Hydrophobic interaction between the TM1 and H8 is essential for rhodopsin trafficking to vertebrate photoreceptor outer segments.

A major unsolved question in vertebrate photoreceptor biology is the mechanism of rhodopsin transport to the outer segment. In rhodopsin-like class A G protein-coupled receptors, hydrophobic interactions between C-terminal α-helix 8 (H8), and transmembrane α-helix-1 (TM1) have been shown to be important for transport to the plasma membrane, however whether this interaction is important for rhodopsin transport to ciliary rod outer segments is not known. We examined the crystal structures of vertebrate rhodopsins and class A G protein-coupled receptors and found a conserved network of predicted hydrophobic interactions. In Xenopus rhodopsin (xRho), this interaction corresponds to F313, L317, and L321 in H8 and M57, V61, and L68 in TM1. To evaluate the role of H8-TM1 hydrophobic interactions in rhodopsin transport, we expressed xRho-EGFP where hydrophobic residues were mutated in Xenopus rods and evaluated the efficiency of outer segment enrichment. We found that substituting L317 and M57 with hydrophilic residues had the strongest impact on xRho mislocalization. Substituting hydrophilic amino acids at positions L68, F313, and L321 also had a significant impact. Replacing L317 with M resulted in significant mislocalization, indicating that the hydrophobic interaction between residues 317 and 57 is exquisitely sensitive. The corresponding experiment in bovine rhodopsin expressed in HEK293 cells had a similar effect, showing that the H8-TM1 hydrophobic network is essential for rhodopsin transport in mammalian species. Thus, for the first time, we show that a hydrophobic interaction between H8 and TM1 is critical for efficient rhodopsin transport to the vertebrate photoreceptor ciliary outer segment.

Outcomes of vascular closure devices for femoral venous hemostasis following catheter ablation of atrial fibrillation.

INTRODUCTION: Access site complications remain common following atrial fibrillation (AF) catheter ablation. Femoral vascular closure devices (VCDs) reduce time to hemostasis compared with manual compression, although large-scale data comparing clinical outcomes between the two approaches are lacking. METHODS: Two cohorts of patients undergoing AF ablation were identified from 36 healthcare organizations using a global federated research network (TriNetX): those receiving a VCD for femoral hemostasis, and those not receiving a VCD. A 1:1 propensity score matching (PSM) model based on baseline characteristics was used to create two comparable cohorts. The primary outcome was a composite of all-cause mortality, vascular complications, bleeding events, and need for blood transfusion. Outcomes were assessed during early (within 7 days of ablation) and extended follow-up (within 8-30 days of ablation). RESULTS: After PSM, 28 872 patients were included (14 436 in each cohort). The primary composite outcome occurred less frequently in the VCD cohort during early (1.97% vs. 2.60%, odds ratio (OR) 0.76, 95% confidence interval (CI) 0.65-0.88; p < .001) and extended follow-up (1.15% vs. 1.43%, OR 0.80, 95% CI 0.65-0.98; p = .032). This was driven by a lower rate of vascular complications during early follow-up in the VCD cohort (0.83% vs. 1.26%, OR 0.66, 95% CI 0.52-0.83; p < .001), and fewer bleeding events during early (0.90% vs. 1.23%, OR 0.73, 95% CI 0.58-0.92; p = .007) and extended follow-up (0.36% vs. 0.59%, OR 0.61, 95% CI 0.43-0.86; p = .005). CONCLUSION: Following AF ablation, femoral venous hemostasis with a VCD was associated with reduced complications compared with hemostasis without a VCD.

Lesion metrics and 12-month outcomes of very-high power short duration radiofrequency ablation (90W/4 s) under mild conscious sedation.

INTRODUCTION: Pulmonary vein isolation (PVI) is often performed under general anaesthesia (GA) or deep sedation. Anaesthetic availability is limited in many centers, and deep sedation is prohibited in some countries without anaesthetic support. Very high-power short duration (vHPSD-90W/4 s) PVI using the Q-Dot catheter is generally well tolerated under mild conscious sedation (MCS) though an understanding of catheter stability and long-term effectiveness is lacking. We analyzed lesion metrics and 12-month freedom from atrial arrythmia with this approach. METHODS: Our approach to radiofrequency (RF) PVI under MCS is standardized and includes a single catheter approach with a steerable sheath. We identified patients undergoing Q-Dot RF PVI between March 2021 and December 2022 in our center, comparing those undergoing vHPSD ablation under MCS (90W/MCS) against those undergoing 50 W ablation under GA (50 W/GA) up to 12 months of follow-up. Data were extracted from clinical records and the CARTO system. RESULTS: Eighty-three patients met our inclusion criteria (51 90W/MCS; 32 50 W/GA). Despite shorter ablation times (353 vs. 886 s; p < .001), the 90 W/MCS group received more lesions (median 87 vs. 58, p < .001), resulting in similar procedure times (149.3 vs. 149.1 min; p = .981). PVI was achieved in all cases, and first pass isolation rates were similar (left wide antral circumferential ablation [WACA] 82.4% vs. 87.5%, p = .758; right WACA 74.5% vs. 78.1%, p = .796; 90 W/MCS vs. 50 W/GA respectively). Analysis of 6647 ablation lesions found similar mean impedance drops (10.0 ± 1.9 Ω vs. 10.0 ± 2.2 Ω; p = .989) and mean contact force (14.6 ± 2.0 g vs. 15.1 ± 1.6 g; p = .248). Only median 2.5% of lesions in the 90 W/MCS cohort failed to achieve ≥ 5 Ω drop. In the 90 W/MCS group, there were no procedural related complications, and 12-month freedom from atrial arrhythmia was observed in 78.4%. CONCLUSION: vHPSD PVI is feasible under MCS, with encouraging acute and long-term procedural outcomes. This provides a compelling option for centers with limited anaesthetic support.

An approach to help differentiate postinfarct scar from borderzone tissue using Ripple Mapping during ventricular tachycardia ablation.

BACKGROUND: Ventricular scar is traditionally highlighted on a bipolar voltage (BiVolt) map in areas of myocardium <0.50 mV. We describe an alternative approach using Ripple Mapping (RM) superimposed onto a BiVolt map to differentiate postinfarct scar from conducting borderzone (BZ) during ventricular tachycardia (VT) ablation. METHODS: Fifteen consecutive patients (left ventricular ejection fraction 30 ± 7%) underwent endocardial left ventricle pentaray mapping (median 5148 points) and ablation targeting areas of late Ripple activation. BiVolt maps were studied offline at initial voltage of 0.50-0.50 mV to binarize the color display (red and purple). RMs were superimposed, and the BiVolt limits were sequentially reduced until only areas devoid of Ripple bars appeared red, defined as RM-scar. The surrounding area supporting conducting Ripple wavefronts in tissue <0.50 mV defined the RM-BZ. RESULTS: RM-scar was significantly smaller than the traditional 0.50 mV cutoff (median 4% vs. 12% shell area, p < .001). 65 ± 16% of tissue <0.50 mV supported Ripple activation within the RM-BZ. The mean BiVolt threshold that differentiated RM-scar from BZ tissue was 0.22 ± 0.07 mV, though this ranged widely (from 0.12 to 0.35 mV). In this study, septal infarcts (7/15) were associated with more rapid VTs (282 vs. 347 ms, p = .001), and had a greater proportion of RM-BZ to RM-scar (median ratio 3.2 vs. 1.2, p = .013) with faster RM-BZ conduction speed (0.72 vs. 0.34 m/s, p = .001). Conversely, scars that supported hemodynamically stable sustained VT (6/15) were slower (367 ± 38 ms), had a smaller proportion of RM-BZ to RM-scar (median ratio 1.2 vs. 3.2, p = .059), and slower RM-BZ conduction speed (0.36 vs. 0.63 m/s, p = .036). RM guided ablation collocated within 66 ± 20% of RM-BZ, most concentrated around the RM-scar perimeter, with significant VT reduction (median 4.0 episodes preablation vs. 0 post, p < .001) at 11 ± 6 months follow-up. CONCLUSION: Postinfarct scars appear significantly smaller than traditional 0.50 mV cut-offs suggest, with voltage thresholds unique to each patient.

Silent cerebral lesions following catheter ablation for atrial fibrillation: a state-of-the-art review.

Atrial fibrillation is associated with neurocognitive comorbidities such as stroke and dementia. Evidence suggests that rhythm control-especially if implemented early-may reduce the risk of cognitive decline. Catheter ablation is highly efficacious for restoring sinus rhythm in the setting of atrial fibrillation; however, ablation within the left atrium has been shown to result in MRI-detected silent cerebral lesions. In this state-of-the-art review article, we discuss the balance of risk between left atrial ablation and rhythm control. We highlight suggestions to lower the risk, as well as the evidence behind newer forms of ablation such as very high power short duration radiofrequency ablation and pulsed field ablation.

Sex Differences in Atrial Fibrillation.

PURPOSE OF REVIEW: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. The estimated lifetime risk of developing AF is higher in men; however, due to differences in life expectancy, the overall prevalence is higher among women, particularly in the older age group. Sex differences play an important role in the pathophysiology, presentation, and clinical outcomes of AF. Awareness of these differences minimizes the potential for disparities in AF management. Our review summarizes the current literature on sex differences in AF, including the epidemiology, pathophysiology, risk factors, clinical symptomatology, mechanisms, treatment, and outcomes. We also explore the implications of these differences for clinical practice and future research. RECENT FINDINGS: Women are more likely to present with atypical symptoms, have a higher stroke risk, and have a worse quality of life with AF when compared to men. Despite this, they are less likely to receive rhythm control strategies and anticoagulants. The sex-based differences in AF pathology and management might be a combination of inherent biological and hormonal differences, and implicit bias of the research entities and treating clinicians. Our review stresses the need for further sex-specific research in the pathophysiology of AF and opens a dialogue on personalized medicine, where management strategies can be tailored to individual patient characteristics, including sex.

Local impedance for the optimization of radiofrequency lesion delivery: A review of bench and clinical data.

INTRODUCTION: Radiofrequency catheter ablation is a cornerstone of treatment for many cardiac arrhythmias. Progression in three-dimensional mapping and contact-force sensing technologies have improved our capability to achieve success, but challenges still remain. METHODS: In this article, we discuss the importance of overall circuit impedance in radiofrequency lesion formation. This is followed by a review of the literature regarding recently developed "local impedance" technology and its current and future potential applications and limitations, in the context of established surrogate markers currently used to infer effective ablation. RESULTS: We discuss the role of local impedance in assessing myocardial substrate, as well as its role in clinical studies of ablation. We also discuss safety considerations, limitations and ongoing research. CONCLUSION: Local impedance is a novel tool which has the potential to tailor ablation in a manner distinct from other established metrics.

Functional compartmentalization of photoreceptor neurons.

Retinal photoreceptors are neurons that convert dynamically changing patterns of light into electrical signals that are processed by retinal interneurons and ultimately transmitted to vision centers in the brain. They represent the essential first step in seeing without which the remainder of the visual system is rendered moot. To support this role, the major functions of photoreceptors are segregated into three main specialized compartments-the outer segment, the inner segment, and the pre-synaptic terminal. This compartmentalization is crucial for photoreceptor function-disruption leads to devastating blinding diseases for which therapies remain elusive. In this review, we examine the current understanding of the molecular and physical mechanisms underlying photoreceptor functional compartmentalization and highlight areas where significant knowledge gaps remain.

Steric volume exclusion sets soluble protein concentrations in photoreceptor sensory cilia.

Proteins segregate into discrete subcellular compartments via a variety of mechanisms, including motor protein transport, local binding, and diffusion barriers. This physical separation of cell functions serves, in part, as a mechanism for controlling compartment activity by allowing regulation of local protein concentrations. In this study we explored how soluble protein size impacts access to the confined space within the retinal photoreceptor outer segment signaling compartment and discovered a strikingly steep relationship. We find that GFP monomers, dimers, and trimers expressed transgenically in frog rods are present in the outer segment at 1.8-, 2.9-, and 6.8-fold lower abundances, relative to the cell body, than the small soluble fluorescent marker, calcein. Theoretical analysis, based on statistical-mechanical models of molecular access to polymer meshes, shows that these observations can be explained by the steric hindrance of molecules occupying the highly constrained spaces between outer segment disc membranes. This mechanism may answer a long-standing question of how the soluble regulatory protein, arrestin, is effectively excluded from the outer segments of dark-adapted rods and cones. Generally, our results suggest an alternate mode for the control of protein access to cell domains based on dynamic, size-dependent compartmental partitioning that does not require diffusion barriers, active transport, or large numbers of immobile binding sites.

Intranasal etripamil for rapid treatment of paroxysmal supraventricular tachycardia.

Paroxysmal supraventricular tachycardia (PSVT) is a common arrhythmia that, although usually benign, can occur unpredictably, cause disabling symptoms and significantly impair quality of life. If spontaneous resolution does not occur, the only current self-treatment is for the patient to attempt vagal maneuvers, however, these are frequently unsuccessful. Hospital attendance is then required for intravenous therapy. Etripamil, an intranasal calcium channel blocker similar to verapamil, may be able to fill this therapeutic gap, allowing rapid self-treatment of PSVT at home. This narrative review discusses the latest evidence for etripamil and its potential role in future clinical practice.

Paroxysmal supraventricular tachycardia (PSVT) is an abnormal heart rhythm, causing the heart to beat rapidly. There are several ways to treat PSVT. This article discusses a new therapy, etripamil. One treatment involves breathing techniques called 'vagal maneuvers'. These avoid medication and sometimes stop the abnormal rhythm, however, in many cases, this does not work. An alternative is a tablet taken when symptoms occur. Unfortunately, tablets take time to absorb, meaning symptoms may continue until the medication takes effect, and this approach does not work for everyone. If these approaches fail, patients suffering from PSVT may need to seek treatment at a hospital. This may involve intravenous therapy, with certain drugs causing unpleasant sensations of chest discomfort. Some patients may also be kept in the hospital for monitoring. Although PSVT can often be cured via a catheter ablation procedure, this is invasive (involving wires inserted via veins in the groin), so not everyone wishes to pursue this, and in some cases, it cannot be performed safely. There is a need for a rapid, safe, and effective treatment that patients can administer at home when PSVT occurs. Etripamil shows promise. Because it is a nasal spray, etripamil allows rapid absorption into the body ­ much faster than a tablet. Etripamil is not yet available on the market; however, several studies have demonstrated its effectiveness and safety, so it may be available in the near future. Promising evidence for etripamil in certain groups, such as elderly patients, is still lacking.

Editorial to "Incidence of nausea/vomiting following propofol sedation with adaptive-servo ventilation for atrial fibrillation ablation".

The incidence of nausea, vomiting, and symptoms relating to vagal nerve injury remains high after atrial fibrillation ablation, with many patients reporting symptoms in the hours to months after their procedure. These are often underreported in literature, and this editorial piece opines about a study assessing this in detail.

Novel stroke prevention strategies following catheter ablation for atrial fibrillation.

Stroke prevention following successful catheter ablation of atrial fibrillation remains a controversial topic. Oral anticoagulation is associated with a significant reduction in stroke risk in the general atrial fibrillation population but may be associated with an increased risk of major bleeding, and the benefit: risk ratio must be considered. Improvement in successful catheter ablation and widespread use of cardiac monitoring devices may allow for novel anticoagulation strategies in a subset of patients with atrial fibrillation, which may optimize stroke prevention while minimizing bleeding risk. In this review, we discuss stroke risk in atrial fibrillation and the effects of successful catheter ablation on thromboembolic risk. We also explore novel strategies for stroke prevention following successful catheter ablation.

Predicting stroke in Asian patients with atrial fibrillation using machine learning: A report from the KERALA-AF registry, with external validation in the APHRS-AF registry.

Atrial fibrillation (AF) is a significant risk factor for stroke. Based on the higher stroke associated with AF in the South Asian population, we constructed a one-year stroke prediction model using machine learning (ML) methods in KERALA-AF South Asian cohort. External validation was performed in the prospective APHRS-AF registry. We studied 2101 patients and 83 were to patients with stroke in KERALA-AF registry. The random forest showed the best predictive performance in the internal validation with receiver operator characteristic curve (AUC) and G-mean of 0.821 and 0.427, respectively. In the external validation, the light gradient boosting machine showed the best predictive performance with AUC and G-mean of 0.670 and 0.083, respectively. We report the first demonstration of ML's applicability in an Indian prospective cohort, although the more modest prediction on external validation in a separate multinational Asian registry suggests the need for ethnic-specific ML models.

Silent pulmonary veins at redo ablation for atrial fibrillation: Implications and approaches.

BACKGROUND: Pulmonary vein isolation (PVI) is the cornerstone of atrial fibrillation (AF) ablation. Despite promising success rates, redo ablation is sometimes required. At redo, PVs may be found to be isolated (silent) or reconnected. We studied patients with silent vs reconnected PVs at redo and analysed associations with adverse outcomes. METHODS: Patients undergoing redo AF ablations between 2013 and 2019 at our institution were included and stratified into silent PVs or reconnected PVs. The primary outcome was a composite of further redo ablation, non-AF ablation, atrioventricular nodal ablation, and death. Secondary outcomes included arrhythmia recurrence. RESULTS: A total of 467 patients were included with mean 4.6 ± 1.7 years follow-up, of whom 48 (10.3%) had silent PVs. The silent PV group had had more often undergone >1 prior ablation (45.8% vs 9.8%; p<0.001), had more persistent AF (62.5% vs 41.1%; p=0.005) and had more non-PV ablation performed both at prior ablation procedures and at the analysed redo ablation. The primary outcome occurred more frequently in those with silent PVs (25% vs 13.8%; p=0.053). Arrhythmia recurrence was also more common in the silent PV group (66.7% vs 50.6%; p=0.047). After multivariable adjustment, female sex (aHR 2.35 [95% CI 2.35-3.96]; p=0.001) and ischaemic heart disease (aHR 3.21 [95% CI 1.56-6.62]; p=0.002) were independently associated with the primary outcome, and left atrial enlargement (aHR 1.58 [95% CI 1.20-2.08]; p=0.001) and >1 prior ablation (aHR 1.88 [95% CI 1.30-2.72]; p<0.001) were independently associated with arrhythmia recurrence. Whilst a finding of silent PVs was not itself significant after multivariable adjustment, this provides an easily assessable parameter at clinically indicated redo ablation which informs the clinician of the likelihood of a worse future prognosis. CONCLUSIONS: Patients with silent PVs at redo AF ablation have worse clinical outcomes.

Cost, efficiency, and outcomes of pulsed field ablation vs thermal ablation for atrial fibrillation: A real-world study.

BACKGROUND: With the exponential growth of catheter ablation for atrial fibrillation (AF), there is increasing interest in associated health care costs. Pulsed field ablation (PFA) using a single-shot pentaspline multielectrode catheter has been shown to be safe and effective for AF ablation, but its cost efficiency compared to conventional thermal ablation modalities (cryoballoon [CB] or radiofrequency [RF]) has not been evaluated. OBJECTIVE: The purpose of this study was to compare cost, efficiency, effectiveness, and safety between PFA, CB, and RF for AF ablation. METHODS: We studied 707 consecutive patients (PFA: 208 [46.0%]; CB: 325 [29.4%]; RF: 174 [24.6%]) undergoing first-time AF ablation. Individual procedural costs were calculated, including equipment, laboratory use, and hospital stay, and compared between ablation modalities, as were effectiveness and safety. RESULTS: Skin-to-skin times and catheter laboratory times were significantly shorter with PFA (68 and 102 minutes, respectively) than with CB (91 and 122 minutes) and RF (89 and 123 minutes) (P < .001). General anesthesia use differed across modalities (PFA 100%; CB 10.2%; RF 61.5%) (P < .001). Major complications occurred in 1% of cases, with no significant differences between modalities. Shorter procedural times resulted in lower staffing and laboratory costs with PFA, but these savings were offset by substantially higher equipment costs, resulting in higher overall median costs with PFA (£10,010) than with CB (£8106) and RF (£8949) (P < .001). CONCLUSION: In this contemporary real-world study of the 3 major AF ablation modalities used concurrently, PFA had shorter skin-to-skin and catheter laboratory times than did CB and RF, with similarly low rates of complications. However, PFA procedures were considerably more expensive, largely because of higher equipment cost.

Durability of thermal pulmonary vein isolation in persistent atrial fibrillation assessed by mandated repeat invasive study.

BACKGROUND: No study has assessed the durability of pulmonary vein isolation (PVI) with radiofrequency (RF) and cryoballoon (CB) in patients with persistent atrial fibrillation. These data are especially lacking for those with significantly diseased left atria (LA). OBJECTIVES: The goals of this study were to assess PVI durability in patients with significant LA disease and to compare reconnection rates between RF and CB. METHODS: Forty-four patients (mean age 63 years; 34 (77%) male; median time since atrial fibrillation diagnosis 22.5 months; median indexed LA volume 36 mL/m2) were randomized 1:1 to RF or CB PVI. A redo procedure using ultra-high-density electroanatomic mapping was mandated at 2 months, where PV reconnections were identified and reisolated. RESULTS: Thirty-eight patients underwent both procedures (CB n = 17; RF n = 21). Index RF procedures were longer (median 158 minutes vs 97 minutes; P < .001) but required less fluoroscopy (9.5 minutes vs 23 minutes; P < .001). At the index RF procedure, a median of 47% of LA myocardium had voltage < 0.5 mV, suggesting that half of the mapped LA comprised scar. PV reconnection was observed in 73 of 152 PVs (48.0%) and was more frequent with CB (58.8%) than with RF (39.3%) (P = .022). Reconnection of at least 1 PV was detected in >75% of patients. Significantly more ablation was required during the redo procedure to reisolate PVs in the CB arm (median 10.8 minutes vs 1.2 minutes; P < .001). CONCLUSION: PVI durability may be poor in those with significant LA scarring and dilatation, even with modern thermal ablation technologies. RF resulted in significantly better PVI durability than did CB in this complex population. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT04111731.