Search

Background: Recent data suggest that luminal esophageal temperature (LET) monitoring during high-power short-duration (HPSD) ablation may be inadequate to prevent esophageal thermal injury during radiofrequency (RF) ablation. This is due in part to delayed responses to thermal latency and the continued temperature rise that occurs in tissues even after the cessation of RF energy with HPSD settings. Proactive esophageal cooling has been shown to reduce severe esophageal thermal injury during medium-power medium-duration RF ablation, but less is known about the effects in HPSD ablation. Objective: We aimed to quantify the time course of esophageal damage in scenarios with and without proactive esophageal cooling, hypothesizing a reduction in the resulting tissue damage with proactive esophageal cooling. Methods: Using a computer model of RF ablation in the left atrium adjacent to the esophagus, we calculated temperature over time using ablation power of 50 W for 10 s and 90 W for 4 s. We then determined the fraction of resulting damage to esophageal tissue via the Arrhenius equation and by the percentage of tissue above lethal isotherm temperature of 50°C. Transmurality of injury was then plotted over time, and results were compared between ablation with and without proactive esophageal cooling. Results: Esophageal damage increased even after the cessation of RF energy, suggesting significant thermal latency effects under HPSD ablation. Lesion growth continued for >10 s after cessation of 50 W ablation energy, and for >12 s after cessation of 90 W ablation energy without cooling. With proactive cooling, lesion growth after cessation of ablation energy was essentially halted. Without esophageal cooling, maximum injury transmurality reached 79% with 50 W, and 58% with 90 W. With esophageal cooling, injury transmurality remained below 20% with 50 W, and 10% with 90 W, representing reductions of 75% and 83%, respectively. Conclusions: RF ablation using HPSD settings demonstrates significant latency of effect, with tissue damage and lesion growth continuing beyond the cessation of application of RF energy. Proactive esophageal cooling significantly dampens this effect, reducing esophageal injury by up to 83%.

Background: Increasing data suggest that elevated body temperature may be helpful in resolving a variety of diseases, including sepsis, acute respiratory distress syndrome (ARDS), and viral illnesses. SARS-CoV-2, which causes coronavirus disease 2019 (COVID-19), may be more temperature sensitive than other coronaviruses, particularly with respect to the binding affinity of its viral entry via the ACE2 receptor. A mechanical provision of elevated temperature focused in a body region of high viral activity in patients undergoing mechanical ventilation may offer a therapeutic option that avoids arrhythmias seen with some pharmaceutical treatments. We investigated the potential to actively provide core warming to the lungs of patients with a commercially available heat transfer device via mathematical modeling, and examine the influence of blood perfusion on temperature using this approach. Methods: Using the software Comsol Multiphysics, we modeled and simulated heat transfer in the body from an intraesophageal warming device, taking into account the airflow from patient ventilation. The simulation was focused on heat transfer and warming of the lungs and performed on a simplified geometry of an adult human body and airway from the pharynx to the lungs. Results: The simulations were run over a range of values for blood perfusion rate, which was a parameter expected to have high influence in overall heat transfer, since the heat capacity and density remain almost constant. The simulation results show a temperature distribution which agrees with the expected clinical experience, with the skin surface at a lower temperature than the rest of the body due to convective cooling in a typical hospital environment. The highest temperature in this case is the device warming water temperature, and that heat diffuses by conduction to the nearby tissues, including the air flowing in the airways. At the range of blood perfusion investigated, maximum lung temperature ranged from 37.6°C to 38.6°C. Conclusions: The provision of core warming via commercially available technology currently utilized in the intensive care unit, emergency department, and operating room can increase regional temperature of lung tissue and airway passages. This warming may offer an innovative approach to treating infectious diseases from viral illnesses such as COVID-19, while avoiding the arrhythmogenic complications of currently used pharmaceutical treatments.

Introduction: Atrioesophageal fistula (AEF) is a severe complication of left atrial ablation for the treatment of atrial fibrillation. Thermal injury is the proposed mechanism, and a potential pathway occurs through exceeding the lethal isotherm of esophageal tissue in contact with the left atrial posterior wall. Active cooling with a novel cooling device has been shown to significantly reduce thermal injury, with no AEFs encountered after more than 4200 treatments worldwide. We aimed to evaluate the effects of active cooling when specifically using newer high-power short-duration (HPSD) ablation settings to further estimate the protective mechanisms of this novel approach to reduce serious injury. Hypothesis: Active cooling may preclude attainment of a lethal isotherm in esophageal tissue under HPSD ablation. Methods: We developed a model of the left atrium and esophagus, and simulated radiofrequency (RF) ablation of the left atrium under HPSD settings. Tissue thickness was set to typical posterior-wall parameters (Figure). Power settings were evaluated at 50 W for 10 seconds, and 90 W for 4 seconds. Active cooling was set to a typical 4 °C coolant temperature. Lethal isotherm temperature was taken as 50 °C. Results: In both scenarios of HPSD ablation, the peak esophageal mucosal temperature reached 39° C in control conditions, using no active cooling. With active cooling in place, peak temperatures remained below 11 °C (Figure). Peak temperatures at the epi-esophageal region of esophageal tissue exceeded the lethal isotherm of 50 °C in control conditions, but remained at or below the lethal isotherm with active cooling in place. Conclusions: Based on our mathematical modeling, esophageal cooling significantly reduced temperature rise and prevented the achievement of temperatures thought to be lethal to esophageal tissue. This finding may offer a mechanistic rationale for the absence of serious esophageal injury encountered to date using this approach.

Background: Atrioesophageal fistula (AEF) is a severe complication of left atrial radiofrequency (RF) ablation for the treatment of atrial fibrillation. Proactive cooling with a novel cooling device has been shown to significantly reduce thermal injury, with no AEFs yet encountered after thousands of treatments worldwide. Computer modeling suggested that lethal temperatures could be avoided with moderate-power and moderate-duration RF ablation. We aimed to evaluate the effects of proactive cooling during high-power short-duration (HPSD) ablation, and compare the computed results to clinical data and recently published experimental data. Methods: A computer model accounting for the left atrium and esophagus including the active cooling device was created. We used both the Arrhenius equation and 50oC isotherm to estimate the esophageal thermal damage during 50 W, 10 second and 90 W, 4 second RF ablations. Results: Under control conditions, temperatures across the esophageal wall exceeded the lethal isotherm, in agreement with recent experimental data. With proactive esophageal cooling in place, temperatures in the esophageal tissue were significantly reduced, with the resulting fraction of esophageal damage reduced by 74% under 50 W and 10 seconds of ablation, and by 82% under 90 W and 4 seconds of ablation. Esophageal damage was restricted to the epi-esophageal region, sparing the remainder of the esophageal tissue, including the mucosal surface. Conclusions: Proactive esophageal cooling significantly reduced temperatures and the resulting fraction of damage in the esophagus during HPSD ablation. These findings offer a mechanistic rationale explaining the absence of AEF encountered to date using proactive esophageal cooling.

Treatments based on nanocarriers such as nanoparticles have emerged as alternatives to overcome common limitations and side effects caused by traditional treatments against cancer and neurological diseases. The main attribute of nanoparticles stems from the fact that they can transport pharmacological agents in a guided manner. This allows drugs to selectively target diseased rather than healthy tissues. This work was aimed at modeling and simulating fluid flow inside small arteries and experimentally validating the model through quantitative measurements of pressure and flow rates. The validity of the model was evaluated in the light of different indexes of percentage agreement between simulated and measured values. The model was previously verified via mesh convergence analysis and qualitative observations of velocity profile. Our findings provide a robust basis for studying nanoparticle transport in arteries as the developed platform enables their releasing and remote manipulation both in silico and in vitro. RESUMEN : Los tratamientos basados en nanoportadores como las nanopartículas han surgido como alternativa para superar las limitaciones y los efectos secundarios de los tratamientos tradicionales contra el cáncer y las enfermedades neurológicas. La principal ventaja de las nanopartículas radica en el hecho de que pueden transportar agentes farmacológicos de forma guiada, de modo que las drogas alcanzan preferiblemente tejidos afectados en vez de tejidos sanos. Este trabajo se enfocó en el modelado y simulación del flujo de fluido en arterias pequeñas y la validación experimental del modelo a través de medidas cuantitativas de presión y tasas de flujo, a la luz de diferentes índices de porcentaje de ajuste entre los valores simulados y medidos. El modelo fue previamente verificado mediante el análisis de convergencia de la malla y las observaciones cualitativas del perfil de velocidad. Nuestros hallazgos sirven como base sólida para el estudio del transporte de nanopartículas dentro de las arterias, ya que la plataforma desarrollada puede ser empleada para su liberación y manipulación remota tanto in silico como in vitro. COL0054963

Molecular dynamic (MD) simulation is an approach frequently employed in computational biology for exhaustive sampling of the protein-ligand conformational space. Hence, it is useful for structural analysis and the study of molecular interactions. In this study, we report on a MD simulation protocol to understand the dynamics of β-secretase 1 (BACE1) and 2 (BACE2), widely known to play a critical role in the etiology of Alzheimer’s disease, by a structure change evaluation of their transmembrane domains while inserted in a simulated neural membrane system. We considered two different levels in membrane cholesterol content. Because there is no evidence supporting the capacity of BACE1 and BACE2 to exist as a dimer, single and double (BACE1/BACE1, BACE2/BACE2, BACE1/BACE2) systems, either in parallel or antiparallel orientation, were prepared for each run. Analysis of tridimensional structure of BACE1 and BACE2, after 10ns of MD simulation, revealed a correlation between higher cholesterol levels and both peptide refolding and changes in the secondary structure of both transmembrane domains in single and double systems. Interestingly, our results also indicate a potential interaction in the double system BACE2/BACE2, particularly when the domains had an antiparallel orientation. RESUMEN : Las simulaciones de dinámica molecular (MD) son una aproximación que se emplea frecuentemente en biología computacional para muestreo exhaustivo del espacio conformacional proteína-ligando. Por este motivo, son útiles para el análisis estructural y el estudio de interacciones moleculares. En este estudio, reportamos sobre el protocolo de simulación MD para entender la dinámica de las β-secretasa 1 (BACE1) y 2 (BACE2), los cuales se sabe ampliamente que juegan un papel transcendental en la enfermedad de Alzheimer. Esto se logró evaluando los cambios estructurales en los dominios a través de la membrana mientras se encontraban insertos en un complejo de membrana neuronal simulada. Aquí se consideraron dos niveles en el contenido de colesterol de la membrana. Debido a que no existe evidencia reportada soportando la capacidad de dimerización de BACE1 y BACE2, se prepararon sistemas sencillos y dobles (BACE1/BACE1, BACE2/BACE2, BACE1/BACE2) tanto en orientación paralela como antiparalela para cada corrida. Después de 10ns de simulación MD, el análisis de la estructura tridimensional reveló una correlación entre los altos niveles de colesterol y tanto el replegamiento de péptidos como los cambios en la estructura secundaria de ambos dominios transmembranales en sistemas simples y dobles. Interesantemente, nuestros resultados también indican un marcado potencial de interacción en el Sistema doble BACE2/BACE2, particularmente cuando los dominios asumen una orientación antiparalela. COL0054963 COL0001923

Introduction Recent clinical data show that high-power, short-duration (HPSD) radiofrequency (RF) ablation can result in a similar esophageal injury rate as traditional low-power, long-duration (LPLD) ablation. Existing methods to prevent esophageal injury have yielded mixed results and can result in prolonged procedure time, potentially increasing the incidence of post-operative cognitive dysfunction. A new esophageal cooling device currently available for whole-body temperature modulation is being studied for the prevention of esophageal injury during LPLD RF ablation and cryoablation. We sought to develop a mathematical model of HPSD ablation in order to quantify the capability of this new esophageal cooling device to protect from esophageal injury under high-power conditions. Methods Using a model we developed of HPSD RF ablation in the left atrium, we measured the change in esophageal lesion formation and the depth of lesions (measured as percent transmurality) with the esophageal cooling device in place and operating at a temperature from 5°C to 37°C. Tissue parameters, including thermal conductivity, were set to average values obtained from existing literature, and energy settings were evaluated at 50W for between 5 and 10 seconds, and at 90W for a duration of 4 seconds. Results Esophageal injury as measured by percent transmurality was considerably higher at 50W and 10s duration than at 90W of power with 4s duration, although both settings showed potential for esophageal injury. The protective effect of the esophageal cooling device was evident for both cases, with a greater effect when using 50W for 10s (Figure 1). At the coldest device settings, using a 5 min pre-cooling period also reduced the transmurality of the intended atrial lesions. Esophageal protection in HPSD ablation Conclusions Esophageal cooling with a new patient temperature management device shows protective effects against thermal injury during RF ablation across a range of tissue thermal conductivity, using a variety of high-power settings, including 90W applied for 4 seconds. Adjusting the cooling power by adjusting the circulating water temperature in the device allows for a tailoring of the protective effects to operating conditions. Acknowledgement/Funding Attune Medical