Omitting transesophageal echocardiography before catheter ablation of atrial fibrillation.

BACKGROUND: Data about necessity of performing transesophageal echocardiography (TOE) prior to every catheter ablation (CA) of atrial fibrillation (AF) is scarce. We aimed to evaluate the safety of an individualized risk-based approach to TOE with respect to thromboembolic cerebrovascular events (CVE) in patients undergoing CA for AF or left atrial tachycardia (AT). METHODS: We performed a retrospective clinical study based on our institutional registry database. Patients undergoing CA for AF or left-sided AT following initial AF ablation at two participating centers were enrolled. Prior to the procedure, patients were scheduled for TOE only if they had a history of thromboembolic stroke, left atrial appendage (LAA) thrombus, or inappropriate anticoagulation regimen in the previous 3 to 4 weeks. The incidence of periprocedural cerebrovascular thromboembolic events was assessed. RESULTS: We analyzed 1155 patients (median age 70 years, 54.8% male, 48.1% had persistent AF/AT). In 261 patients, a TOE was performed; in 2 patients (0.7%), an LAA thrombus was detected, which led to cancellation of the catheter ablation; in 894 patients, the TOE was omitted. Of the 1153 (0.35%) patients who underwent ablation, 4 (0.35%) experienced a CVE (one TIA and three strokes). The rate of CVE in our study does not exceed that reported in most multicenter trials. The low event rates limited statistical analysis of possible risk factors for CVE. In all 4 patients with CVE, post-CVE imaging showed the absence of LAA thrombus. CONCLUSIONS: An individualized selective approach to TOE before catheter ablation of AF or left AT showed a very low risk of overt intraprocedural thromboembolic events for the population in our study. A further randomized controlled study is needed to determine whether TOE prior to catheter ablation without ICE could be omitted in patients with uninterrupted OAC without previous thromboembolic events or a history of left atrial thrombus.

Functional electrographic flow patterns in patients with persistent atrial fibrillation predict outcome of catheter ablation.

AIMS: Electrographic flow (EGF) mapping is a method to detect action potential sources within the atria. In a double-blinded retrospective study we evaluated whether sources detected by EGF are related to procedural outcome. METHODS: EGF maps were retrospectively generated using the Ablamap® software from unipolar data recorded with a 64-pole basket catheter from patients who previously underwent focal impulse and rotor modulation-guided ablation. We analyzed patient outcomes based on source activity (SAC) and variability. Freedom from atrial fibrillation (AF) was defined as no recurrence of AF, atypical flutter or atrial tachycardia at the follow-up visits. RESULTS: EGF maps were from 123 atria in 64 patients with persistent or long-standing persistent AF. Procedural outcome correlation with SAC peaked at >26%. S-type EGF signature (source-dependent AF) is characterized by stable sources with SAC > 26% and C-type (source-independent AF) is characterized by sources with SAC ≤ 26%. Cases with AF recurrence at 3-, 6-, or 12-month follow-up showed a median final SAC 34%; while AF-free patients had sources with significantly lower median final SAC 21% (p = .0006). Patients with final SAC and Variability above both thresholds had 94% recurrence, while recurrence was only 36% for patients with leading source SAC and variability below threshold (p = .0001). S-type EGF signature post-ablation was associated with an AF recurrence rate 88.5% versus 38.1% with C-type EGF signature. CONCLUSIONS: EGF mapping enables the visualization of active AF sources. Sources with SAC > 26% appear relevant and their presence post-ablation correlates with high rates of AF recurrence.

Pathophysiological Mechanisms of Premature Ventricular Complexes.

Premature ventricular complexes (PVCs) are the most common ventricular arrhythmia. Despite the high prevalence, the cause of PVCs remains elusive in most patients. A better understanding of the underlying pathophysiological mechanism may help to steer future research. This review aims to provide an overview of the potential pathophysiological mechanisms of PVCs and their differentiation.

Contact-Force-Sensing-Based Radiofrequency Catheter Ablation in Paroxysmal Supraventricular Tachycardias (COBRA-PATH): a randomized controlled trial.

BACKGROUND: Multiple studies have demonstrated the importance of adequate catheter-tissue contact in the creation of effective lesions during radiofrequency catheter ablation. The development of contact force (CF)-sensing catheters has contributed significantly to improve clinical outcomes in atrial fibrillation. However, CF-sensing technology is not used in the ablation of paroxysmal supraventricular tachycardia (PSVT). The possible reason for this is that PSVT ablation with the conventional approach (i.e. nonirrigated, non-CF-sensing catheters) is considered a relatively low-risk procedure with fairly high success rates (short and long term). The aim of this study is to determine whether CF sensing can further improve the outcomes of PSVT ablation. METHODS/DESIGN: The COBRA-PATH study is a single-center, two-armed, randomized controlled trial. Patients without structural heart disease being referred for electrophysiology study, because of PSVT and potential treatment with radiofrequency (RF) catheter ablation, will be randomly assigned to either manual ablation with standard nonirrigated ablation catheters or manual ablation with an open-irrigated ablation catheter equipped with CF sensing (used in a virtual nonirrigated modus). The primary study endpoint is the difference in the number of RF applications during the ablation of atrioventricular nodal re-entry tachycardia, and that of Wolff-Parkinson-White syndrome and atrioventricular re-entrant tachycardia. Secondary outcome parameters include acute and long-term procedural success rates, overall duration of RF applications, procedure/fluoroscopy durations and safety parameters. DISCUSSION: We expect to see a reduced number/duration of RF applications required to achieve effective lesion creation, and consequently a decrease in total procedure/fluoroscopy times. Although a significant improvement in procedural success rates (acute/long term) might not be feasible to demonstrate (given the relatively high success rate of the standard ablation method), the possible decrease in procedure duration and the consequential reduction of radiation exposure has important clinical implications for both operators and patients undergoing the procedure. TRIAL REGISTRATION: ClinicalTrials, NCT04078685. Retrospectively registered on 2 September 2019.

Introducing a novel catheter-tissue contact feedback feature in robotic navigated catheter ablation: Utility, feasibility, and safety.

BACKGROUND: The quality of catheter-tissue contact is one of the most important determinants of catheter ablation (CA) success. The absence of catheter-tissue contact feedback has been regarded a major limitation of remote magnetic navigation (RMN)-guided CA. The e-Contact module (ECM) is a novel feature designed for RMN that measures the quality of catheter-tissue contact. OBJECTIVE: The purpose of this study was to describe the first clinical experience with this feature and to test its effect on procedural parameters and interference with other ablation equipment during CA procedures as well as its safety. METHODS: This was a prospective, single-center, 2-phase study investigating ECM use during complex RMN procedures in 30 patients. Impact of ECM on procedural parameters was evaluated in the feasibility phase (FP), and its interference with other equipment was tested in the interference phase (IP) using pacing maneuvers at 3 randomly selected right atrial sites. Intracardiac electrograms were evaluated for disturbances by 2 independent electrophysiologists. RESULTS: For FP, mean procedural time was 162 ± 66 minutes, fluoroscopy time 21 ± 9 minutes, and ablation time 34 ± 21 minutes. For IP, no significant differences in pacing capture or thresholds were found (ECM- vs ECM+: site 1: 2.05 vs 2.21 mA; P = .320; site 2: 2.15 vs 2.12 mA; P = .873; site 3: 2.51 vs 2.50 mA; P = .976). Electrogram disturbances did not significantly differ between ECM- and ECM+. No adverse events were reported. CONCLUSION: The ECM is a novel catheter-tissue contact technology designed for RMN-guided CA. Our study suggests that this feature is feasible and does not interfere with other electrophysiology equipment while maintaining an excellent safety profile.

Prospective evaluation of iatrogenic atrial septal defect after cryoballoon or radiofrequency catheter ablation of atrial fibrillation-"EVITA" study.

PURPOSE: Iatrogenic atrial septal defect (IASD) after catheter ablation (CA) for atrial fibrillation (AF) due to transseptal puncture (TSP) can occur. The aim of this prospective study was to describe the incidence of IASD and to detect any cerebrovascular accident (CVA) after radiofrequency (RF) and cryoballoon (CB) CA. METHODS: Between July 2014 and September 2016, 94 patients (pts) (RF; 48, CB; 46, 30 (31.9%) women, mean age = 60 ± 9.7 years) with paroxysmal AF were enrolled who underwent CA procedure for the first time. During RF ablation a single (n = 30, 62.5%) or double (n = 18, 37.5%) TSP was performed. Transoesophageal echocardiography before the procedure and at the 3-month and 12-month follow-up (FU) was accomplished. During the FU period, we evaluated the occurrence of any postprocedural CVA. RESULTS: At the 3-month FU, IASD was detected in 17/94 (18.1%) pts; in 9/48 (18.8%) pts in the RF while in 8/46 (17.4%) pts in the CB group (p = 0.866), all of them with left-to-right shunt. In the RF group, 6/30 (20%) pts with a single TSP while 3/18 (16.7%) pts in the double TSP group had IASD (p = 0.780). 14/17 (82.4%) IASDs showed high spontaneous closure rate at the 12-month FU. None of the pts died or suffered from CVA. CONCLUSION: Persistent IASD can occur rather frequently following AF CA. No significant difference was observed between the RF and CB techniques concerning the presence of IASD at 3-month. IASDs showed a high spontaneous closure rate. No cerebral thromboembolic event was observed in the 12-month FU period.

Coupling interval variability of premature ventricular contractions in patients with different underlying pathology: an insight into the arrhythmia mechanism.

PURPOSE: Coupling interval (CI) variability of premature ventricular contractions (PVCs) is influenced by the underlying arrhythmia mechanism. The aim of this study was to compare CI variability of PVCs in different myocardial disease entities, in order to gain insight into their arrhythmia mechanism. METHODS: Sixty-four patients with four underlying pathologies were included: idiopathic (n = 16), non-ischemic dilated cardiomyopathy (NIDCM) (n = 16), familial cardiomyopathy (PLN/LMNA) (n = 16), and post-MI (n = 16)-associated PVCs. The post-MI group was included as a reference, on account of its known re-entry mechanism. On Holter registrations, the first 20 CIs of the dominant PVC morphology were measured manually after which median ΔCI and mean SD of CI/√R-R (= CI of PVC corrected for underlying heart rate) were obtained. Two observers independently measured PVC CIs on pre-selected Holter registrations in order to determine inter- and intra-observer reliability. RESULTS: The largest ΔCI was seen in the PLN/LMNA group (220 ms (120-295)), the lowest in the idiopathic group (120 ms (100-190)). The ΔCI in the PLN/LMNA group was significantly larger than the post-MI group (220 ms (120-295) vs 130 ms (105-155), p = 0.023). Mean SD of CI/√R-R in the PLN/LMNA group was also significantly higher than in the post-MI group (p = 0.044). Inter- and intra-observer reliability was good (ICC = 0.91 vs 0.86 and 0.96 vs 0.77, respectively). CONCLUSIONS: Low ΔCI and SD of CI/√R-R of idiopathic and NIDCM PVCs suggest that the underlying arrhythmia mechanisms might be re-entry or triggered activity. Abnormal automaticity or modulated parasystole are unlikely mechanisms. High CI variability in PLN/LMNA patients suggests that the re-entry and triggered activity are less likely mechanisms in this group.

The C1 domain of Vav3, a novel potential therapeutic target.

Vav1/2/3 comprise a protein family with guanyl nucleotide exchange activity for Rho and Rac as well as with motifs conferring adapter activity. Biologically, Vav1 plays a critical role in hematologic cell signaling, whereas Vav2/3 have a wider tissue distribution, but all 3 Vav proteins are implicated in cancer development. A structural feature of Vav1/2/3 is the presence of an atypical C1 domain, which possesses close structural homology to the typical C1 domains of protein kinase C but which fails to bind the second messenger diacylglycerol or the potent analogs, the phorbol esters. Previously, we have shown that five residues in the Vav1 C1 domain are responsible for its lack of phorbol ester binding. Here, we show that the lack of phorbol ester binding of Vav3 has a similar basis. We then explore the consequences of phorbol ester binding to a modified Vav3 in which the C1 domain has been altered to allow phorbol ester binding. We find both disruption of the guanyl nucleotide exchange activity of the modified Vav 3 as well as a shift in localization to the membrane upon phorbol ester treatment. This change in localization is associated with altered interactions with other signaling proteins. The studies provide a first step in assessing the potential for the design of custom C1 domain targeted molecules selective for the atypical C1 domains of Vav family proteins.

Sleep Medications Containing Melatonin can Potentially Induce Ventricular Arrhythmias in Structurally Normal Hearts: A 2-Patient Report.

Idiopathic ventricular arrhythmias (IVAs) are relatively common in the general population and usually have a good prognosis. However, frequent premature ventricular contractions (PVCs) can lower the quality of life (in symptomatic cases) and can cause cardiomyopathy and sudden cardiac death. In this report, we demonstrate a novel trigger for IVAs. Melatonin use for treating sleep disorders has increased significantly in recent years. We provide here the first human evidence of its proarrhythmic effect by presenting 2 patients (with normal myocardium) with symptomatic PVCs, while on melatonin. Discontinuation of melatonin stopped PVCs in both patients. Our findings highlight the importance of identifying precipitating factors for IVAs.

Disappearance of Idiopathic Outflow Tract Premature Ventricular Contractions After Catheter Ablation of Overt Accessory Pathways.

BACKGROUND: Multiple mechanisms have been proposed for idiopathic premature ventricular contractions (PVCs) originating from the outflow tracts (OTs). Recent observations such as the coexistence of these arrhythmias with atrioventricular nodal reentrant tachycardias and the association between discrete prepotentials and successful ablation sites of ventricular arrhythmias (VAs) from the OTs suggest a common link. OBJECTIVE: In this case series we draw attention to a unique association between accessory pathways (APs) and idiopathic PVCs from the OTs, disappearing after AP ablation. METHODS: We identified 6 cases in collaboration with several international electrophysiology centers, which presented with pre-excitation in association with OT, and in 1 case inflow tract (IT), PVCs on 12-lead surface ECG. RESULTS: Six cases displayed pre-excitation and PVCs, in 5 cases originating from the right ventricular outflow tract (RVOT) and in 1 case from the right ventricular inflow tract (RVIT). In all patients, PVCs were monomorphic and had fixed coupling intervals, in 3 cases presenting in bigeminy. Catheter ablation of the AP led to the simultaneous disappearance of PVCs in 5 of 6 cases. The sites of ablation were remote from the OTs in all these cases. In most cases, the occurrence of OT PVCs was closely associated with the presence of pre-excitation. CONCLUSION: The coexistence of pre-excitation and PVCs from the OTs and the fact that in 5 of 6 cases PVCs disappeared after AP ablation suggests a common mechanism for arrhythmia genesis.

Charge density influences C1 domain ligand affinity and membrane interactions.

The C1 domain, which represents the recognition motif on protein kinase C for the lipophilic second messenger diacylglycerol and its ultrapotent analogues, the phorbol esters, has emerged as a promising therapeutic target for cancer and other indications. Potential target selectivity is markedly enhanced both because binding reflects ternary complex formation between the ligand, C1 domain, and phospholipid, and because binding drives membrane insertion of the C1 domain, permitting aspects of the C1 domain surface outside the binding site, per se, to influence binding energetics. Here, focusing on charged residues identified in atypical C1 domains which contribute to their loss of ligand binding activity, we showed that increasing charge along the rim of the binding cleft of the protein kinase C δ C1 b domain raises the requirement for anionic phospholipids. Correspondingly, it shifts the selectivity of C1 domain translocation to the plasma membrane, which is more negatively charged than internal membranes. This change in localization is most pronounced in the case of more hydrophilic ligands, which provide weaker membrane stabilization than do the more hydrophobic ligands and thus contributes an element to the structure-activity relations for C1 domain ligands. Coexpressing pairs of C1-containing constructs with differing charges each expressing a distinct fluorescent tag provided a powerful tool to demonstrate the effect of increasing charge in the C1 domain.

Biological profile of the less lipophilic and synthetically more accessible bryostatin 7 closely resembles that of bryostatin 1.

The bryostatins are a group of 20 macrolides isolated by Pettit and co-workers from the marine organism Bugula neritina. Bryostatin 1, the flagship member of the family, has been the subject of intense chemical and biological investigations due to its remarkably diverse biological activities, including promising indications as therapy for cancer, Alzheimer's disease, and HIV. Other bryostatins, however, have attracted far less attention, most probably due to their relatively low natural abundance and associated scarcity of supply. Among all macrolides in this family, bryostatin 7 is biologically the most potent protein kinase C (PKC) ligand (in terms of binding affinity) and also the first bryostatin to be synthesized in the laboratory. Nonetheless, almost no biological studies have been carried out on this agent. We describe herein the total synthesis of bryostatin 7 based on our pyran annulation technology, which allows for the first detailed biological characterizations of bryostatin 7 with side-by-side comparisons to bryostatin 1. The results suggest that the more easily synthesized and less lipophilic bryostatin 7 may be an effective surrogate for bryostatin 1.

Protein kinase C isoforms have differential roles in the regulation of human sebocyte biology.

Protein kinase C (PKC) isoforms have crucial roles in cutaneous signaling. Interestingly, we lack information about their involvement in human sebaceous gland biology. Therefore, in this current study, we investigated the functions of the PKC system in human immortalized SZ95 sebocytes. Using molecular biological approaches, imaging, and functional assays, we report that SZ95 sebocytes express the conventional cPKCα; the novel nPKCδ, ɛ, and η; and the atypical aPKCζ. Activation of the PKC system by phorbol 12-myristate 13-acetate (PMA) stimulated lipid synthesis (a hallmark of differentiation) and resulted in translocation and then downregulation of cPKCα and nPKCδ. In good accord with these findings, the effect of PMA was effectively abrogated by inhibitors and short interfering RNA-mediated "silencing" of cPKCα and nPKCδ. Of further importance, molecular or pharmacological inhibition of nPKCδ also prevented the lipogenic and apoptosis-promoting action of arachidonic acid. Finally, we also found that "knockdown" of the endogenous aPKCζ activity markedly increased basal lipid synthesis and apoptosis, suggesting its constitutive activity in suppressing these processes. Collectively, our findings strongly argue for the fact that certain PKCs have pivotal, isoform-specific, differential, and antagonistic roles in the regulation of human sebaceous gland-derived sebocyte biology.

Molecular basis for failure of "atypical" C1 domain of Vav1 to bind diacylglycerol/phorbol ester.

C1 domains, the recognition motif of the second messenger diacylglycerol and of the phorbol esters, are classified as typical (ligand-responsive) or atypical (not ligand-responsive). The C1 domain of Vav1, a guanine nucleotide exchange factor, plays a critical role in regulation of Vav activity through stabilization of the Dbl homology domain, which is responsible for exchange activity of Vav. Although the C1 domain of Vav1 is classified as atypical, it retains a binding pocket geometry homologous to that of the typical C1 domains of PKCs. This study clarifies the basis for its failure to bind ligands. Substituting Vav1-specific residues into the C1b domain of PKCδ, we identified five crucial residues (Glu(9), Glu(10), Thr(11), Thr(24), and Tyr(26)) along the rim of the binding cleft that weaken binding potency in a cumulative fashion. Reciprocally, replacing these incompatible residues in the Vav1 C1 domain with the corresponding residues from PKCδ C1b (δC1b) conferred high potency for phorbol ester binding. Computer modeling predicts that these unique residues in Vav1 increase the hydrophilicity of the rim of the binding pocket, impairing membrane association and thereby preventing formation of the ternary C1-ligand-membrane binding complex. The initial design of diacylglycerol-lactones to exploit these Vav1 unique residues showed enhanced selectivity for C1 domains incorporating these residues, suggesting a strategy for the development of ligands targeting Vav1.

Transient receptor potential vanilloid-1 signaling as a regulator of human sebocyte biology.

Transient receptor potential vanilloid-1 (TRPV1), originally described as a central integrator of nociception, is expressed on human epidermal and hair follicle keratinocytes and is involved in regulation of cell growth and death. In human pilosebaceous units, we had shown that TRPV1 stimulation inhibits hair shaft elongation and matrix keratinocyte proliferation, and induces premature hair follicle regression and keratinocyte apoptosis. In the current study, we have explored the role of TRPV1-mediated signaling in sebaceous gland (SG) biology, using a human sebocyte cell culture model (SZ95 sebocytes). Demonstrating that human skin SG in situ and SZ95 sebocytes in vitro express TRPV1, we show that the prototypic TRPV1 agonist, capsaicin, selectively inhibits basal and arachidonic acid-induced lipid synthesis in a dose-, time-, and extracellular calcium-dependent and a TRPV1-specific manner. Low-dose capsaicin stimulates cellular proliferation via TRPV1, whereas higher concentrations inhibit sebocyte growth and induce cell death independent of TRPV1. Moreover, capsaicin suppresses the expression of genes involved in lipid homeostasis and of selected proinflammatory cytokines. Collectively, these findings support the concept that TRPV1 signaling is a significant, previously unreported player in human sebocyte biology and identify TRPV1 as a promising target in the clinical management of inflammatory SG disorders (for example, acne vulgaris).

Endocannabinoids enhance lipid synthesis and apoptosis of human sebocytes via cannabinoid receptor-2-mediated signaling.

We had previously shown that both locally produced endocannabinoids and exocannabinoids, via cannabinoid receptor-1 (CB1), are powerful inhibitors of human hair growth. To further investigate the role of the cannabinoid system in pilosebaceous unit biology, we have explored in the current study whether and how endocannabinoids have an impact on human sebaceous gland biology, using human SZ95 sebocytes as cell culture model. Here, we provide the first evidence that SZ95 sebocytes express CB2 but not CB1. Also, prototypic endocannabinoids (arachidonoyl ethanolamide/anandamide, 2-arachidonoyl glycerol) are present in SZ95 sebocytes and dose-dependently induce lipid production and (chiefly apoptosis-driven) cell death. Endocannabinoids also up-regulate the expression of key genes involved in lipid synthesis (e.g., PPAR transcription factors and some of their target genes). These actions are selectively mediated by CB2-coupled signaling involving the MAPK pathway, as revealed by specific agonists/antagonists and by RNA interference. Because cells with "silenced" CB2 exhibited significantly suppressed basal lipid production, our results collectively suggest that human sebocytes utilize a paracrine-autocrine, endogenously active, CB2-mediated endocannabinoid signaling system for positively regulating lipid production and cell death. CB2 antagonists or agonists therefore deserve to be explored in the management of skin disorders characterized by sebaceous gland dysfunctions (e.g., acne vulgaris, seborrhea, dry skin).

TRP channels as novel players in the pathogenesis and therapy of itch.

Itch (pruritus) is a sensory phenomenon characterized by a (usually) negative affective component and the initiation of a special behavioral act, i.e. scratching. Older studies predominantly have interpreted itch as a type of pain. Recent neurophysiological findings, however, have provided compelling evidence that itch (although it indeed has intimate connections to pain) rather needs to be understood as a separate sensory modality. Therefore, a novel pruriceptive system has been proposed, within which itch-inducing peripheral mediators (pruritogens), itch-selective receptors (pruriceptors), sensory afferents and spinal cord neurons, and defined, itch-processing central nervous system regions display complex, layered responses to itch. In this review, we begin with a current overview on the neurophysiology of pruritus, and distinguish it from that of pain. We then focus on the functional characteristics of the large family of transient receptor potential (TRP) channels in skin-coupled sensory mechanisms, including itch and pain. In particular, we argue that - due to their expression patterns, activation mechanisms, regulatory roles, and pharmacological sensitivities - certain thermosensitive TRP channels are key players in pruritus pathogenesis. We close by proposing a novel, TRP-centered concept of pruritus pathogenesis and sketch important future experimental directions towards the therapeutic targeting of TRP channels in the clinical management of itch.