Impact of surrounding tissue-type and peri-electrode gap in stereoelectroencephalography guided (SEEG) radiofrequency thermocoagulation (RF-TC): a computational study.

PURPOSE: To use computational modeling to provide a complete and logical description of the electrical and thermal behavior during stereoelectroencephalography-guided (SEEG) radiofrequency thermo-coagulation (RF-TC). METHODS: A coupled electrical-thermal model was used to obtain the temperature distributions in the tissue during RF-TC. The computer model was first validated by an ex vivo model based on liver fragments and later used to study the impact of three different factors on the coagulation zone size: 1) the difference in the tissue surrounding the electrode (gray/white matter), 2) the presence of a peri-electrode gap occupied by cerebrospinal fluid (CSF), and 3) the energy setting used (power-duration). RESULTS: The model built for the experimental validation was able to predict both the evolution of impedance and the short diameter of the coagulation zone (error < 0.01 mm) reasonably well but overestimated the long diameter by 2 - 3 mm. After adapting the model to clinical conditions, the simulation showed that: 1) Impedance roll-off limited the coagulation size but involved overheating (around 100 °C); 2) The type of tissue around the contacts (gray vs. white matter) had a moderate impact on the coagulation size (maximum difference 0.84 mm), and 3) the peri-electrode gap considerably altered the temperature distributions, avoided overheating, although the diameter of the coagulation zone was not very different from the no-gap case (<0.2 mm). CONCLUSIONS: This study showed that computer modeling, especially subject- and scenario-specific modeling, can be used to estimate in advance the electrical and thermal performance of the RF-TC in brain tissue.

Shedding Light on Dark Chemical Matter: The Discovery of a SARS-CoV-2 Mpro Main Protease Inhibitor through Intensive Virtual Screening and In Vitro Evaluation.

The development of specific antiviral therapies targeting SARS-CoV-2 remains fundamental because of the continued high incidence of COVID-19 and limited accessibility to antivirals in some countries. In this context, dark chemical matter (DCM), a set of drug-like compounds with outstanding selectivity profiles that have never shown bioactivity despite being extensively assayed, appears to be an excellent starting point for drug development. Accordingly, in this study, we performed a high-throughput screening to identify inhibitors of the SARS-CoV-2 main protease (Mpro) using DCM compounds as ligands. Multiple receptors and two different docking scoring functions were employed to identify the best molecular docking poses. The selected structures were subjected to extensive conventional and Gaussian accelerated molecular dynamics. From the results, four compounds with the best molecular behavior and binding energy were selected for experimental testing, one of which presented inhibitory activity with a Ki value of 48 ± 5 µM. Through virtual screening, we identified a significant starting point for drug development, shedding new light on DCM compounds.

A Step Forward toward Selective Activation/Inhibition of Bak, a Pro-Apoptotic Member of the Bcl-2 Protein Family: Discovery of New Prospective Allosteric Sites Using Molecular Dynamics.

Bak is a pro-apoptotic protein and a member of the Bcl-2 family that plays a key role in apoptosis, a programmed cell death mechanism of multicellular organisms. Its activation under death stimuli triggers the permeabilization of the mitochondrial outer membrane that represents a point of no return in the apoptotic pathway. This process is deregulated in many tumors where Bak is inactivated, whereas in other cases like in neurodegeneration, it exhibits an excessive response leading to disorders such as the Alzheimer disease. Members of the Bcl-2 family share a common 3D structure, exhibiting an extremely similar orthosteric binding site, a place where both pro and antiapoptotic proteins bind. This similarity raises a selectivity issue that hampers the identification of new drugs, capable of altering Bak activation in a selective manner. An alternative activation site triggered by antibodies has been recently identified, opening the opportunity to undertake new drug discovery studies. Despite this recent identification, an exhaustive study to identify cryptic pockets as prospective allosteric sites has not been yet performed. Thus, the present study aims to characterize novel hotspots in the Bak structure. For this purpose, we have carried out extensive molecular dynamics simulations using three different Bak systems including Bak in its apo form, Bak in complex with its endogen activator Bim and an intermediate form, set up by removing Bim from the previous complex. The results reported in the present work shed some light on future docking studies on Bak through the identification of new prospective allosteric sites, not previously described in this protein.

Discovery of Hit Compounds Targeting the P4 Allosteric Site of K-RAS, Identified through Ensemble-Based Virtual Screening.

Mutants of Ras are oncogenic drivers of a large number of human tumors. Despite being recognized as an attractive target for the treatment of cancer, the high affinity for its substrate tagged the protein as undruggable for a few years. The identification of cryptic pockets on the protein surface gave the opportunity to identify molecules capable of acting as allosteric modulators. Several molecules were disclosed in recent years, with sotorasib and adagrasib already approved for clinical use. The present study makes use of computational methods to characterize eight prospective allosteric pockets (P1-P8) in K-Ras, four of which (P1-P4) were previously characterized in the literature. The present study also describes the results of a virtual screening study focused on the discovery of hit compounds, binders of the P4 site that can be considered as peptidomimetics of a fragment of the SOS αI helix, a guanine exchange factor of Ras. After a detailed description of the computational procedure followed, we disclose five hit compounds, prospective binders of the P4 allosteric site that exhibit an inhibitory capability higher than 30% in a cell proliferation assay at 50 µM.

How far the zone of heat-induced transient block extends beyond the lesion during RF catheter cardiac ablation.

PURPOSE: While radiofrequency catheter ablation (RFCA) creates a lesion consisting of the tissue points subjected to lethal heating, the sublethal heating (SH) undergone by the surrounding tissue can cause transient electrophysiological block. The size of the zone of heat-induced transient block (HiTB) has not been quantified to date. Our objective was to use computer modeling to provide an initial estimate. METHODS AND MATERIALS: We used previous experimental data together with the Arrhenius damage index (Ω) to fix the Ω values that delineate this zone: a lower limit of 0.1-0.4 and upper limit of 1.0 (lesion boundary). An RFCA computer model was used with different power-duration settings, catheter positions and electrode insertion depths, together with dispersion of the tissue's electrical and thermal characteristics. RESULTS: The HiTB zone extends in depth to a minimum and maximum distance of 0.5 mm and 2 mm beyond the lesion limit, respectively, while its maximum width varies with the energy delivered, extending to a minimum of 0.6 mm and a maximum of 2.5 mm beyond the lesion, reaching 3.5 mm when high energy settings are used (25 W-20s, 500 J). The dispersion of the tissue's thermal and electrical characteristics affects the size of the HiTB zone by ±0.3 mm in depth and ±0.5 mm in maximum width. CONCLUSIONS: Our results suggest that the size of the zone of heat-induced transient block during RFCA could extend beyond the lesion limit by a maximum of 2 mm in depth and approximately 2.5 mm in width.

Is occlusion of the main pancreatic duct by thermal ablation really safe? A surgical innovation assessed according to IDEAL recommendations.

INTRODUCTION: Pre-clinical studies suggest that thermal ablation of the main pancreatic duct (TAMPD) is more recommendable than glue for reducing postoperative pancreatic fistula (POPF). Our aims were (1) to analyze the changes in the pancreas of patients after TAMPD and (2) to correlate the clinical findings with those obtained from a study on an animal model. MATERIALS AND METHODS: A retrospective early feasibility study of a marketed device for a novel clinical application was carried out on a small number of subjects (n = 8) in whom TAMPD was conducted to manage the pancreatic stump after a pancreatectoduodenectomy (PD). Morphological changes in the remaining pancreas were assessed by computed tomography for 365 days after TAMPD. RESULTS: All the patients showed either Grade A or B POPF, which generally resolved within the first 30 days. The duct's maximum diameter significantly increased after TAMPD from 1.5 ± 0.8 mm to 8.6 ± 2.9 mm after 7 days (p = .025) and was then reduced to 2.6 ± 0.8 mm after 365 days PO (p < .0001). The animal model suggests that TAMPD induces dilation of the duct lumen by enzymatic digestion of ablated tissue after a few days and complete exocrine atrophy after a few weeks. CONCLUSIONS: TAMPD leads to long-term exocrine pancreatic atrophy by completely occluding the duct. However, the ductal dilatation that occurred soon after TAMPD could even favor POPF, which suggests that TAMPD should be conducted several weeks before PD, ideally by digestive endoscopy.

Relationship between luminal esophageal temperature and volume of esophageal injury during RF ablation: In silico study comparing low power-moderate duration vs. high power-short duration.

OBJECTIVE: To model the evolution of peak temperature and volume of damaged esophagus during and after radiofrequency (RF) ablation using low power-moderate duration (LPMD) versus high power-short duration (HPSD) or very high power-very short duration (VHPVSD) settings. METHODS: An in silico simulation model of RF ablation accounting for left atrial wall thickness, nearby organs and tissues, as well as catheter contact force. The model used the Arrhenius equation to derive a thermal damage model and estimate the volume of esophageal damage over time during and after RF application under conditions of LPMD (30 W, 20 s), HPSD (50 W, 6 s), and VHPVSD (90 W, 4 s). RESULTS: There was a close correlation between maximum peak temperature after RF application and volume of esophageal damage, with highest correlation (R2 = 0.97) and highest volume of esophageal injury in the LPMD group. A greater increase in peak temperature and greater relative increase in esophageal injury volume in the HPSD (240%) and VHPSD (270%) simulations occurred after RF termination. Increased endocardial to esophageal thickness was associated with a longer time to maximum peak temperature (R2 > 0.92), especially in the HPSD/VHPVSD simulations, and no esophageal injury was seen when the distances were >4.5 mm for LPMD or >3.5 mm for HPSD. CONCLUSION: LPMD is associated with a larger total volume of esophageal damage due to the greater total RF energy delivery. HPSD and VHPVSD shows significant thermal latency (resulting from conductive tissue heating after RF termination), suggesting a requirement for fewer esophageal temperature cutoffs during ablation.

Peptidic Scaffolds Enable Rapid and Multivariate Secondary Sphere Evolution for an Abiotic Metallocatalyst.

Metalloenzymes have benefited from the iterative process of evolution to achieve the precise arrangements of secondary sphere non-covalent interactions that enhance metal-centered catalysis. Iterative synthesis of scaffolds that display complex secondary sphere elements in abiotic systems can be highly challenging and time-intensive. To overcome this synthetic bottleneck, we developed a highly modular and rapid synthetic strategy, leveraging the efficiency of solid-phase peptide synthesis and conformational control afforded by non-canonical residues to construct a ligand platform displaying up to four unique residues of varying electronics and sterics in the secondary coordination sphere. As a proof-of-concept that peptidic secondary sphere can cooperate with the metal complex, we applied this scaffold to a well-known, modestly active C-H oxidizing Fe catalyst to evolve specific non-covalent interactions that is more than double its catalytic activity. Solution-state NMR structures of several catalyst variants suggest that higher activity is correlated with a hydrophobic pocket above the Fe center that may enhance the formation of a catalyst-substrate complex. Above all, we show that peptides are a convenient, highly modular, and structurally defined ligand platform for creating secondary coordination spheres that comprise multiple, diverse functional groups.

Effects of solvents on the conformational profile of Balaram's peptide: a computational study.

The present work reports the results of a computational study aimed at characterizing the conformational profile of Balaram's peptide (Ace-Leu-Val-Val-Aib-Gly-Leu-Val-Val-NHMe) in different solvents, including chloroform, dimethyl sulfoxide, methanol and water. For this purpose, 10 µs molecular dynamics trajectories were computed in explicit solvents for each system, starting from an extended conformation. The results of the present study confirm the former NMR and CD findings and provide further insights that permit fine-tuning of the conclusions previously derived. The present results show that the peptide exhibits a helical conformation in chloroform, but a mixture of ß-hairpin and Ω-shape conformations, as the predominant structures in DMSO and MeOH. Finally, the peptide does not exhibit a preferred conformation in water, although significant populations of helical and ß-hairpin conformations are available. The present results underline the role of solvents in the conformational profile of a peptide and it is an example of the complementarity between computational methods and spectroscopy studies.

Percutaneous Versus Transcutaneous Electrical Nerve Stimulation for the Treatment of Musculoskeletal Pain. A Systematic Review and Meta-Analysis.

BACKGROUND: The justification for this review is the need for high-quality evidence to assist in the decision-making process when applying percutaneous electrical nerve stimulation (PENS) or transcutaneous electrical nerve stimulation (TENS) in a clinical setting. The main aim was to determine if the use of PENS is more effective and should be recommended when compared to TENS for the reduction of musculoskeletal pain intensity. METHODS: A search for randomized controlled trials (RCTs) was performed. Studies published until 31/12/2020, comparing the effectiveness of PENS and TENS, were considered. The main outcome was pain assessed with a visual analog scale or numerical pain rating scale. RESULTS: Nine RCTs were included in the qualitative analysis, with seven of them in the quantitative analysis (n = 527). The overall effect of PENS on pain was statistically but not clinically superior to TENS (mean difference [MD]=-1.0 cm; 95% confidence interval [CI]: -1.5 to -0.4) with a high level of heterogeneity (I2=76%, P > .01). When only studies with a lower risk of bias (n = 3) were analyzed, the heterogeneity decreased to I = 0% (P = .06) and no difference was observed between TENS and PENS (MD=-0.81 cm; 95% CI:-1.6 to 0.02) with a moderate recommendation level according to GRADE. There were no data concerning adverse effects. CONCLUSIONS: There is low-quality of evidence for more pain intensity reduction with PENS, but the difference was not clinically significant. However, when only studies with low risk of bias are meta-analyzed, there is a moderate quality of evidence that there is no difference when TENS or PENS is applied for pain intensity.

Topical application of an amygdalin analogue reduces inflammation and keratinocyte proliferation in a psoriasis mouse model.

Psoriasis is a chronic inflammatory skin disease without cure. Systemic and biological therapies are the most effective treatments for patients with severe psoriasis. However, these drugs can cause serious side effects from extended use. Safe and effective topical drugs are needed to decrease psoriatic plaques and reduce the risk of adverse effects. Amygdalin analogues are stable small molecules that showed benefits in psoriasis xenografts to immune-deficient mice by systemic application. However, whether topical application of these amygdalin analogues could reduce the progression of the psoriatic phenotype in an immune-competent organism is unknown. Here, we analyse the efficiency of topical application of an amygdalin analogue cream on a well-established genetic and immune-competent mouse model of psoriasis. Topical application of an amygdalin analogue cream ameliorates psoriasis-like disease in mice, reduces epidermal hyperplasia and skin inflammation. Amygdalin analogue treatment leads to reduced expression of local pro-inflammatory cytokines, but systemic pro-inflammatory cytokines that are highly expressed in psoriasis patients such as IL-17A, IL6 or G-CSF are also decreased. Furthermore, expression of important mediators of psoriasis initiation and epidermal hyperplasia, such as TNFa, S100A9 and TSLP, is decreased in lesional epidermis after amygdalin analogue treatment. In conclusion, we show that amygdalin analogue reduces the proliferative capacity of psoriasis-like stimulated keratinocytes and their inflammatory response in vivo and in vitro. These results suggest that topical application of amygdalin analogues may represent a safe and effective treatment for psoriasis.

Discovery of Diverse Natural Products as Inhibitors of SARS-CoV-2 Mpro Protease through Virtual Screening.

SARS-CoV-2 is a type of coronavirus responsible for the international outbreak of respiratory illness termed COVID-19 that forced the World Health Organization to declare a pandemic infectious disease situation of international concern at the beginning of 2020. The need for a swift response against COVID-19 prompted to consider different sources to identify bioactive compounds that can be used as therapeutic agents, including available drugs and natural products. Accordingly, this work reports the results of a virtual screening process aimed at identifying antiviral natural product inhibitors of the SARS-CoV-2 Mpro viral protease. For this purpose, ca. 2000 compounds of the Selleck database of Natural Compounds were the subject of an ensemble docking process targeting the Mpro protease. Molecules that showed binding to most of the protein conformations were retained for a further step that involved the computation of the binding free energy of the ligand-Mpro complex along a molecular dynamics trajectory. The compounds that showed a smooth binding free energy behavior were selected for in vitro testing. From the resulting set of compounds, five compounds exhibited an antiviral profile, and they are disclosed in the present work.

Fragment dissolved molecular dynamics: a systematic and efficient method to locate binding sites.

Diverse computational methods to support fragment-based drug discovery (FBDD) are available in the literature. Despite their demonstrated efficacy in supporting FBDD campaigns, they exhibit some drawbacks such as protein denaturation or ligand aggregation that have not yet been clearly overcome in the framework of biomolecular simulations. In the present work, we discuss a systematic semi-automatic novel computational procedure, designed to surpass these difficulties. The method, named fragment dissolved Molecular Dynamics (fdMD), utilizes simulation boxes of solvated small fragments, adding a repulsive Lennard-Jones potential term to avoid aggregation, which can be easily used to solvate the targets of interest. This method has the advantage of solvating the target with a low number of ligands, thus preventing the denaturation of the target, while simultaneously generating a database of ligand-solvated boxes that can be used in further studies. A number of scripts are made available to analyze the results and obtain the descriptors proposed as a means to trustfully discard spurious binding sites. To test our method, four test cases of different complexity have been solvated with ligand boxes and four molecular dynamics runs of 200 ns length have been run for each system, which have been extended up to 1 µs when needed. The reported results point out that the selected number of replicas are enough to identify the correct binding sites irrespective of the initial structure, even in the case of proteins having several close binding sites for the same ligand. We also propose a set of descriptors to analyze the results, among which the average MMGBSA and the average KDEEP energies have emerged as the most robust ones.

Molecular Determinants for the Activation/Inhibition of Bak Protein by BH3 Peptides.

Apoptosis is a key cell death pathway in mammalian cells. Understanding this process and its regulation has been a subject of study in the last three decades. Members of the Bcl-2 family of proteins are involved in the regulation of apoptosis through mitochondrial poration with the subsequent initiation of apoptosis. Deregulation of proapoptotic proteins contributes to the progression of many tumor processes. Understanding how these pore-forming Bcl-2 proteins Bak and Bax are activated is key to find new anticancer treatments. As no drug capable of activating Bak has been disclosed yet, the study of the structural features of BH3 peptides-known as Bak activators-relevant for binding along with its binding energy decomposition analysis, becomes essential for designing novel small-molecule mimics of BH3. Interestingly, a BH3 Bim analogue-inactivating Bak has recently been discovered, opening a question on the molecular features that determine the functions of BH3 peptides. Therefore, the present work is aimed at understanding the way BH3 peptides activate or inactivate Bak in order to identify differential structural features that can be used in drug design. For this purpose, complexes of Bak with an activator and an inhibitor have been subjected to a molecular dynamics study. Structural differences were assessed by means of the fluctuations of the corresponding principal components. Moreover, the MMPB/GBSA approach was used to compute the binding free energy of the diverse complexes to identify those residues of the BH3 peptide that exhibit the larger contributions to complex formation. The results obtained in this work show differences between activators and inhibitors, both in structural and energetic terms, which can be used in the design of new molecules that can activate or inactivate proapoptotic Bak.

Differences in applied electrical power between full thorax models and limited-domain models for RF cardiac ablation.

Purpose: Most modeling studies on radiofrequency cardiac ablation (RFCA) are based on limited-domain models, which means the computational domain is restricted to a few centimeters of myocardium and blood around the active electrode. When mimicking constant power RFCA procedures (e.g., atrial fibrillation ablation) it is important to know how much power is absorbed around the active electrode and how much in the rest of the tissues before reaching the dispersive electrode.Methods: 3D thorax full models were built by progressively incorporating different organs and tissues with simplified geometries (cardiac chamber, cardiac wall, subcutaneous tissue and skin, spine, lungs and aorta). Other 2D limited-domain models were also built based on fragments of myocardium and blood. The electrical problem was solved for each model to estimate the spatial power distribution around the active electrode.Results: From 79 to 82% of the power was absorbed in a 4 cm-radius sphere around the active electrode in the full thorax model at active electrode insertion depths of between 0.5 and 2.5 mm, while the impedance values ranged from 104 to 118 Ω, which were consistent with those found (from 83 to 103 Ω) in a 4 cm radius cylindrical limited domain model.Conclusion: The applied power in limited-domain RFCA models is approximately 80% of that applied in full thorax models, which is equivalent to the power programed in a clinical setting.

Computer Modeling for Radiofrequency Bipolar Ablation Inside Ducts and Vessels: Relation Between Pullback Speed and Impedance Progress.

BACKGROUND AND OBJECTIVES: Radiofrequency (RF)-induced ablation can be carried out inside ducts and vessels by simultaneously dragging a bipolar catheter while applying RF power. Our objective was to characterize the relation between pullback speed, impedance progress, and temperature distribution. STUDY DESIGN/MATERIALS AND METHODS: We built a numerical model including a bipolar catheter, which is dragged inside a duct while RF power is applied between a pair of electrodes. The model solved a triple-coupled electrical, thermal, and mechanical problem. Lesions were assessed by an Arrhenius model. The numerical model's thermal and electrical characteristics were chosen to obtain the same initial impedance value as in the experiments: 560 Ω at 16°C (sample temperature). RESULTS: The catheter initially remained still, and the impedance was falling during the application of power. When pullback speed was too slow (<0.4 mm/s) impedance continued to drop when the catheter began to move, creating deep lesions, overheating and impedance roll-off, while at the faster speed (0.4-1.0 mm/s) impedance first rose slightly and then reached a plateau. There was a strong inverse relation between pullback speed and lesion depth. The hottest point was always around the second electrode, creating a kind of hot wake. CONCLUSIONS: These findings confirm the close relationship between pullback speed and impedance progress, and suggest that the latter factor could be used to guide the procedure and achieve effective and safe ablations along the inner path of a duct or vessel. Lasers Surg. Med. © 2020 Wiley Periodicals, Inc.

Discovery of a Bradykinin B2 Partial Agonist Profile of Raloxifene in a Drug Repurposing Campaign.

Covid-19 urges a deeper understanding of the underlying molecular mechanisms involved in illness progression to provide a prompt therapeutical response with an adequate use of available drugs, including drug repurposing. Recently, it was suggested that a dysregulated bradykinin signaling can trigger the cytokine storm observed in patients with severe Covid-19. In the scope of a drug repurposing campaign undertaken to identify bradykinin antagonists, raloxifene was identified as prospective compound in a virtual screening process. The pharmacodynamics profile of raloxifene towards bradykinin receptors is reported in the present work, showing a weak selective partial agonist profile at the B2 receptor. In view of this new profile, its possible use as a therapeutical agent for the treatment of severe Covid-19 is discussed.

Molecular features characterizing non-peptide selectivity to the human B1 and B2 bradykinin receptors.

Bradykinin is produced in response to inflammation, trauma, burns, shock, allergy and some cardiovascular diseases. Actions of this peptide are mediated through two different G-protein coupled receptors, named B1 and B2 that have different pharmacological characteristics. The former is up-regulated during inflammation episodes or tissue trauma whereas, the latter is constitutively expressed in a variety of cell types. In a previous work we have characterized the molecular features that explain the observed structure-activity results for both receptors by means of molecular modeling studies, using diverse ligands for both receptors. These results were summarized in the form of two different pharmacophores that provided new insights to be used for the design of novel molecules with antagonistic profile. In the present work, we compare these pharmacophores to understand the features that characterize ligand selectivity to the two bradykinin receptors. The study shows that most of the residues involved in the binding pocket are similar in both receptors and consequently are the pharmacophores obtained. The main difference between the two pharmacophores remains on point #5 that involves a polar moiety for the B1 receptor and an aromatic ring for the B2 receptor. Accordingly, analysis of the prospective bound conformation of several non-selective small molecule ligands of the bradykinin receptors permits to conclude that fulfilment of point#5 is a requirement to produce selective ligands. However, the study also shows that this is a necessary condition only, since ligands need also to be bulky enough to avoid binding to these receptors in diverse poses. These results provide new insights for a better understanding of the molecular features that ligands are required to exhibit to be selective bradykinin ligands.

Thermal impact of balloon occlusion of the coronary sinus during mitral isthmus radiofrequency ablation: an in-silico study.

Purpose: Although experimental data have suggested that temporary occlusion of the coronary sinus (CS) can facilitate the creation of transmural lesions across the atrial wall (AW) during mitral isthmus radiofrequency (RF) ablation, no computer modeling study has yet been made on the effect of the blood flow inside the epicardial vessels and its stoppage by an occlusion balloon.Methods: Computer simulations using constant power were conducted to study these phenomena by two methods: (1) by setting blood velocity in the CS to zero, which mimics a distal occlusion; and (2) by including a balloon filled with air in the model just below the ablation site, which mimics a proximal occlusion.Results: For short ablations (15 s) and perpendicular electrode/tissue orientation, lesion size was smaller with proximal occlusion compared to distal or no occlusion, regardless of the AW-CS distance (from 0.5 mm to 3.4 mm). For other angulations (0 and 45°) lesion size was almost the same in all cases. For longer ablations (60 s), the internal CS blood flow (no occlusion) considerably reduced lesion size, while stoppage combined with the proximal presence of a balloon produced the largest lesions. This performance was similar for different catheter angulations (0, 45 and 90°). Balloon length (from 10 to 40 mm) was found to be an irrelevant parameter when proximal occlusion was modeled.Conclusions: Using an air-filled balloon to occlude CS facilitates mitral isthmus ablation in long ablations, while proximal occlusion could impede transmural lesions in the case of short ablations (15 s).

Should fluid dynamics be included in computer models of RF cardiac ablation by irrigated-tip electrodes?

BACKGROUND: Although accurate modeling of the thermal performance of irrigated-tip electrodes in radiofrequency cardiac ablation requires the solution of a triple coupled problem involving simultaneous electrical conduction, heat transfer, and fluid dynamics, in certain cases it is difficult to combine the software with the expertise necessary to solve these coupled problems, so that reduced models have to be considered. We here focus on a reduced model which avoids the fluid dynamics problem by setting a constant temperature at the electrode tip. Our aim was to compare the reduced and full models in terms of predicting lesion dimensions and the temperatures reached in tissue and blood. RESULTS: The results showed that the reduced model overestimates the lesion surface width by up to 5 mm (i.e. 70%) for any electrode insertion depth and blood flow rate. Likewise, it drastically overestimates the maximum blood temperature by more than 15 °C in all cases. However, the reduced model is able to predict lesion depth reasonably well (within 0.1 mm of the full model), and also the maximum tissue temperature (difference always less than 3 °C). These results were valid throughout the entire ablation time (60 s) and regardless of blood flow rate and electrode insertion depth (ranging from 0.5 to 1.5 mm). CONCLUSIONS: The findings suggest that the reduced model is not able to predict either the lesion surface width or the maximum temperature reached in the blood, and so would not be suitable for the study of issues related to blood temperature, such as the incidence of thrombus formation during ablation. However, it could be used to study issues related to maximum tissue temperature, such as the steam pop phenomenon.