57 research outputs found

    Definición de patrones electrocardiográficos para su reconocimiento en una aplicación informática

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    Aprendizaje de la electrocardiografía para los alumnos de 3º y 4º de Medicina a partir de una biblioteca de electrocardiografía tutelada, creada en un proyecto de innovación y mejora de la calidad docente de 2013. Se trata de detallar los patrones electrocardiográficos reales de todas las alteraciones electrocardiográficas descritas para que puedan ser llevados a una aplicación gráfica de identificación para dispositivos móviles que diagnostique los electrocardiogramas mediante su escaneo

    Pulmonary Vein Activity Organization to Determine Atrial Fibrillation Recurrence: Preliminary Data from a Pilot Study

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    [EN] Ablation of pulmonary veins has emerged as a key procedure for normal rhythm restoration in atrial fibrillation patients. However, up to half of ablated Atrial fibrillation (AF) patients suffer recurrences during the first year. In this article, simultaneous intra-atrial recordings registered at pulmonary veins previous to the ablation procedure were analyzed. Spatial cross-correlation and transfer entropy were computed in order to estimate spatial organization. Results showed that, in patients with arrhythmia recurrence, pulmonary vein electrical activity was less correlated than in patients that maintained sinus rhythm. Moreover, correlation function between dipoles showed higher delays in patients with AF recurrence. Results with transfer entropy were consistent with spatial cross-correlation measurements. These results show that arrhythmia drivers located at the pulmonary veins are associated with a higher organization of the electrical activations after the ablation of these sites.This research was funded by Spanish Ministry of Research and Innovation : PID2019-109547RB-I00. This research was supported by the PID2019-109547RB-I00 National Research Program RETOS from the Spanish Ministry of Research and Innovation and partialy by GVA (PROMETEO/2018/078) & ISCIII (CB16/11/00486). Thanks to Michael Charles Willoughby for English language and scientific editing services.Cervigón, R.; Moreno, J.; Millet Roig, J.; Pérez-Villacastín, J.; Castells, F. (2020). Pulmonary Vein Activity Organization to Determine Atrial Fibrillation Recurrence: Preliminary Data from a Pilot Study. Mathematics. 8(10):1-13. https://doi.org/10.3390/math8101813S113810Andrade, J., Khairy, P., Dobrev, D., & Nattel, S. (2014). The Clinical Profile and Pathophysiology of Atrial Fibrillation. Circulation Research, 114(9), 1453-1468. doi:10.1161/circresaha.114.303211Kim, M. H., Johnston, S. S., Chu, B.-C., Dalal, M. R., & Schulman, K. L. (2011). Estimation of Total Incremental Health Care Costs in Patients With Atrial Fibrillation in the United States. Circulation: Cardiovascular Quality and Outcomes, 4(3), 313-320. doi:10.1161/circoutcomes.110.958165Andersson, T., Magnuson, A., Bryngelsson, I.-L., Frøbert, O., Henriksson, K. M., Edvardsson, N., & Poçi, D. (2013). All-cause mortality in 272 186 patients hospitalized with incident atrial fibrillation 1995–2008: a Swedish nationwide long-term case–control study. European Heart Journal, 34(14), 1061-1067. doi:10.1093/eurheartj/ehs469Chugh, S. S., Havmoeller, R., Narayanan, K., Singh, D., Rienstra, M., Benjamin, E. J., … Murray, C. J. L. (2014). Worldwide Epidemiology of Atrial Fibrillation. Circulation, 129(8), 837-847. doi:10.1161/circulationaha.113.005119Saglietto, A., Matta, M., Gaita, F., Jacobs, V., Bunch, T. J., & Anselmino, M. (2019). Stroke-independent contribution of atrial fibrillation to dementia: a meta-analysis. Open Heart, 6(1), e000984. doi:10.1136/openhrt-2018-000984Wattigney, W. A. (2002). Increased Atrial Fibrillation Mortality: United States, 1980-1998. American Journal of Epidemiology, 155(9), 819-826. doi:10.1093/aje/155.9.819Krijthe, B. P., Kunst, A., Benjamin, E. J., Lip, G. Y. H., Franco, O. H., Hofman, A., … Heeringa, J. (2013). Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060. European Heart Journal, 34(35), 2746-2751. doi:10.1093/eurheartj/eht280January, C. T., Wann, L. S., Calkins, H., Chen, L. Y., Cigarroa, J. E., Cleveland, J. C., … Yancy, C. W. (2019). 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. Heart Rhythm, 16(8), e66-e93. doi:10.1016/j.hrthm.2019.01.024Haïssaguerre, M., Jaïs, P., Shah, D. C., Takahashi, A., Hocini, M., Quiniou, G., … Clémenty, J. (1998). Spontaneous Initiation of Atrial Fibrillation by Ectopic Beats Originating in the Pulmonary Veins. New England Journal of Medicine, 339(10), 659-666. doi:10.1056/nejm199809033391003Allessie, M. A., Bonke, F. I., & Schopman, F. J. (1976). Circus movement in rabbit atrial muscle as a mechanism of tachycardia. II. The role of nonuniform recovery of excitability in the occurrence of unidirectional block, as studied with multiple microelectrodes. Circulation Research, 39(2), 168-177. doi:10.1161/01.res.39.2.168Kirchhof, P., Benussi, S., Kotecha, D., Ahlsson, A., Atar, D., Casadei, B., … Zeppenfeld, K. (2016). 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Europace, 18(11), 1609-1678. doi:10.1093/europace/euw295Calkins, H., Kuck, K. H., Cappato, R., Brugada, J., Camm, A. J., Chen, S.-A., … Wilber, D. (2012). 2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: Recommendations for Patient Selection, Procedural Techniques, Patient Management and Follow-up, Definitions, Endpoints, and Research Trial Design. Heart Rhythm, 9(4), 632-696.e21. doi:10.1016/j.hrthm.2011.12.016Ganesan, A. N., Shipp, N. J., Brooks, A. G., Kuklik, P., Lau, D. H., Lim, H. S., … Sanders, P. (2013). Long‐term Outcomes of Catheter Ablation of Atrial Fibrillation: A Systematic Review and Meta‐analysis. Journal of the American Heart Association, 2(2). doi:10.1161/jaha.112.004549Pison, L., Tilz, R., Jalife, J., & Haïssaguerre, M. (2016). Pulmonary vein triggers, focal sources, rotors and atrial cardiomyopathy: implications for the choice of the most effective ablation therapy. Journal of Internal Medicine, 279(5), 449-456. doi:10.1111/joim.12490Kirchhof, P., Benussi, S., Kotecha, D., Ahlsson, A., Atar, D., Casadei, B., … Vardas, P. (2017). 2016 ESC Guidelines for the Management of Atrial Fibrillation Developed in Collaboration With EACTS. Revista Española de Cardiología (English Edition), 70(1), 50. doi:10.1016/j.rec.2016.11.033Botteron, G. W., & Smith, J. M. (1995). A technique for measurement of the extent of spatial organization of atrial activation during atrial fibrillation in the intact human heart. IEEE Transactions on Biomedical Engineering, 42(6), 579-586. doi:10.1109/10.387197Cervigón, R., Moreno, J., Millet, J., Pérez-Villacastín, J., & Castells, F. (2010). Propofol Effects on Atrial Fibrillation Wavefront Delays. IEEE Transactions on Biomedical Engineering, 57(8), 1877-1885. doi:10.1109/tbme.2009.2037312Cervigón, R., Castells, F., Gómez-Pulido, J., Pérez-Villacastín, J., & Moreno, J. (2018). Granger Causality and Jensen–Shannon Divergence to Determine Dominant Atrial Area in Atrial Fibrillation. Entropy, 20(1), 57. doi:10.3390/e20010057CASTELLS, F., CERVIGÓN, R., & MILLET, J. (2013). 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Circulation, 110(15), 2090-2096. doi:10.1161/01.cir.0000144459.37455.eeChen, S.-A., Hsieh, M.-H., Tai, C.-T., Tsai, C.-F., Prakash, V. S., Yu, W.-C., … Chang, M.-S. (1999). Initiation of Atrial Fibrillation by Ectopic Beats Originating From the Pulmonary Veins. Circulation, 100(18), 1879-1886. doi:10.1161/01.cir.100.18.1879SOTOMI, Y., KIKKAWA, T., INOUE, K., TANAKA, K., TOYOSHIMA, Y., OKA, T., … FUJII, K. (2014). Regional Difference of Optimal Contact Force to Prevent Acute Pulmonary Vein Reconnection During Radiofrequency Catheter Ablation for Atrial Fibrillation. Journal of Cardiovascular Electrophysiology, 25(9), 941-947. doi:10.1111/jce.12443BALK, E. M., GARLITSKI, A. C., ALSHEIKH-ALI, A. A., TERASAWA, T., CHUNG, M., & IP, S. (2010). Predictors of Atrial Fibrillation Recurrence After Radiofrequency Catheter Ablation: A Systematic Review. Journal of Cardiovascular Electrophysiology, 21(11), 1208-1216. doi:10.1111/j.1540-8167.2010.01798.xAd, N., Holmes, S. D., Patel, J., Je, H. G., & Shuman, D. J. (2017). The Need for Consistent Predictors of Success for Surgical Ablation of Atrial Fibrillation. Innovations: Technology and Techniques in Cardiothoracic and Vascular Surgery, 12(6), 421-429. doi:10.1097/imi.0000000000000426Njoku, A., Kannabhiran, M., Arora, R., Reddy, P., Gopinathannair, R., Lakkireddy, D., & Dominic, P. (2017). Left atrial volume predicts atrial fibrillation recurrence after radiofrequency ablation: a meta-analysis. EP Europace, 20(1), 33-42. doi:10.1093/europace/eux013Ropella, K. M., Sahakian, A. V., Baerman, J. M., & Swiryn, S. (1989). The coherence spectrum. A quantitative discriminator of fibrillatory and nonfibrillatory cardiac rhythms. Circulation, 80(1), 112-119. doi:10.1161/01.cir.80.1.112Cervigón, R., Moreno, J., Sánchez, C., Reilly, R. B., Villacastín, J., Millet, J., & Castells, F. (2008). Atrial fibrillation organization: quantification of propofol effects. 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    TBC: A simple algorithm to rule out abnormalities in electrocardiograms of patients with pacemakers

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    Background: The aim of the study was to create a straightforward method to rule out abnormalities in electrocardiograms (ECGs) performed in patients with pacemakers. Methods: The TBC method screens the ECG for any of the following findings: Tachycardia with pacing spikes, Bradycardia without spikes and Chaos with spikes unrelated to QRS-T complexes. T was considered to advise for patient assessment and B and C to require referral for urgent pacemaker evalu­ation. The diagnostic accuracy of the algorithm was validated using a cohort of 151 ECGs with normal and dysfunctional pacemakers. The effect of the algorithm was then evaluated for diagnostic skills and management of patients with pacemakers by non-cardiologists, comparing their diagnostic accuracy before and after teaching the algorithm. Results: The TBC algorithm had a sensitivity of 86% and a specificity of 94% in diagnosing a mal­functioning pacemaker. The diagnostic skills and patient referral were significantly improved (74.8% vs. 89.5%, p < 0.001; and 57.4% vs. 83%, p < 0.001). Conclusions: TBC is an easy to remember and apply method to rule out severe abnormalities in ECGs of patients with pacemakers. TBC algorithm has a very good diagnostic capability and is easily applied by non-expert physicians with good results

    Instantaneous Amplitude and Frequency Modulations Detect the Footprint of Rotational Activity and Reveal Stable Driver Regions as Targets for Persistent Atrial Fibrillation Ablation

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    RATIONALE: Costly proprietary panoramic multielectrode (64-256) acquisition systems are being increasingly used together with conventional electroanatomical mapping systems for persistent atrial fibrillation (PersAF) ablation. However, such approaches target alleged drivers (rotational/focal) regardless of their activation frequency dynamics. OBJECTIVES: To test the hypothesis that stable regions of higher than surrounding instantaneous frequency modulation (iFM) drive PersAF and determine whether rotational activity is specific for such regions. METHODS AND RESULTS: First, novel single-signal algorithms based on instantaneous amplitude modulation (iAM) and iFM to detect rotational-footprints without panoramic multielectrode acquisition systems were tested in 125 optical movies from 5 ex vivo Langendorff-perfused PersAF sheep hearts (sensitivity/specificity, 92.6/97.5%; accuracy, 2.5-mm) and in computer simulations. Then, 16 pigs underwent high-rate atrial pacing to develop PersAF. After a median (interquartile range [IQR]) of 4.4 (IQR, 2.5-9.9) months of high-rate atrial pacing followed by 4.1 (IQR, 2.7-5.4) months of self-sustained PersAF, pigs underwent in vivo high-density electroanatomical atrial mapping (4920 [IQR, 4435-5855] 8-second unipolar signals per map). The first 4 out of 16 pigs were used to adapt ex vivo optical proccessing of iFM/iAM to in vivo electrical signals. In the remaining 12 out of 16 pigs, regions of higher than surrounding average iFM were considered leading-drivers. Two leading-driver + rotational-footprint maps were generated 2.6 (IQR, 2.4-2.9) hours apart to test leading-driver spatiotemporal stability and guide ablation. Leading-driver regions (2.5 [IQR, 2.0-4.0] regions/map) exactly colocalized (95.7%) in the 2 maps, and their ablation terminated PersAF in 92.3% of procedures (radiofrequency until termination, 16.9 [IQR, 9.2-35.8] minutes; until nonsustainability, 20.4 [IQR, 12.8-44.0] minutes). Rotational-footprints were found at every leading-driver region, albeit most (76.8% [IQR, 70.5%-83.6%]) were located outside. Finally, the translational ability of this approach was tested in 3 PersAF redo patients. CONCLUSIONS: Both rotational-footprints and spatiotemporally stable leading-driver regions can be located using iFM/iAM algorithms without panoramic multielectrode acquisition systems. In pigs, ablation of leading-driver regions usually terminates PersAF and prevents its sustainability. Rotational activations are sensitive but not specific to such regions. Single-signal iFM/iAM algorithms could be integrated into conventional electroanatomical mapping systems to improve driver detection accuracy and reduce the cost of patient-tailored/mechanistic approaches.This study was supported by the European Regional Development Fund and the Spanish Ministry of Science, Innovation and Universities (SAF2016-80324-R). The CNIC is supported by the Spanish Ministry of Science, Innovation and Universities and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S

    Anatomical targets and expected outcomes of catheter-based ablation of atrial fibrillation in 2020.

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    Anatomical-based approaches, targeting either pulmonary vein isolation (PVI) or additional extra PV regions, represent the most commonly used ablation treatments in symptomatic patients with atrial fibrillation (AF) recurrences despite antiarrhythmic drug therapy. PVI remains the main anatomical target during catheter-based AF ablation, with the aid of new technological advances as contact force monitoring to increase safety and effective radiofrequency (RF) lesions. Nowadays, cryoballoon ablation has also achieved the same level of scientific evidence in patients with paroxysmal AF undergoing PVI. In parallel, electrical isolation of extra PV targets has progressively increased, which is associated with a steady increase in complex cases undergoing ablation. Several atrial regions as the left atrial posterior wall, the vein of Marshall, the left atrial appendage, or the coronary sinus have been described in different series as locations potentially involved in AF initiation and maintenance. Targeting these regions may be challenging using conventional point-by-point RF delivery, which has opened new opportunities for coadjuvant alternatives as balloon ablation or selective ethanol injection. Although more extensive ablation may increase intraprocedural AF termination and freedom from arrhythmias during the follow-up, some of the targets to achieve such outcomes are not exempt of potential severe complications. Here, we review and discuss current anatomical approaches and the main ablation technologies to target atrial regions associated with AF initiation and maintenance.This work was supported by the European Regional Development Fund, the Spanish Ministry of Science and Innovation (SAF2016- 80324-R), and the Fundación Interhospitalaria para la Investigación Cardiovascular (FIC). The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Spanish Ministry of Science and Innovation and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Giulio La Rosa has received a fellowship grant from the joint program between the Heart Rhythm Association of the Spanish Society of Cardiology (ARC) and CNIC.S

    In vivo ratiometric optical mapping enables high-resolution cardiac electrophysiology in pig models

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    AIMS: Cardiac optical mapping is the gold standard for measuring complex electrophysiology in ex vivo heart preparations. However, new methods for optical mapping in vivo have been elusive. We aimed at developing and validating an experimental method for performing in vivo cardiac optical mapping in pig models. METHODS AND RESULTS: First, we characterized ex vivo the excitation-ratiometric properties during pacing and ventricular fibrillation (VF) of two near-infrared voltage-sensitive dyes (di-4-ANBDQBS/di-4-ANEQ(F)PTEA) optimized for imaging blood-perfused tissue (n = 7). Then, optical-fibre recordings in Langendorff-perfused hearts demonstrated that ratiometry permits the recording of optical action potentials (APs) with minimal motion artefacts during contraction (n = 7). Ratiometric optical mapping ex vivo also showed that optical AP duration (APD) and conduction velocity (CV) measurements can be accurately obtained to test drug effects. Secondly, we developed a percutaneous dye-loading protocol in vivo to perform high-resolution ratiometric optical mapping of VF dynamics (motion minimal) using a high-speed camera system positioned above the epicardial surface of the exposed heart (n = 11). During pacing (motion substantial) we recorded ratiometric optical signals and activation via a 2D fibre array in contact with the epicardial surface (n = 7). Optical APs in vivo under general anaesthesia showed significantly faster CV [120 (63-138) cm/s vs. 51 (41-64) cm/s; P = 0.032] and a statistical trend to longer APD90 [242 (217-254) ms vs. 192 (182-233) ms; P = 0.095] compared with ex vivo measurements in the contracting heart. The average rate of signal-to-noise ratio (SNR) decay of di-4-ANEQ(F)PTEA in vivo was 0.0671 ± 0.0090 min-1. However, reloading with di-4-ANEQ(F)PTEA fully recovered the initial SNR. Finally, toxicity studies (n = 12) showed that coronary dye injection did not generate systemic nor cardiac damage, although di-4-ANBDQBS injection induced transient hypotension, which was not observed with di-4-ANEQ(F)PTEA. CONCLUSIONS: In vivo optical mapping using voltage ratiometry of near-infrared dyes enables high-resolution cardiac electrophysiology in translational pig models.The CNIC is supported by the Ministry of Science, Innovation and Universities and the Pro CNIC Foundation. The CNIC is a Severo Ochoa Center of Excellence (SEV-2015-0505). This study was supported by grants from Fondo Europeo de Desarrollo Regional (CB16/11/00458), the Spanish Ministry of Science, Innovation and Universities (SAF2016-80324-R, PI16/02110, and DTS17/00136), and by the European Commission (ERA-CVD Joint Call [JTC2016/APCIN-ISCIII-2016], grant#AC16/00021). The study was also partially supported by the Fundacio´n Interhospitalaria para la Investigacio´n Cardiovascular (FIC) and the Heart Rhythm section of the Spanish Society of Cardiology. The work at the University of Connecticut was supported by grant EB001963 from the National Institutes of Health.S

    Estrategia para el aprendizaje activo: Biblioteca audiovisual de casos clínicos reales de la patología cardiovascular más frecuente. Implicaciones para la preparación del examen M.I.R

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    Ofrecer al alumno una formación práctica y real a partir de situaciones de la práctica clínica diaria. Realizar un repositorio de vídeos y preguntas que crezca cada curso académico. Se pretende que esta colección sirva como modelo para la creación posterior de una aplicación informática que permita la interpretación de cualquier electrocardiograma tras escaneo del mismo en dispositivos tales como móviles o tabletas

    Granger Causality and Jensen-Shannon Divergence to Determine Dominant Atrial Area in Atrial Fibrillation

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    [EN] Atrial fibrillation (AF) is already the most commonly occurring arrhythmia. Catheter pulmonary vein ablation has emerged as a treatment that is able to make the arrhythmia disappear; nevertheless, recurrence to arrhythmia is very frequent. In this study, it is proposed to perform an analysis of the electrical signals recorded from bipolar catheters at three locations, pulmonary veins and the right and left atria, before to and during the ablation procedure. Principal Component Analysis (PCA) was applied to reduce data dimension and Granger causality and divergence techniques were applied to analyse connectivity along the atria, in three main regions: pulmonary veins, left atrium (LA) and right atrium (RA). The results showed that, before the procedure, patients with recurrence in the arrhythmia had greater connectivity between atrial areas. Moreover, during the ablation procedure, in patients with recurrence in the arrhythmial both atria were more connected than in patients that maintained sinus rhythms. These results can be helpful for procedures designing to end AF.This work has been supported by the Spanish Government, under the grant DPI2015-70821-R received from the research program Retos de la Sociedad' by the Ministry of Economics and Competitiveness.Cervigón, R.; Castells, F.; Gómez-Pulido, JM.; Pérez-Villacastín, J.; Moreno, J. (2018). Granger Causality and Jensen-Shannon Divergence to Determine Dominant Atrial Area in Atrial Fibrillation. Entropy. 20(1):1-14. https://doi.org/10.3390/e20010057S11420

    Mapping Technologies for Catheter Ablation of Atrial Fibrillation Beyond Pulmonary Vein Isolation

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    Catheter ablation remains the most effective and relatively minimally invasive therapy for rhythm control in patients with AF. Ablation has consistently shown a reduction of arrhythmia-related symptoms and significant improvement in patients’ quality of life compared with medical treatment. The ablation strategy relies on a well-established anatomical approach of effective pulmonary vein isolation. Additional anatomical targets have been reported with the aim of increasing procedure success in complex substrates. However, larger ablated areas with uncertainty of targeting relevant regions for AF initiation or maintenance are not exempt from the potential risk of complications and pro-arrhythmia. Recent developments in mapping tools and computational methods for advanced signal processing during AF have reported novel strategies to identify atrial regions associated with AF maintenance. These novel tools – although mainly limited to research series – represent a significant step forward towards the understanding of complex patterns of propagation during AF and the potential achievement of patient-tailored AF ablation strategies for the near future

    Lesion Index Titration Using Contact-Force Technology Enables Safe and Effective Radiofrequency Lesion Creation at the Root of the Aorta and Pulmonary Artery

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    BACKGROUND: Ablation of some myocardial substrates requires catheter-based radiofrequency delivery at the root of a great artery. We studied the safety and efficacy parameters associated with catheter-based radiofrequency delivery at the root of the aorta and pulmonary artery. METHODS: Thirty-six pigs underwent in-vivo catheter-based ablation under continuous contact-force and lesion index (power, contact-force, and time) monitoring during 60-s radiofrequency delivery with an open-irrigated tip catheter. Twenty-eight animals were allocated to groups receiving 40 W (n=9), 50 W (n=10), or 60 W (n=9) radiofrequency energy, and acute (n=22) and chronic (n=6) arterial wall damage was quantified by multiphoton microscopy in ex vivo samples. Adjacent myocardial lesions were quantified in parallel samples. The remaining 8 pigs were used to validate safety and efficacy parameters. RESULTS: Acute collagen and elastin alterations were significantly associated with radiofrequency power, although chronic assessment revealed vascular wall recovery in lesions without steam pop. The main parameters associated with steam pops were median peak temperature >42°C and impedance falls >23 ohms. Unlike other parameters, lesion index values of 9.1 units (interquartile range, 8.7-9.8) were associated with the presence of adjacent myocardial lesions in both univariate ( P=0.03) and multivariate analyses ( P=0.049; odds ratio, 1.99; 95% CI, 1.02-3.98). In the validation group, lesion index values using 40 W over a range of contact-forces correlated with the size of radiofrequency lesions (R2=0.57; P=0.03), with no angiographic or histopathologic signs of coronary artery damage. CONCLUSIONS: Lesion index values obtained during 40 W radiofrequency applications reliably monitor safe and effective lesion creation at the root of the great arteries.This study was supported by the Fundación Interhospitalaria para la Investigación Cardiovascular (FIC) and the Heart Rhythm Section of the Spanish Society of Cardiology. The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Ministry of Science, Innovation and Universities and the Pro CNIC Foundation. The CNIC is a Severo Ochoa Center of Excellence (SEV-2015- 0505). This study was supported by grants from Fondo Europeo de Desarrollo Regional (CB16/11/00458) and the Spanish Ministry of Science, Innovation and Universities (SAF2016-80324-R).S
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