RF-Energized Intracoronary Guidewire to Enhance Bipolar Ablation of the Interventricular Septum: In-silico Feasibility Study

"This is an Accepted Manuscript of an article published by Taylor & Francis in International Journal of Hyperthermiaon [date of publication], available online: https://doi.org/10.1080/02656736.2018.1425487"[EN] Purpose: Although bipolar radiofrequency (RF) ablation (RFA) is broadly used to eliminate ventricular tachycardias in the interventricular septum wall, it can fail to create transmural lesions in thick ventricular walls. To solve this problem, we explored whether an RF-energised guidewire inserted into the ventricular wall would enhance bipolar RFA in the creation of transmural lesions through the ventricular wall.Methods: We built three-dimensional computational models including two irrigated electrodes placed on opposing sides of the interventricular septum and a metal guidewire inserted into the septum. Computer simulations were conducted to compare the temperature distributions obtained with two ablation modes: bipolar mode (RF power delivered between both irrigated electrode) and time-division multiplexing (TDM) technique, which consists of activating the bipolar mode for 90% of the time and applying RF power between the guidewire and both irrigated electrodes during the remaining time.Results: The TDM technique was the most suitable in terms of creating wider lesions through the entire ventricular wall, avoiding the hour-glass shape of thermal lesions associated with the bipolar mode. This was especially apparent in the case of thick walls (15mm). Furthermore, the TDM technique was able to create transmural lesions even when the guidewire was displaced from the midplane of the wall.Conclusions: An RF-energised guidewire could enhance bipolar RFA by allowing transmural lesions to be made through thick ventricular walls. However, the safety of this new approach must be assessed in future pre-clinical studies, especially in terms of the risk of stenosis and its clinical impact.This work was supported by the Spanish Ministerio de Economia, Industria y Competitividad under "Plan Estatal de Investigacion, Desarrollo e Innovacion Orientada a los Retos de la Sociedad" Grant "TEC2014-52383-C3 (TEC2014-52383-C3-1-R)". A. Gonzalez-Suarez has a "Juan de la Cierva-formacion" Postdoctoral Grant (FJCI-2015-27202) supported by the Spanish Ministerio de Economia, Industria y Competitividad, Secretaria de Estado de Investigacion, Desarrollo e Innovacion.Pérez, JJ.; González Suárez, A.; D Avila, A.; Berjano, E. (2018). RF-Energized Intracoronary Guidewire to Enhance Bipolar Ablation of the Interventricular Septum: In-silico Feasibility Study. International Journal of Hyperthermia. 34(8):1202-1212. https://doi.org/10.1080/02656736.2018.1425487S12021212348Baszko, A., Telec, W., Kałmucki, P., Iwachów, P., Kochman, K., Szymański, R., … Siminiak, T. (2016). Bipolar irrigated radiofrequency ablation of resistant ventricular tachycardia with a septal intramural origin: the initial experience and a description of the method. Clinical Case Reports, 4(10), 957-961. doi:10.1002/ccr3.648Gizurarson, S., Spears, D., Sivagangabalan, G., Farid, T., Ha, A. C. T., Masse, S., … Nanthakumar, K. (2014). Bipolar ablation for deep intra-myocardial circuits: human ex vivo development and in vivo experience. Europace, 16(11), 1684-1688. doi:10.1093/europace/euu001Koruth, J. S., Dukkipati, S., Miller, M. A., Neuzil, P., d’ Avila, A., & Reddy, V. Y. (2012). Bipolar irrigated radiofrequency ablation: A therapeutic option for refractory intramural atrial and ventricular tachycardia circuits. Heart Rhythm, 9(12), 1932-1941. doi:10.1016/j.hrthm.2012.08.001Baldinger, S. H., Kumar, S., Barbhaiya, C. R., Mahida, S., Epstein, L. M., Michaud, G. F., … Stevenson, W. G. (2015). Epicardial Radiofrequency Ablation Failure During Ablation Procedures for Ventricular Arrhythmias. Circulation: Arrhythmia and Electrophysiology, 8(6), 1422-1432. doi:10.1161/circep.115.003202Santangeli, P., Shaw, G. C., & Marchlinski, F. E. (2017). Radiofrequency Wire Facilitated Interventricular Septal Access for Catheter Ablation of Ventricular Tachycardia in a Patient With Aortic and Mitral Mechanical Valves. Circulation: Arrhythmia and Electrophysiology, 10(1). doi:10.1161/circep.116.004771Berjano, E. J., Hornero, F., Atienza, F., & Montero, A. (2003). Long electrodes for radio frequency ablation: comparative study of surface versus intramural application. Medical Engineering & Physics, 25(10), 869-877. doi:10.1016/s1350-4533(03)00125-5McLELLAN, A. J. A., ELLIMS, A. H., PRABHU, S., VOSKOBOINIK, A., ILES, L. M., HARE, J. L., … KISTLER, P. M. (2016). Diffuse Ventricular Fibrosis on Cardiac Magnetic Resonance Imaging Associates With Ventricular Tachycardia in Patients With Hypertrophic Cardiomyopathy. Journal of Cardiovascular Electrophysiology, 27(5), 571-580. doi:10.1111/jce.12948Berjano, E. J. (2006). Theoretical modeling for radiofrequency ablation: state-of-the-art and challenges for the future. BioMedical Engineering OnLine, 5(1). doi:10.1186/1475-925x-5-24Pérez, J. J., González-Suárez, A., & Berjano, E. (2017). Numerical analysis of thermal impact of intramyocardial capillary blood flow during radiofrequency cardiac ablation. International Journal of Hyperthermia, 34(3), 243-249. doi:10.1080/02656736.2017.1336258Labonte, S. (1994). Numerical model for radio-frequency ablation of the endocardium and its experimental validation. IEEE Transactions on Biomedical Engineering, 41(2), 108-115. doi:10.1109/10.284921Doss, J. D. (1982). Calculation of electric fields in conductive media. Medical Physics, 9(4), 566-573. doi:10.1118/1.595107PÉREZ, J. J., D’AVILA, A., ARYANA, A., & BERJANO, E. (2015). Electrical and Thermal Effects of Esophageal Temperature Probes on Radiofrequency Catheter Ablation of Atrial Fibrillation: Results from a Computational Modeling Study. Journal of Cardiovascular Electrophysiology, 26(5), 556-564. doi:10.1111/jce.12630Jo, B., & Aksan, A. (2010). Prediction of the extent of thermal damage in the cornea during conductive keratoplasty. Journal of Thermal Biology, 35(4), 167-174. doi:10.1016/j.jtherbio.2010.02.004Gonzalez-Suarez, A., & Berjano, E. (2016). Comparative Analysis of Different Methods of Modeling the Thermal Effect of Circulating Blood Flow During RF Cardiac Ablation. IEEE Transactions on Biomedical Engineering, 63(2), 250-259. doi:10.1109/tbme.2015.2451178WINTERFIELD, J. R., JENSEN, J., GILBERT, T., MARCHLINSKI, F., NATALE, A., PACKER, D., … WILBER, D. J. (2015). Lesion Size and Safety Comparison Between the Novel Flex Tip on the FlexAbility Ablation Catheter and the Solid Tips on the ThermoCool and ThermoCool SF Ablation Catheters. Journal of Cardiovascular Electrophysiology, 27(1), 102-109. doi:10.1111/jce.12835PÉREZ, J. J., D’AVILA, A., ARYANA, A., TRUJILLO, M., & BERJANO, E. (2016). Can Fat Deposition After Myocardial Infarction Alter the Performance of RF Catheter Ablation of Scar-Related Ventricular Tachycardia?: Results from a Computer Modeling Study. Journal of Cardiovascular Electrophysiology, 27(8), 947-952. doi:10.1111/jce.13006Haines, D. E. (2011). Letter by Haines Regarding Article, «Direct Measurement of the Lethal Isotherm for Radiofrequency Ablation of Myocardial Tissue». Circulation: Arrhythmia and Electrophysiology, 4(5). doi:10.1161/circep.111.965459González-Suárez, A., Trujillo, M., Koruth, J., d’ Avila, A., & Berjano, E. (2014). Radiofrequency cardiac ablation with catheters placed on opposing sides of the ventricular wall: Computer modelling comparing bipolar and unipolar modes. International Journal of Hyperthermia, 30(6), 372-384. doi:10.3109/02656736.2014.949878Gianni, C., Mohanty, S., Trivedi, C., Di Biase, L., Al-Ahmad, A., Natale, A., & David Burkhardt, J. (2017). Alternative Approaches for Ablation of Resistant Ventricular Tachycardia. Cardiac Electrophysiology Clinics, 9(1), 93-98. doi:10.1016/j.ccep.2016.10.006Boll, D. T., Lewin, J. S., Duerk, J. L., & Merkle, E. M. (2003). Do Surgical Clips Interfere with Radiofrequency Thermal Ablation? American Journal of Roentgenology, 180(6), 1557-1560. doi:10.2214/ajr.180.6.1801557Eung Je Woo, Tungjitkusolmun, S., Hong Cao, Jang-Zem Tsai, Webster, J. G., Vorperian, V. R., & Will, J. A. (2000). A new catheter design using needle electrode for subendocardial RF ablation of ventricular muscles: finite element analysis and in vitro experiments. IEEE Transactions on Biomedical Engineering, 47(1), 23-31. doi:10.1109/10.817616BLOUIN, L. T., & MARCUS, F. I. (1989). The Effect of Electrode Design on the Efficiency of Delivery of Radiofrequency Energy to Cardiac Tissue In Vitro. Pacing and Clinical Electrophysiology, 12(1), 136-143. doi:10.1111/j.1540-8159.1989.tb02640.xTao, W., Jian-ping, G., Xu, H., Wen-sheng, L., Liang, C., Guo-ping, C., … Jin-hua, S. (2013). The effects of endovenous radiofrequency ablation on coagulation and the vein wall in an experimental canine model. Vascular, 21(4), 215-219. doi:10.1177/1708538113478762Badham, G. E., Strong, S. M., & Whiteley, M. S. (2014). An in vitro study to optimise treatment of varicose veins with radiofrequency-induced thermo therapy. Phlebology: The Journal of Venous Disease, 30(1), 17-23. doi:10.1177/0268355514552005Kreidieh, B., Rodríguez-Mañero, M., A. Schurmann, P., Ibarra-Cortez, S. H., Dave, A. S., & Valderrábano, M. (2016). Retrograde Coronary Venous Ethanol Infusion for Ablation of Refractory Ventricular Tachycardia. Circulation: Arrhythmia and Electrophysiology, 9(7). doi:10.1161/circep.116.00435

The entropy of ``strange'' billiards inside n-simplexes

In the present work we investigate a new type of billiards defined inside of $n$--simplex regions. We determine an invariant ergodic (SRB) measure of the dynamics for any dimension. In using symbolic dynamics, the (KS or metric) entropy is computed and we find that the system is chaotic for all cases $n>2$.Comment: 8 pages, uuencoded compressed postscript fil

Genome-wide association study of primary open-angle glaucoma in continental and admixed African populations.

Primary open angle glaucoma (POAG) is a complex disease with a major genetic contribution. Its prevalence varies greatly among ethnic groups, and is up to five times more frequent in black African populations compared to Europeans. So far, worldwide efforts to elucidate the genetic complexity of POAG in African populations has been limited. We conducted a genome-wide association study in 1113 POAG cases and 1826 controls from Tanzanian, South African and African American study samples. Apart from confirming evidence of association at TXNRD2 (rs16984299; OR[T] 1.20; P = 0.003), we found that a genetic risk score combining the effects of the 15 previously reported POAG loci was significantly associated with POAG in our samples (OR 1.56; 95% CI 1.26-1.93; P = 4.79 × 10-5). By genome-wide association testing we identified a novel candidate locus, rs141186647, harboring EXOC4 (OR[A] 0.48; P = 3.75 × 10-8), a gene transcribing a component of the exocyst complex involved in vesicle transport. The low frequency and high degree of genetic heterogeneity at this region hampered validation of this finding in predominantly West-African replication sets. Our results suggest that established genetic risk factors play a role in African POAG, however, they do not explain the higher disease load. The high heterogeneity within Africans remains a challenge to identify the genetic commonalities for POAG in this ethnicity, and demands studies of extremely large size

A meta-analysis of gene expression signatures of blood pressure and hypertension

Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p<0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%-9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension.Tianxiao Huan, Tõnu Esko, Marjolein J. Peters, Luke C. Pilling, Katharina Schramm, Claudia Schurmann, Brian H. Chen, Chunyu Liu, Roby Joehanes, Andrew D. Johnson, Chen Yao, Sai-xia Ying, Paul Courchesne, Lili Milani, Nalini Raghavachari, Richard Wang, Poching Liu, Eva Reinmaa, Abbas Dehghan, Albert Hofman, André G. Uitterlinden, Dena G. Hernandez, Stefania Bandinelli, Andrew Singleton, David Melzer, Andres Metspalu, Maren Carstensen, Harald Grallert, Christian Herder, Thomas Meitinger, Annette Peters, Michael Roden, Melanie Waldenberger, Marcus Dörr, Stephan B. Felix, Tanja Zeller, International Consortium for Blood Pressure GWAS, ICBP, Ramachandran Vasan, Christopher J. O'Donnell, Peter J. Munson, Xia Yang, Holger Prokisch, Uwe Völker, Joyce B. J. van Meurs, Luigi Ferrucci, Daniel Lev

ARF GTPases and their GEFs and GAPs: concepts and challenges

Detailed structural, biochemical, cell biological, and genetic studies of any gene/protein are required to develop models of its actions in cells. Studying a protein family in the aggregate yields additional information, as one can include analyses of their coevolution, acquisition or loss of functionalities, structural pliability, and the emergence of shared or variations in molecular mechanisms. An even richer understanding of cell biology can be achieved through evaluating functionally linked protein families. In this review, we summarize current knowledge of three protein families: the ARF GTPases, the guanine nucleotide exchange factors (ARF GEFs) that activate them, and the GTPase-activating proteins (ARF GAPs) that have the ability to both propagate and terminate signaling. However, despite decades of scrutiny, our understanding of how these essential proteins function in cells remains fragmentary. We believe that the inherent complexity of ARF signaling and its regulation by GEFs and GAPs will require the concerted effort of many laboratories working together, ideally within a consortium to optimally pool information and resources. The collaborative study of these three functionally connected families ( \u3e /=70 mammalian genes) will yield transformative insights into regulation of cell signaling

Different HLA-DRB1 allele distributions in distinct clinical subgroups of sarcoidosis patients

<p>Abstract</p> <p>Background</p> <p>A strong genetic influence by the MHC class II region has been reported in sarcoidosis, however in many studies with different results. This may possibly be caused by actual differences between distinct ethnic groups, too small sample sizes, or because of lack of accurate clinical subgrouping.</p> <p>Subjects and methods</p> <p>In this study we HLA typed a large patient population (n = 754) recruited from one single centre. Patients were sub-grouped into those with Löfgren's syndrome (LS) (n = 302) and those without (non-Löfgren's) (n = 452), and the majority of them were clinically classified into those with recovery within two years (resolving) and those with signs of disease for more than two years (non-resolving). PCR was used for determination of HLA-DRB1 alleles. Swedish healthy blood donors (n = 1366) served as controls.</p> <p>Results</p> <p>There was a dramatic difference in the distribution of HLA alleles in LS compared to non-LS patients (p = 4 × 10^-36). Most notably, DRB1*01, DRB1*03 and DRB1*14, clearly differed in LS and non-LS patients. In relation to disease course, DRB1*07, DRB1*14 and DRB1*15 generally associated with, while DRB1*01 and DRB1*03 protected against, a non-resolving disease. Interestingly, the clinical influence of DRB1*03 (good prognosis) dominated over that of DRB1*15 (bad prognosis).</p> <p>Conclusions</p> <p>We found several significant differences between LS and non-LS patients and we therefore suggest that genetic association studies in sarcoidosis should include a careful clinical characterisation and sub-grouping of patients, in order to reveal true genetic associations. This may be particularly accurate to do in the heterogeneous non-LS group of patients.</p

The physiological variability of channel density in hippocampal CA1 pyramidal cells and interneurons explored using a unified data-driven modeling workflow

Every neuron is part of a network, exerting its function by transforming multiple spatiotemporal synaptic input patterns into a single spiking output. This function is specified by the particular shape and passive electrical properties of the neuronal membrane, and the composition and spatial distribution of ion channels across its processes. For a variety of physiological or pathological reasons, the intrinsic input/output function may change during a neuron’s lifetime. This process results in high variability in the peak specific conductance of ion channels in individual neurons. The mechanisms responsible for this variability are not well understood, although there are clear indications from experiment and modeling that degeneracy and correlation among multiple channels may be involved. Here, we studied this issue in biophysical models of hippocampal CA1 pyramidal neurons and interneurons. Using a unified data-driven simulation workflow and starting from a set of experimental recordings and morphological reconstructions obtained from rats, we built and analyzed several ensembles of morphologically and biophysically accurate single cell models with intrinsic electrophysiological properties consistent with experimental findings. The results suggest that the set of conductances expressed in any given hippocampal neuron may be considered as belonging to two groups: one subset is responsible for the major characteristics of the firing behavior in each population and the other responsible for a robust degeneracy. Analysis of the model neurons suggests several experimentally testable predictions related to the combination and relative proportion of the different conductances that should be expressed on the membrane of different types of neurons for them to fulfill their role in the hippocampus circuitry