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Original research article
Impact of body mass index on the outcome of catheter ablation of atrial fibrillation
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  1. Benedict M Glover1,
  2. Kathryn L Hong1,
  3. Nikolaos Dagres2,
  4. Elena Arbelo3,
  5. Cécile Laroche4,
  6. Sam Riahi5,6,
  7. Matteo Bertini7,
  8. Evgeny N Mikhaylov8,
  9. Joseph Galvin9,
  10. Marek Kiliszek10,
  11. Evgeny Pokushalov11,
  12. Josef Kautzner12,
  13. Naiara Calvo13,
  14. Carina Blomström-Lundqvist14,
  15. Josep Brugada3
  16. on behalf of the ESC-EHRA Atrial Fibrillation Ablation Long-Term Registry investigators
    1. 1 Department of Cardiology, Queen’s University, Kingston, Ontario, Canada
    2. 2 Department of Electrophysiology, University Leipzig–Heart Center, Leipzig, Germany
    3. 3 Department of Cardiology, Cardiovascular Institute, Hospital Clinic de Barcelona, University of Barcelona, Barcelona, Spain
    4. 4 EURObservational Research Programme (EORP), European Society of Cardiology, Sophia Antipolis, France
    5. 5 Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark
    6. 6 Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
    7. 7 Department of Cardiology, S. Anna Hospital, University of Ferrara, Ferrara, Italy
    8. 8 Arrhythmia Department and Neuromodulation Unit, Almazov National Medical Research Centre, Saint-Petersburg, Russia
    9. 9 Cardiology Department, Mater Misericordiae University Hospital, Dublin, Ireland
    10. 10 Department of Cardiology and Internal Diseases, Military Institute of Medicine, Warsaw, Poland
    11. 11 Arrhythmia Department and Electrophysiology Laboratory, State Research Institute of Circulation Pathology, Novosibirsk, Russia
    12. 12 Institute for Clinical and Experimental Medicine, Prague, Czech Republic
    13. 13 Cardiology Department, Clinica Universidad de Navarra, Pamplona, Spain
    14. 14 Department of Medical Science and Cardiology, Uppsala University, Uppsala, Sweden
    1. Correspondence to Dr Benedict M Glover, Department of Cardiology, Queen’s University, Kingston ON K7L 3N6, Canada; benedict.glover{at}queensu.ca

    Abstract

    Objectives The association between obesity and atrial fibrillation (AF) is well-established. We aimed to evaluate the impact of index body mass index (BMI) on AF recurrence at 12 months following catheter ablation using propensity-weighted analysis. In addition, periprocedural complications and fluoroscopy details were examined to assess overall safety in relationship to increasing BMI ranges.

    Methods Baseline, periprocedural and follow-up data were collected on consecutive patients scheduled for AF ablation. There were no specific exclusion criteria. Patients were categorised according to baseline BMI in order to assess the outcomes for each category.

    Results Among 3333 patients, 728 (21.8%) were classified as normal (BMI <25.0 kg/m2), 1537 (46.1%) as overweight (BMI 25.5–29.0 kg/m2) and 1068 (32.0%) as obese (BMI ≥30.0 kg/m2). Procedural duration and radiation dose were higher for overweight and obese patients compared with those with a normal BMI (p=0.002 and p<0.001, respectively). An index BMI ≥30 kg/m2 led to a 1.2-fold increased likelihood of experiencing recurrent AF at 12-months follow-up as compared with overweight patients (HR 1.223; 95% CI 1.047 to 1.429; p=0.011), while no significant correlation was found between overweight and normal BMI groups (HR 0.954; 95% CI 0.798 to 1.140; p=0.605) and obese versus normal BMI (HR 1.16; 95% CI 0.965 to 1.412; p=0.112).

    Conclusions Patients with a baseline BMI ≥30 kg/m2 have a higher recurrence rate of AF following catheter ablation and therefore lifestyle modification to target obesity preprocedure should be considered in these patients.

    • atrial fibrillation
    • catheter ablation
    • obesity

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    Introduction

    Catheter ablation of symptomatic atrial fibrillation (AF) is recommended for patients in which medication is either ineffective or not tolerated or in keeping with patient preference for the management of both paroxysmal (Class I, Level of evidence A) and persistent (Class IIa, Level of evidence C) AF.1 Previously, catheter-based intervention has been shown to be more effective than antiarrhythmic drug (AAD) therapy as second-line therapy and compares favourably when used as first-line therapy in paroxysmal AF.2 While it is generally accepted that patients with obesity appear to gain comparable symptomatic improvements following catheter ablation3, some studies have demonstrated an increase in the rate of AF recurrences following catheter ablation4 5 with variable ranges for a body mass index (BMI) over which a reduced efficacy is seen. Other studies have demonstrated that obese patients require more than twice the effective radiation dose as compared with normal-weight patients.6

    Additionally, despite the amount of evidence linking obesity and AF, there is a paucity of data to describe the impact of BMI on periprocedural and postprocedural outcomes following catheter ablation. Previous data support a higher periprocedural complication rate for patients with obesity undergoing ablation,7 although these results remain elusive. The Atrial Fibrillation Ablation Registry was conducted by the European Heart Rhythm Association (EHRA) of the European Society of Cardiology (ESC). Data were collected to assess key features of catheter ablation for AF and the outcomes up to 12 months following the procedure. We therefore sought to determine the impact of obesity on the outcomes for catheter ablation for AF using contemporary large multicentre population data. Our primary objective was to assess the recurrence rate of AF in overweight and obese patients following catheter-based intervention. Our secondary objectives were to determine the impact of BMI at the time of catheter ablation on overall procedural safety and outcomes.

    Methods

    Primary objective

    To assess the efficacy of catheter ablation, as defined by AF recurrence at 12-months follow-up, in treating obese patients with AF.

    Secondary objective

    To assess the periprocedural complications, procedure time and radiation dose associated with catheter ablation for overweight and obese patients with AF.

    Study design and setting

    The AF Ablation Long-Term Registry is a prospective, multicentre, observational registry of consecutive patients undergoing an ablation procedure for AF at 104 centres in 27 countries within the ESC. All centres performing AF ablation in each country were invited, independent of the number of annual ablation procedures performed, and they accepted on a voluntary basis. National coordinators were responsible for obtaining approval by the national and/or local institutional review board, depending on regulations in each country.

    Study participants

    Centres were asked to enrol all consecutive patients (up to a maximum of 50) scheduled for AF ablation procedure between April 2012 and April 2015, and to follow them up for 12 months. Both first and repeat ablations were included. There were no specific exclusion criteria and all patients signed an informed consent before collection of any data.

    Data collection

    All centres were asked to complete a one-time site questionnaire describing the type and size of the centre, reference area population, facilities and the number of invasive procedures performed annually. An electronic case report form was developed to capture the following information for each enrolled patient:

    • Enrolment data: demographics, risk factors and comorbidities; precipitating factors; type of AF, symptoms, pharmacological and non-pharmacological treatments; prior AF management; invasive/non-invasive diagnostic procedures; ECG and echocardiographic data; indications for AF ablation.

    • Procedural data: laboratory setting, catheters used, type of energy, imaging techniques, anaesthesia, anticoagulation used, ablation strategy, X-ray exposure parameters, outcome parameters used to define procedural success and complications.

    • Postprocedural data: hospital stay duration, medication after the procedure, complications.

    • 12-month follow-up data: symptom status, clinical evaluations and admissions, other diagnostic procedures, follow-up ECG findings, status regarding arrhythmia recurrence and type of recurrence (if any), adverse events, medication.

    Centres planned their follow-up according to their usual clinical practice. The database was set up at the European Heart House of the ESC (France). In total, 23 out of 104 (22.1%) participating centres, across 14 countries, were randomly subject to on-site monitoring. In these centres, consecutiveness of the inclusion of patients and accuracy of the recorded data in the database compared with source data were verified.

    Definitions

    AF was defined as paroxysmal, persistent or long-standing persistent AF following the recommendations of the 2016 ESC guidelines.1 At inclusion, BMI was categorised according to the WHO’s definitions for normal (BMI 18.5–24.99 kg/m2), overweight (BMI 25.0–29.9 kg/m2) and obese (BMI ≥30 kg/m2) BMI ranges.8 The severity of patient-reported symptoms during AF was classified using the EHRA Score.9 Arrhythmia recurrence was defined as an electrocardiographically documented episode of AF or atrial arrhythmia including AF or atrial flutter (AFL) lasting at least 30 s, but excluding cavotricuspid isthmus-dependent flutter. A 3-month blanking period was employed postablation. One-year success was defined as freedom from symptomatic AF in the absence of antiarrhythmic therapy as assessed from the end of the 3-month blanking period to 12 months following the ablation procedure.10 Recurrences of any atrial arrhythmia within the first 3 months after the procedure were classified as early recurrences and were not considered as failure.

    Statistical analysis

    All patients with an unclassified type of AF and who did not undergo ablation procedure were excluded from the analysis. The 12-month follow-up data of patients enrolled in the in-hospital phase were used for the analyses. Continuous variables were reported as median and IQR. Categorical variables were reported as percentages. Group comparisons were made and a weighted p value <0.05 was considered statistically significant. To reduce the effect of potential confounding bias in an observational study, we also performed rigorous adjustment for differences in patient baseline characteristics using propensity score methods. The underlying propensity model covariates included age (continuous); binary indicators for sex and in-hospital diagnosis of AF; hypertension; diabetes; heart failure; administration of beta-blockers; amiodarone; flecainide; propafenone; dronedarone; quinidine and other antiarrhythmic medication, and CHA2DS2-VASc scores included as continuous variables. Analyses of AF recurrence at 12 months were then performed using Cox proportional hazards models, applying the propensity weights for the adjusted results. Both the unadjusted and the propensity-weighted HR and corresponding 95% CI are presented.

    All analyses were performed using SAS statistical software version 9.3 (SAS Institute, Cary, North Carolina, USA). In order to control for potential selection bias, Wald’s confidence limits for an HR were used. The confidence limits for the HR used estimated covariance matrix.

    Results

    Patient population

    Between April 2012 and April 2015, 3630 patients were enrolled in the registry. Participating centres included 64 university hospitals, 23 community/district hospitals and 17 private clinics, with a median number of 585.0 hospital beds (IQR 270.0–978.0). The hospital reference area included a median number of 40 000 inhabitants (IQR 18 544–1 60 000). The median annual number of AF ablations in the participating centres was 113.0 (IQR 58.0–250.0), with 52 centres performing >100 ablations/year and 17 centres <50 ablations/year.

    Baseline clinical characteristics by BMI

    Between April 2012 and April 2015, 3333 patients were enrolled into the registry. Baseline characteristics are shown in table 1. Within this cohort, 21.8% study patients had a BMI <25.0 kg/m2 (mean BMI 23.1±1.6), 46.1% were overweight (mean BMI 27.3±1.4) and 32.0% of patients were considered obese with a BMI>30 kg/m2 (mean BMI 33.6±3.3). Within the obese category, 8.3% of patients had a BMI>35 kg/m2. A significantly higher incidence of diabetes mellitus (p<0.001), hypertension (p<0.001), hypercholesterolaemia (p<0.001) and sleep apnoea (p=0.005) was observed in overweight and obese patients, with the highest proportion of these comorbid conditions observed in those with a BMI>30 kg/m2.

    Table 1

    Baseline characteristics of all patients grouped according to BMI: normal BMI, overweight and obese

    Twelve-month follow-up

    Complete data for the assessment of 12-month ablation outcomes were available in 2948 patients (87.6%). Twelve-month follow-up evaluations were conducted at a median of 12.4 months (IQR 11.9–13.4) by an in-person clinical visit (52.8%), telephone discussion with the patient (44.2%) or contact with the patient’s general practitioner (3.0%). Diagnostic methods for the detection of arrhythmia recurrences included periodical clinical visits with ECG (59.7%) and Holter monitoring (64.4%). Transtelephonic monitoring and implanted monitoring systems were only used in 3.5% of cases. A repeat ablation procedure for recurrent AF was undertaken in a total of 636 patients, of which 127 (17.4%), 309 (20.1%) and 200 (18.7%) were classified with normal, overweight and obese BMI indexes, respectively.

    Periprocedural complications

    Procedural details associated with each BMI category are displayed in table 2. The incidence of periprocedural complications was similar across all three groups. However, effective radiation dose and overall procedural duration were significantly higher for overweight and obese patients compared with those with a normal BMI (p=0.002 and p<0.001, respectively).

    Table 2

    Procedural details and complications stratified by BMI category

    Ablation strategies and outcome

    The majority of patients underwent a first-time AF ablation procedure (78.3%) with 19.1% requiring a redo procedure for AF and 2.5% for other atrial arrhythmias. There was no significant difference between BMI groups with respect to the proportion of patients undergoing first-time, redo AF or redo atrial tachycardia ablations.

    The median procedure duration was significantly higher in overweight (154.0 min, IQR 120.0–200.0) and obese (170.0 min, IQR 120.0–202.5) patients as compared with those with a normal BMI (150.0 min, IQR 115.0–195.0) (p=0.017). Notably, BMI range did not influence the ablation strategies chosen for patients with paroxysmal AF undergoing pulmonary vein isolation (PVI) (table 2). PVI was attempted in 96.3% of all patients, with bidirectional block achieved in 76.5% of patients. For those treated with PVI for paroxysmal AF, linear lesions verification of conduction block was demonstrated in 40.7% of patients who underwent a roof line, 17.3% of patients who underwent a mitral isthmus line, 82.4% of patients who underwent a linear lesion of the posterior wall and 75.0% of patients with any other left atrial linear ablation. There was no significant difference between BMI groups for any of these parameters.

    When adverse events of catheter ablation were compared between individuals with a BMI <25 kg/m2 and those with overweight and obese BMI ranges, there was no significant correlation detected between increasing BMI values and the incidence of procedural complications including groin haematoma, pericarditis, cardiac perforation and phrenic nerve palsy.

    BMI as a predictor of AF recurrence

    Before adjustment, obese patients had a 37.7% recurrence of AF at 12-month follow-up compared with 32.3% and 32.4% for normal and overweight patients, respectively. There were 1001 patients (34.1%) with a recurrence of AF, of whom 847 (28.8%) had AF and 162 (5.5%) had atypical AFL.

    Table 3 shows the adjusted HRs for AF recurrence at 12-month follow-up following propensity score weighting. Multivariate adjustment for cofactors demonstrated that index BMI had a significant effect on AF recurrence when obese and overweight patients were compared (HR 1.223; 95% CI 1.047 to 1.429; p=0.011). Weighted Cox regression comparisons demonstrated that obese patients are 1.2 times more likely to experience a recurrent AF episode at 12 months than their overweight counterparts. No significant difference was observed between obese patients and those with a normal index BMI.

    Table 3

    Factors which may be associated with AF recurrence in patients undergoing catheter ablation based on multivariate Cox regression survival models after adjustment

    Following adjustment for selected covariates, the type of AF was independently correlated with AF recurrence, specifically with respect to paroxysmal versus long-standing persistent (HR 0.806; 95% CI 0.696 to 0.934, p=0.004). Additionally, the achievement of entrance and exit block (HR 0.817; 95% CI 0.701 to 0.954, p=0.010) and the postoperative administration of AAD therapy (HR 1.200; 95% CI 1.035 to 1.391, p=0.016) were significantly correlated with AF recurrence at 12-month follow-up.

    Discussion

    Main findings

    In the current study, almost half of all patients in this registry were overweight and one-third were classified as obese. Our principle findings are such that in a large clinical registry of patients undergoing catheter ablation, obesity was independently associated with AF recurrence at 12 months when compared with being overweight at baseline. In keeping with previous studies,11 12 an increase in BMI was associated with increased radiation exposure, though not with an increase in periprocedural complications. There was also a high prevalence of hypertension, diabetes mellitus, structural heart disease and sleep apnoea in patients with an increased BMI at the time of catheter ablation. These conditions are important contributors to AF development and maintenance. Additional factors associated with postprocedural success for patients across all BMI ranges included the presence of paroxysmal rather than persistent AF and a younger age. This is concordant with prior data associating the presence of persistent AF and age as independent factors associated with long-term AF recurrence.13

    AF ablation outcomes and obesity

    Although evidence supports the use of catheter-based ablation for the treatment of patients with arrhythmia, the effect of BMI on AF ablation outcomes remains unclear. To date, studies have demonstrated inconclusive results with respect to procedural outcomes and failure. A meta-analysis involving 5864 individuals demonstrated a 13% greater excess risk of AF recurrence postablation for every 5-unit increase in BMI.13 Other studies have demonstrated an increase in complications among underweight and the morbidly obese, with a paradoxical decrease in complication rates among the moderately obese.14 While numerous reports have also found limited correlation between obesity and ablation complications,15 a recently published study of overweight, obese and morbidly obese patients undergoing catheter ablation revealed a lower success for paroxysmal AF when the BMI was ≥40 kg/m2 and for persistent AF when the BMI was ≥35 kg/m2.5 In this study, 15.3% of patients had a BMI ≥35 kg/m2 compared with only 8.3% in our current study. Although we cannot exclude a selection bias, it is likely that this reflects a European population compared with a North American population where obesity is commonplace.

    Likewise, in the largest study of patients undergoing segmental or circumferential PVI, AF was eliminated in 74%, 73% and 69% of lean, overweight and obese patients, respectively. Higher rates of adverse postprocedural events were also observed in higher BMI groups.16 We observed similar associations in our study cohort as AF recurrence rates at follow-up were significantly higher in obese patients when compared with patients with an overweight index BMI. Multivariate weighted analysis validated index BMI as an independent correlate of AF recurrence at 12-month follow-up, with a greater likelihood of recurrence in obese versus overweight patients. This suggests that BMI coupled with other concomitant conditions associated with obesity, such as obstructive sleep apnoea, may be responsible for poorer outcomes following catheter ablation. The fact that there was no significant difference in recurrence rates in obese versus normal BMI suggests that the normal group included those with a low BMI who may have a higher incidence of recurrence and there may be a BMI range closer to what is defined as overweight who have a lower recurrence rate.

    Concerning periprocedural complications, no differences in mean fluoroscopy time were observed among BMI groups, whereas radiation exposure was significantly higher in obese and overweight patients as compared with patients with a normal index BMI. This is concordant with previous evidence demonstrating that the amount of radiation exposure for obese patients is more than twice the effective radiation dose than that for patients with a normal BMI.6 Finally, no significant differences in major complications were observed between the various BMI groups undergoing catheter ablation. These results were validated by the large majority of patients achieving freedom from AF without antiarrhythmic agents.

    Our results showed that significantly more patients with AF recurrence at 12-month follow-up received AAD therapy following catheter ablation. In a large prospective registry of patients undergoing PVI, the reintroduction of AADs for AF recurrence after ablation resulted in 5-year arrhythmia-free success in up to 70% of 125 patients with multiple failed procedures.17

    Identifying certain patient characteristics that predict the maintenance of sinus rhythm following catheter ablation is critical in limiting cardiovascular complications and associated healthcare costs. Since a BMI classification ≥30 kg/m2 is correlated with a 1.2-fold increased likelihood of AF recurrence after catheter ablation when compared with overweight patients, the clinical approaches to management of elevated BMI in this population of patients begets further attention.

    Obesity is one of the major stimuli for metabolic syndrome and cardiac remodelling, both of which contribute to the propagation and maintenance of AF. In light of suboptimal outcomes, emerging focus has been placed on enhancing the likelihood of success of current surgical treatment or favourably modifying the underlying AF substrate.18 Recent evidence highly suggests that maintained weight loss could be a critical component in reducing AF recurrence rates after index catheter ablation in obese patients.19

    Limitations

    This registry was based on voluntary participation of all centres. Furthermore, the centres were selected proportionately to the size of the population of the participating countries in order to favour representativeness of the cohort. However, not all contacted centres contributed to the registry in its pilot phase. Conversely, the high rate of response (73% of contacted centres) minimises the risk of an inclusion bias. It should also be highlighted that only medium to high expertise centres were approached and selected. Yet, the participants were followed in national registries with very limited loss to follow-up. The interpretation of 12-month outcomes following catheter ablation is also limited by potential uncontrolled confounders and the lack of homogeneous arrhythmia monitoring. The number of clinical visits and cardiac rhythm monitoring limits the extent of meaningful comparisons between centres.

    Missing data did occur in our registry due the fact that it is an observational study and the investigator was not obliged to answer to all questions. Missing data were not included in the analysis of the data.

    The ESC-EHRA Long-Term Atrial Fibrillation Ablation Registry still remains the largest international prospective registry evaluating the impact of BMI on arrhythmia recurrences and outcomes following catheter ablation. Therefore, while several noteworthy correlations can be drawn from these results, future studies should focus on ameliorating bias associated with patient selection and extending the clinical follow-up period beyond 12 months.

    Conclusion

    Having an elevated BMI ≥30 kg/m2 is independently associated with AF recurrence at 12-month follow-up when compared with having an overweight BMI classification at the time of catheter ablation. Although index BMI is associated with higher effective radiation doses during the procedure, it is not associated with increased rates of procedural complications.

    Key messages

    What is already known on this subject?

    • To date, results have been variable when assessing the potential relationship between an elevated body mass index (BMI) and the outcome from catheter ablation for atrial fibrillation (AF). A recently published single centre retrospective study of overweight, obese and morbidly obese patients undergoing catheter ablation revealed a lower success for paroxysmal AF when the BMI was ≥40 kg/m2 and for persistent AF when the BMI was ≥35 kg/m2.

    What might this study add?

    • This is the largest multicentre registry conducted to date examining the association between BMI and the safety and efficacy of radiofrequency catheter ablation for AF. This study shows that obesity increases the recurrence rate of AF following catheter ablation when compared with patients who were overweight. Obesity also increases procedural duration and radiation exposure but not periprocedural complication rates.

    How might this impact on clinical practice?

    • Catheter ablation should be carefully considered in the treatment of obese patients with AF. Intensive weight loss and lifestyle modification should be recommended to patients in this BMI category prior to performing a catheter ablation.

    Supplemental material

    Acknowledgments

    Registry Executive Committee and Steering Committee of the EURObservational Research Programme (EORP). Data collection was conducted by the EORP department from the ESC by Elin Folkesson Lefrancq as project officer, and Viviane Missiamenou as data manager. Statistical analyses were performed by Cécile Laroche. Overall activities were coordinated and supervised by Dr Aldo P. Maggioni (EORP Scientific Coordinator). All investigators are listed in the supplementary appendix 1.

    References

    Footnotes

    • Contributors All coauthors contributed equally to this publication.

    • Funding Since the start of EORP, the following companies have supported the programme: Abbott Vascular International (2011–2014), Amgen Cardiovascular (2009–2018), AstraZeneca (2014–2017), Bayer AG (2009–2018), Boehringer Ingelheim (2009–2019), Boston Scientific (2009–2012), The Bristol Myers Squibb and Pfizer Alliance (2011–2019), Daiichi Sankyo Europe (2011–2020), The Alliance Daiichi Sankyo Europe and Eli Lilly and Company (2014–2017), Edwards (2016–2019), Gedeon Richter (2014–2016), Menarini International Operation (2009–2012), MSD-Merck & Co. (2011–2014), Novartis Pharma AG (2014–2017), ResMed (2014–2016), Sanofi (2009–2011), SERVIER (2009–2018).

    • Competing interests ENM reports consultant fees from Biosense Webster, speaker’s bureau: Biosense Webster, Boehringer Ingelheim and Medtronic; MK reports teaching contract with Johnson & Jonhnson and with Abbott (formerly St. Jude Medical); ND reports grants from Biotronik, Abbott (formerly St Jude Medical) and Boston Scientific to the institution outside the submitted work.

    • Patient consent Not required.

    • Ethics approval All institutions who took part in this registry obtained approval from their individual REBs.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Collaborators Committees and Investigators Executive Committee: Nikolaos Dagres, Josep Brugada, Elena Arbelo,Luigi Tavazzi, Carina Blomström Lundqvist, Evgeny Pokushalov, Josef Kautzner, Aldo P. Maggioni. Steering Committee (National Coordinators): Clemens Steinwender, Alexandr Chasnoits, Georges Mairesse, Tosho Balabanski, Josef Kautzner, Sam Riahi, Mostafa Nawar, Mervat Abul El Maaty, Pekka Raatikainen, Frederic Anselme, Thorsten Lewalter, Turgut Brodherr, Michalis Efremidis, Laszlo Geller, Ben Glover, Roy Beinart,Michael Glikson, Fiorenzo Gaita, Roin Rekvava, Oskars Kalejs, SergeTrines, Zbigniew Kalarus, Mario Martins Oliveira, Pedro Adragao, Radu Ciudin, Evgeny Mikhaylov, Matjaz Sinkovec, Julian Perez Villacastin,Carina Blomström-Lundqvist, Oleg Sychov, Paul Roberts. Investigators: Austria, Graz D Daniel Scherr; Martin Manninger;Bernadette Mastnak; Innsbruck Otamr Pachinger; Florian Hintringer; Markus Stühlinger; Linz Clemens Steinwender;Belgium, Yvoir Olivier Xhaet; Bulgaria, Sofia Tchavdar Shalganov; Milko Stoyanov; Mihail Protich; Sofia Vassil Traykov; Daniel Marchov; Genadi Kaninski; BELARUS Minsk Alexandr Chasnoits; Czech Republic, Prague Robert Cihak;Hradec Kralove Ludek Haman; Germany, Frankfurt Boris Schmidt; K.R. Julian Chun; Laura Perrotta; Stefano Bordignon;Hamburg Roland Tilz; Hamburg Stephan Willems; Leipzig Gerhard Hindricks; München Turgut Brodherr; Ilia S.Koutsouraki; Thorsten Lewalter; Denmark, Aalborg Sam Riahi; Bodil Ginnerup Sørensen; Egypt, Cairo Wagdi Galal; Cairo Amir Abdel Wahab; Cairo S Sherif Mokhtar; Spain, Alicante Ignacio Gil Ortega; Juan Gabriel Martinez Martinez; Badajoz Manuel Doblado Calatrava; Barcelona Roger Villuendas Sabate; Barcelona Lluis Mont Girbau;Bilbao Maria Fe Arcocha; Larraitz Gaztañaga; Estibaliz Zamarreño; Granada Miguel Álvarez; Rosa Macías; LasPalmas de Gran Canaria Federico Segura Villalobos; Juan Carlos Rodríguez Pérez; Madrid Nicasio Perez Castellano; Victoria Cañadas; Juan J Gonzalez Ferrer; David Filgueiras; Madrid Jose Manuel Rubio Campal; Pepa Sánchez-Borque; Juan Benezet-Mazuecos; Madrid Jorge Toquero Ramos; FernandezLozano; Victor Castro Urda; Malaga Alberto Barrera Cordero;Carmen Medina Palomo; Amalio Ruiz-Salas; Javier Alzueta; Madrid Rafael Peinado; David Filqueiras-Rama; Alfonso Gómez Gallanti;Daniel Garófalo; Pamplona Naiara Calvo; Santander JuanJ ose Olalla Antolin; Sevilla Alonso Pedrote; Eduardo Arana-Rueda; Lorena García-Riesco; Finland, Turku Juha Lund; Tampere Pekka Raatikainen; France, Grenoble Pascal Defaye; Peggy Jacon; Sandrine Venier; Florian Dugenet; SaintDenis Olivier Piot; Xavier Copie; Olivier Paziaud; Antoine Lepillier; Saint Etienne Antoine Da Costa; Cécile Romeyer-Bouchard; Toulouse Serge Boveda; Jean-Paul Albenque;Nicolas Combes; Stéphane Combes Marseille AngeFerracci; André Pisapia; Greece, Athens Demosthenes Katritsis; Athens Konstantinos Letsas; Kostas Vlachos; Louiza Lioni; Thessaloniki Vassilios P. Vassilikos; Hungary, Budapest Laszlo Geller, Nándor Szegedi; Gábor Széplaki;Tamás Tahin; Debrecen Zoltan Csanadi; Gabor Sandorfi;Alexandra Kiss; Edina Nagy-Balo; Szeged Laszlo Saghy; Ireland, Dublin Benedict M. Glover; Joseph Galvin; Edward Keelan; Israel, Ramat Roy Beinart; Michael Glikson; Eyal Nof; Italy, Acquaviva delle Fonti Massimo Grimaldi; Federico Quadrini; Antonio Di Monaco; Federica Troisi; Castellanza Massimo Tritto; Elvira Renzullo; Antonio Sanzo; Domenico Zagari;Cotignola Carlo Pappone; Crema Pietro Maria Giovanni Agricola; Milano Paolo Della Bella; Napoli Giuseppe Stabile; Assunta Iuliano; Pisa Maria Grazia Bongiorni; Roma Leonardo Calo; Ermenegildo de Ruvo; Luigi Sciarra; Torino Matteo Anselmino; Fiorenzo Gaita; Federico Ferraris; Varese Roberto De Ponti; Raffaella Marazzi; Lorenzo A. Doni; Kazakhstan, Almaty Roin Rekvava; Anna Kim; Latvia, Riga Oskars Kalejs; Netherlands, Breda Sander Molhoek;Groningen Isabelle Van Gelder; Michiel Rienstra; Leiden Serge Trines; Marieke G. Compier; Maastricht Laurent Pison; Harry J. Crijns; Kevin Vernooy; Justin Luermans; Rotterdam LucJordaens; Natasja de Groot; Tamas Szili-Torok; Rohit Bhagwandien;Zwolle Arif Elvan; Thomas Buist; Pim Gal; Poland, Lodz Andrzej Lubinski; Gdansk Tomasz Krolak; Katowice Seweryn Nowak, Katarzyna Mizia-Stec; Anna Maria Wnuk-Wojnar;Krakow Jacek Lelakowski; Szczecin Jaroslaw Kazmierczak;Warszawa Piotr Kulakowski; Jakub Baran; Warszawa Grzegorz Opolski; Marek Kiliszek; Piotr Lodziński; Sonia Borodzicz;Paweł Balsam; Poznan Krzysztof Blaszyk; Warszawa Mariusz Pytkowski; Rafal Kuteszko; Jan Ciszewski; Wroclaw Artur Fuglewicz; Zabrze Zbigniew Kalarus; Aleksandra Woźniak;Karolina Adamczyk; Portugal, Carnaxide Lisboa Pedro Adragao; Lisboa Pedro Cunha; Romania, Iasi Mihaela Grecu; Grigore Tinica; Cluj-Napoca Lucian Muresan; Radu Rosu; Russian Federation, Kemerovo Egor Khomenko;Khanty-Mansiysk Nikita Scharikov; Krasnoyarsk Dmitry Zamanov; Krasnoyarsk Evgenii Kropotkin; Novosibirsk Evgeny Pokushalov; Alexander Romanov; Sevda Bayramova;Saint-Petersburg Evgeny N. Mikhaylov; Dmitry S. Lebedev; Anna V. Patsouk; Saint-Petersburg Sergey Yashin; Saint-Petersburg Dmitry Kryzhanovskiy; Saransk Vyacheslav Bazayev; Surgut Denis Morgunov; Ilya Silin; Tomsk Sergey Popov; Tyumen Vadim Kuznetsov; Swedon, Linköping Anders Jönsson;Lund Pyotr Platonov; Fredrik Holmqvist; Ole Kongstad; ShiwenYuan; Umeå Niklas Höglund; Uppsala Helena Malmborg;David Mörtsell; Slovenia, Ljubljana Matjaz Sinkovec;Andrej Pernat; United Kingdom, Southampton John Morgan; Paul Roberts; Elizabeth F. Greenwood; Lisa L. Fletcher; Ukraine, Donetsk Tetiana Kravchenko; Kiev Alexander Doronin; Maryna Meshkova; Odessa Iurii Karpenko; Alex Goryatchiy; Anna Abramova.

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