly, treatment with transcription inhibitors rescues the DNA end resection defects of BMI-1-depleted cells, suggesting BMI-1-dependent transcriptional silencing mediates DNA end resection. Moreover, we find that H2A ubiquitylation at K119 (H2AK119ub) promotes end resection. Taken together, our results identify BMI-1-mediated transcriptional silencing and promotion of H2AK119ub deposition as essential regulators of DNA end resection and thus the progression of HR.

Lead-Related Venous Obstruction in Patients With Implanted Cardiac Devices: JACC Review Topic of the Week.

Cardiac implantable electronic device implantation rates have increased in recent decades. Venous obstruction of the subclavian, brachiocephalic, or superior vena cava veins represents an important complication of implanted leads. These forms of venous obstruction can result in significant symptoms as well as present a barrier to the implantation of additional device leads. The risk factors for the development of these complications remain poorly understood, and diagnosis relies on clinical recognition and cross-sectional imaging. Anticoagulation remains the mainstay of treatment, and thrombus debulking, lead extraction, venoplasty, and stenting are all important therapeutic interventions. This review provides a multidisciplinary-based approach to the evaluation and management of cardiac implantable electronic device lead-associated venous obstruction.

Lead-associated Superior Vena Cava Syndrome.

Superior vena cava (SVC) syndrome is a rare complication associated with transvenous cardiac implantable electronic devices that may present with a variety of manifestations. Various strategies such as transvenous lead extraction, anticoagulation, venoplasty, and stenting have been used to treat this condition, but the optimal management protocols have yet to be defined. Subcutaneous implantable cardioverter-defibrillator (ICD) (S-ICD) therapy can be an alternative option to a transvenous system for those who require future ICD surveillance. We present a case of lead-associated SVC syndrome where thoracic venous congestion due to SVC obstruction influenced preimplant S-ICD QRS vector screening. Following treatment of venous obstruction, QRS amplitude may change and patients who were not initially S-ICD candidates may later become eligible.

The Role of Polycomb Group Protein BMI1 in DNA Repair and Genomic Stability.

The polycomb group (PcG) proteins are a class of transcriptional repressors that mediate gene silencing through histone post-translational modifications. They are involved in the maintenance of stem cell self-renewal and proliferation, processes that are often dysregulated in cancer. Apart from their canonical functions in epigenetic gene silencing, several studies have uncovered a function for PcG proteins in DNA damage signaling and repair. In particular, members of the poly-comb group complexes (PRC) 1 and 2 have been shown to recruit to sites of DNA damage and mediate DNA double-strand break repair. Here, we review current understanding of the PRCs and their roles in cancer development. We then focus on the PRC1 member BMI1, discussing the current state of knowledge of its role in DNA repair and genome integrity, and outline how it can be targeted pharmacologically.

SUMOylation mediates CtIP's functions in DNA end resection and replication fork protection.

Double-strand breaks and stalled replication forks are a significant threat to genomic stability that can lead to chromosomal rearrangements or cell death. The protein CtIP promotes DNA end resection, an early step in homologous recombination repair, and has been found to protect perturbed forks from excessive nucleolytic degradation. However, it remains unknown how CtIP's function in fork protection is regulated. Here, we show that CtIP recruitment to sites of DNA damage and replication stress is impaired upon global inhibition of SUMOylation. We demonstrate that CtIP is a target for modification by SUMO-2 and that this occurs constitutively during S phase. The modification is dependent on the activities of cyclin-dependent kinases and the PI-3-kinase-related kinase ATR on CtIP's carboxyl-terminal region, an interaction with the replication factor PCNA, and the E3 SUMO ligase PIAS4. We also identify residue K578 as a key residue that contributes to CtIP SUMOylation. Functionally, a CtIP mutant where K578 is substituted with a non-SUMOylatable arginine residue is defective in promoting DNA end resection, homologous recombination, and in protecting stalled replication forks from excessive nucleolytic degradation. Our results shed further light on the tightly coordinated regulation of CtIP by SUMOylation in the maintenance of genome stability.

Arrhythmia in Cardiac Sarcoidosis.

Cardiac sarcoidosis (CS) is a complex disease that can manifest as a diverse array of arrhythmias. CS patients may be at higher risk for sudden cardiac death (SCD), and, in some cases, SCD may be the first presenting symptom of the underlying disease. As such, identification, risk stratification, and management of CS-related arrhythmia are crucial in the care of these patients. Left untreated, CS carries significant arrhythmogenic morbidity and mortality. Cardiac manifestations of CS are a consequence of an inflammatory process resulting in the myocardial deposition of noncaseating granulomas. Endomyocardial biopsy remains the gold standard for diagnosis; however, biopsy yield is limited by the patchy distribution of the granulomas. As such, recent guidelines have improved clinical diagnostic pathways relying on advanced cardiac imaging to help in the diagnosis of CS. To date, corticosteroids are the best studied agent to treat CS but are associated with significant risks and limited benefits. Implantable cardioverter-defibrillators have an important role in SCD risk reduction. Catheter ablation in conjunction with antiarrhythmics seems to reduce ventricular arrhythmia burden. However, the appropriate selection of these patients is crucial as ablation is likely more helpful in the setting of a myocardial scar substrate versus arrhythmia driven by active inflammation. Further studies investigating CS pathophysiology, the pathway to diagnosis, arrhythmogenic manifestations, and SCD risk stratification will be crucial to reduce the high morbidity and mortality of this disease.