Pulsed Field or Conventional Thermal Ablation for Paroxysmal Atrial Fibrillation.

BACKGROUND: Catheter-based pulmonary vein isolation is an effective treatment for paroxysmal atrial fibrillation. Pulsed field ablation, which delivers microsecond high-voltage electrical fields, may limit damage to tissues outside the myocardium. The efficacy and safety of pulsed field ablation as compared with conventional thermal ablation are not known. METHODS: In this randomized, single-blind, noninferiority trial, we assigned patients with drug-refractory paroxysmal atrial fibrillation in a 1:1 ratio to undergo pulsed field ablation or conventional radiofrequency or cryoballoon ablation. The primary efficacy end point was freedom from a composite of initial procedural failure, documented atrial tachyarrhythmia after a 3-month blanking period, antiarrhythmic drug use, cardioversion, or repeat ablation. The primary safety end point included acute and chronic device- and procedure-related serious adverse events. RESULTS: A total of 305 patients were assigned to undergo pulsed field ablation, and 302 were assigned to undergo thermal ablation. At 1 year, the primary efficacy end point was met (i.e., no events occurred) in 204 patients (estimated probability, 73.3%) who underwent pulsed field ablation and 194 patients (estimated probability, 71.3%) who underwent thermal ablation (between-group difference, 2.0 percentage points; 95% Bayesian credible interval, -5.2 to 9.2; posterior probability of noninferiority, >0.999). Primary safety end-point events occurred in 6 patients (estimated incidence, 2.1%) who underwent pulsed field ablation and 4 patients (estimated incidence, 1.5%) who underwent thermal ablation (between-group difference, 0.6 percentage points; 95% Bayesian credible interval, -1.5 to 2.8; posterior probability of noninferiority, >0.999). CONCLUSIONS: Among patients with paroxysmal atrial fibrillation receiving a catheter-based therapy, pulsed field ablation was noninferior to conventional thermal ablation with respect to freedom from a composite of initial procedural failure, documented atrial tachyarrhythmia after a 3-month blanking period, antiarrhythmic drug use, cardioversion, or repeat ablation and with respect to device- and procedure-related serious adverse events at 1 year. (Funded by Farapulse-Boston Scientific; ADVENT ClinicalTrials.gov number, NCT04612244.).

Pulmonary vein narrowing after pulsed field versus thermal ablation.

AIMS: When it occurs, pulmonary vein (PV) stenosis after atrial fibrillation (AF) ablation is associated with significant morbidity. Even mild-to-moderate PV narrowing may have long-term implications. Unlike thermal ablation energies, such as radiofrequency (RF) or cryothermy, pulsed field ablation (PFA) is a non-thermal modality associated with less fibrotic proliferation. Herein, we compared the effects of PFA vs. thermal ablation on PV narrowing after AF ablation. METHODS AND RESULTS: ADVENT was a multi-centre, randomized, single-blind study comparing PFA (pentaspline catheter) with thermal ablation-force-sensing RF or cryoballoon (CB)-to treat drug-refractory paroxysmal AF. Pulmonary vein diameter and aggregate cross-sectional area were obtained by baseline and 3-month imaging. The pre-specified, formally tested, secondary safety endpoint compared a measure of PV narrowing between PFA vs. thermal groups, with superiority defined by posterior probability > 0.975. Among subjects randomized to PFA (n = 305) or thermal ablation (n = 302), 259 PFA and 255 thermal ablation (137 RF and 118 CB) subjects had complete baseline and 3-month PV imaging. No subject had significant (≥70%) PV stenosis. Change in aggregate PV cross-sectional area was less with PFA (-0.9%) than thermal ablation (-12%, posterior probability > 0.999)-primarily driven by the RF sub-cohort (-19.5%) vs. CB sub-cohort (-3.3%). Almost half of all PFA PV diameters did not decrease, but the majority (80%) of RF PVs decreased, regardless of PV anatomic location. CONCLUSION: In this first randomized comparison of PFA vs. thermal ablation, PFA resulted in less PV narrowing-thereby underscoring the qualitatively differential and favourable impact of PFA on PV tissue.

Contact force catheter ablation for the treatment of persistent atrial fibrillation: Results from the PERSIST-END study.

INTRODUCTION: Use of a novel magnetic sensor enabled optical contact force ablation catheter has been established to be safe and effective for treatment of symptomatic drug-refractory paroxysmal atrial fibrillation (AF) but has yet to be demonstrated in the persistent AF (PersAF) population. METHODS: PERSIST-END was a multicenter, prospective, nonrandomized, investigational study designed to demonstrate the safety and effectiveness of TactiCath™ Ablation Catheter, Sensor Enabled™(SE) (TactiCath SE) for use in the treatment of subjects with documented PersAF refractory or intolerant to at least one Class I/III AAD. The ablation strategy included pulmonary vein isolation and additional targets at physician discretion. Follow-up through 15-months, including a 3-month blanking period and 3-month therapy consolidation period, was performed with cardiac event and Holter monitoring. Primary safety, primary effectiveness, clinical success, and quality of life (QOL) endpoints were analyzed. RESULTS: Of 224 subjects enrolled at 21 investigational sites in the United States and Australia, 223 underwent ablation with the investigational catheter. The primary safety event rate was 3.1% (seven events in seven subjects). The Kaplan-Meier estimate of freedom from AF/atrial flutter/atrial tachycardia recurrence at 15-months was 61.6% and clinical success at 15 months was 89.8%. Subject QOL significantly improved following ablation as assessed via AFEQT (31.6 point increase, p < .0001) and EQ-5D-5L (10.7 point increase, p < .0001) and was met with a 53% reduction in all cause cardiovascular healthcare utilization. CONCLUSION: The sensor-enabled force-sensing catheter is safe and effective for the treatment of drug refractory recurrent symptomatic PersAF, reducing arrhythmia recurrence while improving QOL and healthcare utilization.

Prognostic value of chronic kidney disease in patients undergoing left atrial appendage occlusion.

AIMS: Atrial fibrillation (AF) and chronic kidney disease (CKD) often coexist and share an increased risk of thrombo-embolism (TE). CKD concomitantly predisposes towards a pro-haemorrhagic state. Our aim was to evaluate the prognostic value of CKD in patients undergoing percutaneous left atrial appendage occlusion (LAAO). METHODS AND RESULTS: A total of 2124 consecutive AF patients undergoing LAAO were categorized into CKD stage 1+2 (n = 1089), CKD stage 3 (n = 796), CKD stage 4 (n = 170), and CKD stage 5 (n = 69) based on the estimated glomerular filtration rate at baseline. The primary endpoint included cardiovascular (CV) mortality, TE, and major bleeding. The expected annual TE and major bleeding risks were estimated based on the CHA2DS2-VASc and HAS-BLED scores. A non-significant higher incidence of major peri-procedural adverse events (1.7 vs. 2.3 vs. 4.1 vs. 4.3) was observed with worsening CKD (P = 0.14). The mean follow-up period was 13 ± 7 months (2226 patient-years). In comparison to CKD stage 1+2 as a reference, the incidence of the primary endpoint was significantly higher in CKD stage 3 (log-rank P-value = 0.04), CKD stage 4 (log-rank P-value = 0.01), and CKD stage 5 (log-rank P-value = 0.001). Left atrial appendage occlusion led to a TE risk reduction (RR) of 72, 66, 62, and 41% in each group. The relative RR of major bleeding was 58, 44, 51, and 52%, respectively. CONCLUSION: Patients with moderate-to-severe CKD had a higher incidence of the primary composite endpoint. The relative RR in the incidence of TE and major bleeding was consistent across CKD groups.

In vivo porcine characterization of atrial lesion safety and efficacy utilizing a circular pulsed-field ablation catheter including assessment of collateral damage to adjacent tissue in supratherapeutic ablation applications.

INTRODUCTION: Pulsed-field ablation (PFA), an ablative method that causes cell death by irreversible electroporation, has potential safety advantages over radiofrequency ablation and cryoablation. Pulmonary vein (PV) isolation was performed in a porcine model to characterize safety and performance of a novel, fully-integrated biphasic PFA system comprising a multi-channel generator, variable loop circular catheter, and integrated PFA mapping software module. METHODS: Eight healthy porcine subjects were included. To evaluate safety, multiple ablations were performed, including sites not generally targeted for therapeutic ablation, such as the right inferior PV lumen, right superior PV ostium, and adjacent to the esophagus and phrenic nerve. To evaluate the efficacy, animals were recovered, followed for 30(±3) days, then re-mapped. Gross pathological and histopathological examinations assessed procedural injuries, chronic thrombosis, tissue ablation, penetration depth, healing, and inflammatory response. RESULTS: All eight animals survived follow-up. PV narrowing was not observed acutely nor at follow-up, even when ablation was performed deep to the PV ostium. No injury was seen grossly or histologically in adjacent structures. All PVs were durably isolated, confirmed by bidirectional block at re-map procedure. Histological examination showed complete, transmural necrosis around the circumference of the ablated section of right PVs. CONCLUSION: This preclinical evaluation of a fully-integrated PFA system demonstrated effective and durable ablation of cardiac tissue and PV isolation without collateral damage to adjacent structures, even when ablation was performed in more extreme settings than those used therapeutically. Histological staining confirmed complete transmural cell necrosis around the circumference of the PV ostium at 30 days.

Single-cell RNA sequencing redefines the mesenchymal cell landscape of mouse endometrium.

The endometrium is a dynamic tissue that exhibits remarkable resilience to repeated episodes of differentiation, breakdown, regeneration, and remodeling. Endometrial physiology relies on a complex interplay between the stromal and epithelial compartments with the former containing a mixture of fibroblasts, vascular, and immune cells. There is evidence for rare populations of putative mesenchymal progenitor cells located in the perivascular niche of human endometrium, but the existence of an equivalent cell population in mouse is unclear. We used the Pdgfrb-BAC-eGFP transgenic reporter mouse in combination with bulk and single-cell RNA sequencing to redefine the endometrial mesenchyme. In contrast to previous reports we show that CD146 is expressed in both PDGFRß + perivascular cells and CD31 + endothelial cells. Bulk RNAseq revealed cells in the perivascular niche which express the high levels of Pdgfrb as well as genes previously identified in pericytes and/or vascular smooth muscle cells (Acta2, Myh11, Olfr78, Cspg4, Rgs4, Rgs5, Kcnj8, and Abcc9). scRNA-seq identified five subpopulations of cells including closely related pericytes/vascular smooth muscle cells and three subpopulations of fibroblasts. All three fibroblast populations were PDGFRα+/CD34 + but were distinct in their expression of Ngfr/Spon2/Angptl7 (F1), Cxcl14/Smoc2/Rgs2 (F2), and Clec3b/Col14a1/Mmp3 (F3), with potential functions in the regulation of immune responses, response to wounding, and organization of extracellular matrix, respectively. Immunohistochemistry was used to investigate the spatial distribution of these populations revealing F1/NGFR + cells in most abundance beside epithelial cells. We provide the first definitive analysis of mesenchymal cells in the adult mouse endometrium identifying five subpopulations providing a platform for comparisons between mesenchymal cells in endometrium and other adult tissues which are prone to fibrosis.

Profiling the expression and function of oestrogen receptor isoform ER46 in human endometrial tissues and uterine natural killer cells.

STUDY QUESTION: Does the oestrogen receptor isoform, ER46, contribute to regulation of endometrial function? SUMMARY ANSWER: ER46 is expressed in endometrial tissues, is the predominant ER isoform in first trimester decidua and is localised to the cell membrane of uterine natural killer (uNK) cells where activation of ER46 increases cell motility. WHAT IS KNOWN ALREADY: Oestrogens acting via their cognate receptors are essential regulators of endometrial function and play key roles in establishment of pregnancy. ER46 is a 46-kDa truncated isoform of full length ERα (ER66, encoded by ESR1) that contains both ligand- and DNA-binding domains. Expression of ER46 in the human endometrium has not been investigated previously. ER46 is located at the cell membrane of peripheral blood leukocytes and mediates rapid responses to oestrogens. uNK cells are a phenotypically distinct (CD56brightCD16-) population of tissue-resident immune cells that regulate vascular remodelling within the endometrium and decidua. We have shown that oestrogens stimulate rapid increases in uNK cell motility. Previous characterisation of uNK cells suggests they are ER66-negative, but expression of ER46 has not been characterised. We hypothesise that uNK cells express ER46 and that rapid responses to oestrogens are mediated via this receptor. STUDY DESIGN, SIZE, DURATION: This laboratory-based study used primary human endometrial (n = 24) and decidual tissue biopsies (n = 30) as well as uNK cells which were freshly isolated from first trimester human decidua (n = 18). PARTICIPANTS/MATERIALS, SETTING, METHODS: Primary human endometrial and first trimester decidual tissue biopsies were collected using methods approved by the local institutional ethics committee (LREC/05/51104/12 and LREC/10/51402/59). The expression of ERs (ER66, ER46 and ERß) was assessed by quantitative PCR, western blot and immunohistochemistry. uNK cells were isolated from first-trimester human decidua by magnetic bead sorting. Cell motility of uNK cells was measured by live cell imaging: cells were treated with 17ß-oestradiol conjugated to bovine serum albumin (E2-BSA, 10 nM equivalent), the ERß-selective agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN; 10 nM) or dimethylsulphoxide vehicle control. MAIN RESULTS AND THE ROLE OF CHANCE: ER46 was detected in proliferative and secretory phase tissues by western blot and was the predominant ER isoform in first-trimester decidua samples. Immunohistochemistry revealed that ER46 was co-localised with ER66 in cell nuclei during the proliferative phase but detected in both the cytoplasm and cell membrane of stromal cells in the secretory phase and in decidua. Triple immunofluorescence staining of decidua tissues identified expression of ER46 in the cell membrane of CD56-positive uNK cells which were otherwise ER66-negative. Profiling of isolated uNK cells confirmed expression of ER46 by quantitative PCR and western blot and localised ER46 protein to the cell membrane by immunocytochemistry. Functional analysis of isolated uNK cells using live cell imaging demonstrated that activation of ER46 with E2-BSA significantly increased uNK cell motility. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Expression pattern in endometrial tissue was only determined using samples from proliferative and secretory phases. Assessment of first trimester decidua samples was from a range of gestational ages, which may have precluded insights into gestation-specific changes in these tissues. Our results are based on in vitro responses of primary human cells and we cannot be certain that similar mechanisms occur in situ. WIDER IMPLICATIONS OF THE FINDINGS: E2 is an essential regulator of reproductive competence. This study provides the first evidence for expression of ER46 in the human endometrium and decidua of early pregnancy. We describe a mechanism for regulating the function of human uNK cells via expression of ER46 and demonstrate that selective targeting with E2-BSA regulates uNK cell motility. These novel findings identify a role for ER46 in the human endometrium and provide unique insight into the importance of membrane-initiated signalling in modulating the impact of E2 on uNK cell function in women. Given the importance of uNK cells to regulating vascular remodelling in early pregnancy and the potential for selective targeting of ER46, this may be an attractive future therapeutic target in the treatment of reproductive disorders. STUDY FUNDING/COMPETING INTEREST(S): These studies were supported by Medical Research Council (MRC) Programme Grants G1100356/1 and MR/N024524/1 to PTKS. H.O.D.C. was supported by MRC grant G1002033. The authors declare no competing interests related to the published work.

Device-Related Thrombus After Left Atrial Appendage Closure: Incidence, Predictors, and Outcomes.

BACKGROUND: In patients with atrial fibrillation, left atrial appendage closure with the Watchman device prevents thromboembolism from the left atrial appendage; however, thrombus may form on the left atrial face of the device, and then potentially embolize. Herein, we studied the incidence, predictors, and clinical outcome of device-related thrombus (DRT) using a large series of clinical trial cohorts of patients undergoing Watchman implantation. METHODS: We studied the device arms of 4 prospective Food and Drug Administration trials: PROTECT-AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) (n=463); PREVAIL (Evaluation of the Watchman LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy) (n=269); CAP (Continued Access to PROTECT AF registry) (n=566); and CAP2 (Continued Access to PREVAIL registry) (n=578). Surveillance transesophageal echocardiographs were performed at 45 days and 12 months in all patients, and also at 6 months in the randomized control trials. We assessed both the incidence of DRT during these transesophageal echocardiographs (and other unscheduled transesophageal echocardiographs), and clinical outcomes of postprocedure stroke or systemic embolism (SSE) and adjusted for CHA2DS2-VASC and HAS-BLED scores. RESULTS: Of 1739 patients who received an implant (7159 patient-years follow-up; CHA2DS2-VASc=4.0), DRT was seen in 65 patients (3.74%). The rates of SSE with and without DRT were 7.46 and 1.78 per 100 patient-years (adjusted rate ratio, 3.55; 95% confidence interval [CI], 2.18-5.79; P<0.001), and ischemic SSE rates were 6.28 and 1.65 per 100 patient-years (adjusted rate ratio, 3.22; 95% CI, 1.90-5.45, P<0.001). On multivariable modeling analysis, the predictors of DRT were as follows: history of transient ischemic attack or stroke (odds ratio [OR], 2.31; 95% CI, 1.26-4.25; P=0.007), permanent atrial fibrillation (OR, 2.24; 95% CI, 1.19-4.20; P=0.012); vascular disease (OR, 2.06; 95% CI, 1.08-3.91; P=0.028); left atrial appendage diameter (OR, 1.06 per mm increase; 95% CI, 1.01-1.12; P=0.019); left ventricular ejection fraction (OR, 0.96 per 1% increase; 95% CI, 0.94-0.99; P=0.009). DRT and SSE both occurred in 17 of 65 patients (26.2%). Of the 19 SSE events in these patients with DRT, 9 of 19 (47.4%) and 12 of 19 (63.2%) occurred within 1 and 6 months of DRT detection. Conversely, after left atrial appendage closure, most SSEs (123/142, 86.62%) occurred in patients without DRT. CONCLUSIONS: After left atrial appendage closure with Watchman, DRT (≈3.7%) is not frequent but, when present, is associated with a higher rate of stroke and systemic embolism.

Thromboembolic events and need for anticoagulation therapy following left atrial appendage occlusion in patients with electrical isolation of the appendage.

INTRODUCTION: Electrical isolation of the left atrial appendage (LAA) is an important adjunctive ablation strategy in patients with nonparoxysmal atrial fibrillation (AF). Patients who have impaired LAA contractility following isolation may require long-term oral anticoagulant (OAC) therapy irrespective of their CHADS2 -VASc score. Percutaneous LAA occlusion (LAAO) is a potential alternative to life-long OAC therapy. We aimed to assess the rate of OAC discontinuation and thromboembolic (TE) events following percutaneous LAAO in patients who underwent LAA electrical isolation (LAAI). METHODS: This is a retrospective two-center study of patients who underwent percutaneous LAAO following LAAI. Patients with at least 3-month follow-up were included in the study. The antithrombotic therapy and TE events at the time of the last follow-up were noted. RESULTS: The LAA was successfully occluded in 162 (with Watchman device in 140 [86.4%] and Lariat in 22 [13.6%]). A total of 32 patients had leaks detected on the 45-day transesophageal echocardiogram (TEE); 21 (15%) Watchman and 11 (50%) Lariat cases (P = 0.0001). Two (one Watchman and one Lariat) of the 32 leaks were more than 5 mm. After the 45-day TEE, 150 (92.6%) patients were off-OAC. No TE events were reported in the 150 patients who stopped the anticoagulants. Four (2.47%) patients experienced stroke following the LAAO (three Watchman and one Lariat) procedure while on-OAC, two of which were fatal. At the median follow-up of 18.5 months, 159 (98.15%) patients were off-anticoagulant. CONCLUSION: Up to 98% of patients with LAAI could safely discontinue OAC after undergoing the appendage closure procedure.

Safety and efficiency of porous-tip contact-force catheter for drug-refractory symptomatic paroxysmal atrial fibrillation ablation: results from the SMART SF trial.

Aims: THERMOCOOL SMARTTOUCH® SF Catheter is a new contact-force (CF)-sensing catheter with 56-hole porous tip designed for improved cooling and reduced fluid delivery compared with a standard 6-hole open-irrigated catheter. The SMART SF study examined the periprocedural safety, acute effectiveness, and procedural efficiency of the catheter for drug-refractory symptomatic paroxysmal atrial fibrillation (PAF) ablation. Methods and results: The prospective, open-label, non-randomized SMART-SF was conducted at 17 US sites. Circumferential pulmonary vein (PV) isolation was performed with confirmation of entrance block in all PVs. Stable ablation sites were identified using CARTO VISITAG™ Module. Primary adverse events (AEs; ≤1 week of index procedure), periprocedural AEs within 30 days of ablation procedure, acute effectiveness (confirmation of entrance block for targeted PVs), CF, and procedural parameters were assessed. Overall, 165 patients were enrolled (mean age, 62.7 years; male, 57.9%; white, 97%; left ventricular ejection fraction, 60.1 ± 7%; left atrium diameter, 38.8 ± 6 mm); 159 underwent radiofrequency ablation and comprised the safety cohort. Primary safety performance criteria were met: primary AE rate was 2.5% (4/159; cardiac tamponade [n = 2], thrombo-embolism [n = 1], transient ischaemic attack [n = 1]). All primary AEs resolved/improved within the 1-month follow-up period. Acute procedural effectiveness was attained in 96.2% (95% confidence interval: 92.0-98.6%) of patients. Procedure time, fluoroscopy time, and fluid delivered were observed in comparison to predecessor catheters. Conclusion: In the SMART-SF trial, the predetermined safety performance goal was met, demonstrating the safety and acute effectiveness of the THERMOCOOL SMARTTOUCH® SF Catheter for PAF ablation.

Endometrial Intracrinology: Oestrogens, Androgens and Endometrial Disorders.

Peripheral tissue metabolism of steroids (intracrinology) is now accepted as a key way in which tissues, such as the endometrium, can utilise inactive steroids present in the blood to respond to local physiological demands and 'fine-tune' the activation or inhibition of steroid hormone receptor-dependent processes. Expression of enzymes that play a critical role in the activation and inactivation of bioactive oestrogens (E1, E2) and androgens (A4, T, DHT), as well as expression of steroid hormone receptors, has been detected in endometrial tissues and cells recovered during the menstrual cycle. There is robust evidence that increased expression of aromatase is important for creating a local microenvironment that can support a pregnancy. Measurement of intra-tissue concentrations of steroids using liquid chromatography⁻tandem mass spectrometry has been important in advancing our understanding of a role for androgens in the endometrium, acting both as active ligands for the androgen receptor and as substrates for oestrogen biosynthesis. The emergence of intracrinology, associated with disordered expression of key enzymes such as aromatase, in the aetiology of common women's health disorders such as endometriosis and endometrial cancer has prompted renewed interest in the development of drugs targeting these pathways, opening up new opportunities for targeted therapies and precision medicine.

Androgens regulate scarless repair of the endometrial "wound" in a mouse model of menstruation.

The human endometrium undergoes regular cycles of synchronous tissue shedding (wounding) and repair that occur during menstruation before estrogen-dependent regeneration. Endometrial repair is normally both rapid and scarless. Androgens regulate cutaneous wound healing, but their role in endometrial repair is unknown. We used a murine model of simulated menses; mice were treated with a single dose of the nonaromatizable androgen dihydrotestosterone (DHT; 200 µg/mouse) to coincide with initiation of tissue breakdown. DHT altered the duration of vaginal bleeding and delayed restoration of the luminal epithelium. Analysis of uterine mRNAs 24 h after administration of DHT identified significant changes in metalloproteinases (Mmp3 and -9; P < 0.01), a snail family member (Snai3; P < 0.001), and osteopontin (Spp1; P < 0.001). Chromatin immunoprecipitation analysis identified putative androgen receptor (AR) binding sites in the proximal promoters of Mmp9, Snai3, and Spp1. Striking spatial and temporal changes in immunoexpression of matrix metalloproteinase (MMP) 3/9 and caspase 3 were detected after DHT treatment. These data represent a paradigm shift in our understanding of the role of androgens in endometrial repair and suggest that androgens may have direct impacts on endometrial tissue integrity. These studies provide evidence that the AR is a potential target for drug therapy to treat conditions associated with aberrant endometrial repair processes.-Cousins, F. L., Kirkwood, P. M., Murray, A. A., Collins, F., Gibson, D. A., Saunders, P. T. K. Androgens regulate scarless repair of the endometrial "wound" in a mouse model of menstruation.

Management of Periprocedural and Early Pericardial Effusions With Tamponade Following Ablation of Atrial Fibrillation With Uninterrupted Factor Xa Inhibitors: A Case Series.

INTRODUCTION: Because of the absence of a dedicated reversal agent, the outcome of pericardial effusion (PE) following procedures performed with uninterrupted apixaban or rivaroxaban is unknown. We report the characteristics of PEs presenting with tamponade in patients undergoing AF ablation with uninterrupted factor Xa inhibition (FXaI) to understand their management and prognosis. METHODS AND RESULTS: We performed a multicenter cross-sectional survey in 10 centers across the United States. Patient data were obtained by chart review. In all patients the procedure was performed with uninterrupted FXaI. A total of 16 PEs requiring intervention were reported from 5 centers. Two patients were on apixaban 5 mg BD, the remaining on rivaroxaban 20 mg OD. Eleven PEs occurred in the periprocedural setting, and 5 PEs occurred from 1 to 28 days after the procedure. Pericardiocentesis and drainage were performed in all cases. Protamine and 4-factor prothrombin complex concentrate (4F-PCC) were given in all periprocedural cases. Two patients required surgery: in one case coagulation of the pericardial blood prevented effective drainage, and in the other bleeding was secondary to a steam pop-induced atrial tear. None of the postprocedural cases required FXaI reversal and the dose of rivaroxaban was temporarily reduced. No fatal outcomes or thromboembolic events were reported. CONCLUSION: Pericardiocentesis and drainage with FXaI reversal proved effective in the management of acute PEs with tamponade occurring periprocedurally in patients undergoing AF ablation with uninterrupted FXaI. Early postprocedural effusions can be treated with pericardiocentesis without the need of a reversal agent.

Uterine NK cells regulate endometrial bleeding in women and are suppressed by the progesterone receptor modulator asoprisnil.

Uterine NK cells (uNK) play a role in the regulation of placentation, but their functions in nonpregnant endometrium are not understood. We have previously reported suppression of endometrial bleeding and alteration of spiral artery morphology in women exposed to asoprisnil, a progesterone receptor modulator. We now compare global endometrial gene expression in asoprisnil-treated versus control women, and we demonstrate a statistically significant reduction of genes in the IL-15 pathway, known to play a key role in uNK development and function. Suppression of IL-15 by asoprisnil was also observed at mRNA level (p < 0.05), and immunostaining for NK cell marker CD56 revealed a striking reduction of uNK in asoprisnil-treated endometrium (p < 0.001). IL-15 levels in normal endometrium are progesterone-responsive. Progesterone receptor (PR) positive stromal cells transcribe both IL-15 and IL-15RA. Thus, the response of stromal cells to progesterone will be to increase IL-15 trans-presentation to uNK, supporting their expansion and differentiation. In asoprisnil-treated endometrium, there is a marked downregulation of stromal PR expression and virtual absence of uNK. These novel findings indicate that the IL-15 pathway provides a missing link in the complex interplay among endometrial stromal cells, uNK, and spiral arteries affecting physiologic and pathologic endometrial bleeding.

Illness apprehension, depression, anxiety, and quality of life in liver transplant candidates: implications for psychosocial interventions.

BACKGROUND: End-stage liver disease is associated with diminished quality of life (QOL). Numerous physical and psychosocial problems that affect QOL are common in those undergoing evaluation for liver transplantation. OBJECTIVE: Identifying which of these challenges are most closely associated with QOL would be helpful in developing priority targets for evidence-based interventions specific to those undergoing transplant evaluation. METHOD: A total of 108 adults undergoing psychologic assessment for liver transplant completed clinical interview, neuropsychologic testing, and self-report inventories of depression, anxiety, cognitive appraisal characteristics, support resources, and QOL. RESULTS: Multiple regression analyses revealed that while emotional symptoms (anxiety and depression) were primarily associated with mental QOL, illness apprehension was the only variable uniquely associated with physical QOL after accounting for severity of liver disease, cognitive status, emotional symptoms, and support resources. CONCLUSION: Findings suggest that psychosocial interventions prioritizing reduction of illness-related fear and symptoms of anxiety/depression would likely have the greatest effect on QOL in persons with end-stage liver disease awaiting transplantation.

RISING STARS: Androgens and immune cell function.

Androgens can modulate immune cell function and may contribute to differences in the prevalence and severity of common inflammatory conditions. Although most immune cells are androgen targets, our understanding of how changes in androgen bioavailability can affect immune responses is incomplete. Androgens alter immune cell composition, phenotype, and activation by modulating the expression and secretion of inflammatory mediators or by altering the development and maturation of immune cell precursors. Androgens are generally associated with having suppressive effects on the immune system, but their impacts are cell and tissue context-dependent and can be highly nuanced even within immune cell subsets. In response to androgens, innate immune cells such as neutrophils, monocytes, and macrophages increase the production of the anti-inflammatory cytokine IL-10 and decrease nitric oxide production. Androgens promote the differentiation of T cell subsets and reduce the production of inflammatory mediators, such as IFNG, IL-4 and IL-5. Additionally, androgens/androgen receptor can promote the maturation of B cells. Thus, androgens can be considered as immunomodulatory agents, but further work is required to understand the precise molecular pathways that are regulated at the intersection between endocrine and inflammatory signals. This narrative review focusses on summarising our current understanding of how androgens can alter immune cell function and how this might affect inflammatory responses in health and disease.

Endometriosis: recent advances that could accelerate diagnosis and improve care.

Endometriosis is a common disorder associated with pain, gastrointestinal and urinary symptoms, infertility, and fatigue. It is defined by the presence of endometrial-like lesions found predominantly in the pelvis. Mechanisms that contribute to disease aetiology include changes in hormonal, inflammatory, and pain pathways. In this article, we focus on recent developments in imaging technologies, on our improved understanding of mechanisms contributing to infertility, on drug therapies that are in clinical trials, and on insights from studies on the gut that offer potential to support self-management strategies. We postulate that improvements in the quality of life of patients will be accelerated by reframing endometriosis as a multi-system disorder and learning from treatments targeting symptoms shared between endometriosis, neuroinflammatory, and gastrointestinal disorders.

Bipolar ablation involving coronary venous system for refractory left ventricular summit arrhythmias.

Background: Catheter ablation of premature ventricular complexes (PVCs) and ventricular tachycardia (VT) from the left ventricular summit (LVS) may require advanced ablation techniques. Bipolar ablation from the coronary veins and adjacent endocardial structures can be effective for refractory LVS arrhythmias. Objective: The aim of this study was to investigate the outcomes of bipolar ablation performed between the coronary venous system and adjacent endocardial left ventricular outflow tract (LVOT) or right ventricular outflow tract (RVOT). Methods: This multicenter study included consecutive patients with LVS PVC/VT who underwent bipolar ablation between the anterior interventricular vein (AIV) or great cardiac vein (GCV) and the endocardial LVOT/RVOT after failed unipolar ablation. Ablation was started with powers of 10-20 W and uptitrated to achieve an impedance drop of at least 10%. Angiography was performed in all cases to confirm a safe distance (>5 mm) of the catheter from the major coronary arteries. Results: Between 2013 and 2023, bipolar radiofrequency ablation between the AIV/GCV and the adjacent LVOT/RVOT was attempted in 20 patients (4 female; age 57 ± 16 years). Unipolar ablation from sites of early activation (AIV/GCV, LVOT, aortic cusps, RVOT) failed to effectively suppress the PVC/VT in all subjects. Bipolar ablation was delivered with a maximum power of 30 ± 8 W and total duration of 238 ± 217 s and led to acute PVC/VT elimination in all patients. No procedural-related complications occurred. Over a follow-up period of 30 ± 24 months, the freedom from arrhythmia recurrence was 85% (1 recurrence in the VT group and 2 in the PVC group). PVC burden was reduced from 22% ± 10% to 4% ± 8% (P <.001). Conclusion: In cases of LVS PVC/VT refractory to unipolar ablation, bipolar ablation between the coronary venous system and adjacent endocardial LVOT/RVOT is safe and effective if careful titration of power and intraprocedural angiography are performed to ensure a safe distance from the coronary arteries.

Severity of Ischemic Stroke After Left Atrial Appendage Closure vs Nonwarfarin Oral Anticoagulants.

BACKGROUND: Strokes after left atrial appendage closure (LAAC) prophylaxis are generally less severe than those after warfarin prophylaxis-thought to be secondary to more hemorrhagic strokes with warfarin. Hemorrhagic strokes are similarly infrequent with direct oral anticoagulant (DOAC) prophylaxis, so the primary subtype after either LAAC or DOAC prophylaxis is ischemic stroke (IS). OBJECTIVES: The purpose of this study was to compare the severity of IS using the modified Rankin Scale in atrial fibrillation patients receiving prophylaxis with DOACs vs LAAC. METHODS: A retrospective analysis was performed of consecutive patients undergoing LAAC at 8 centers who developed an IS (ISLAAC) compared with contemporaneous consecutive patients who developed IS during treatment with DOACs (ISDOAC). The primary outcome was disabling/fatal stroke (modified Rankin Scale 3-5) at discharge and 3 months later. RESULTS: Compared with ISDOAC patients (n = 322), ISLAAC patients (n = 125) were older (age 77.2 ± 13.4 years vs 73.1 ± 11.9 years; P = 0.002), with higher HAS-BLED scores (3.0 vs 2.0; P = 0.004) and more frequent prior bleeding events (54.4% vs 23.6%; P < 0.001), but similar CHA2DS2-VASc scores (5.0 vs 5.0; P = 0.28). Strokes were less frequently disabling/fatal with ISLAAC than ISDOAC at both hospital discharge (38.3% vs 70.3%; P < 0.001) and 3 months later (33.3% vs 56.2%; P < 0.001). Differences in stroke severity persisted after propensity score matching. By multivariate regression analysis, ISLAAC was independently associated with fewer disabling/fatal strokes at discharge (OR: 0.22; 95% CI: 0.13-0.39; P < 0.001) and 3 months (OR: 0.25; 95% CI: 0.12-0.50; P < 0.001), and fewer deaths at 3 months (OR: 0.28; 95% CI: 0.12-0.64; P < 0.001). CONCLUSIONS: Ischemic strokes in patients with atrial fibrillation are less often disabling or fatal with LAAC than DOAC prophylaxis.