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ABSTRACTRecent studies demonstrated that the patientswith a positive history of AF are still at risk of thromboembolic events,despite restoration of the sinus rhythm. The primary objective of this study isto identify new imaging-derived biomarkers provided by modern imagingtechnologies, such as Cardiac Computed Tomography Angiography, DelayedEnhancement MR Imaging or Speckle Tracking Echocardiography, as well ashaematological biomarkers, associated with the risk of intracavitary thrombosisin patients with AF, in order to identify the imaging-derived characteristicsassociated with an increased risk of cardio-embolic events.

Imaging datacollected will be post-processed using advanced techniques of computationalmodelling, in order to fully characterise the degree of structural remodellingand the amount of atrial fibrosis. The primary end point of the study isrepresented by the rate of thromboembolic events. Besides this, the rate ofcardiovascular death, the rate of MACE and the rate of the AF recurrence willbe determined.   Key words: atrial fibrillation, atrial fibrosis, inflammation, coagulation,stroke, thrombosis, magnetic resonance, ablation        Atrial fibrillation (AF) is the most commonsustained arrhythmia that can appear in patients with or without cardiaccomorbidities.1  Theincidences of AF is decreasing, however its  prevalence remained constant, one third ofadult population being affected by this devastating disease.

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2,3 Therisk of stroke in patients with AF decreased in the last few years, howeverthis was not accompanied by a decrease in mortality risk.2 Recentstudies have demonstrated that patients with a positive history of AF are stillat risk of thromboembolic events, despite sinus rhythm restoration, thereforethe blood stagnation in the atria is not the only contributor to thedevelopment of intracavitary thrombus.4,5,6 In the ASSERT study only8% of patients with stroke or systemic embolism had atrial fibrillation in the last30 days prior to the embolic event.7 Along with atrial stasis,several mechanisms are involved in pathogenesis of atrial thrombosis in AF,such as atrial fibrosis, epicardial adiposity8,9, localinflammation, hypercoagulability10, endothelial dysfunction,structural pathologies, neurohumoral and genetics factors.4 It hasbeen described in the literature that atrial fibrosis significantly increasethe incidence of stroke and that the degree of atrial fibrosis is significantlyhigher in patients with stroke17. Atrial fibrosis plays an important role in theappearance, maintenance and recurrence of AF and in the effectiveness ofcatheter ablation.

At the same time, atrial fibrosis is a consequence of AF,therefore producing a vicious circle in which “AF begets AF”.11 Atrialfibrosis is caused by: atrial fibrillation, rapid atrial myocyte depolarization13,inflammation, mechanical stretch, atrial distension13, cardiacinjury11, electrical derangements11, accumulation ofintracellular Ca ions, autocrine and paracrine mediators12, oxidativestress14, diabetes, obesity15,  hypercoagulability (activation of PAR1receptors by thrombin)16, genetic factors and systemic autoimmunedisease. Cardiovascular comorbidities and age (<75) did not appear tocorrelate with the grade of atrial fibrosis17. Atrial fibrosis canbe noninvasively assessed and quantified using delayed enhancement (DE) MRI18.Inflammation can be a cause or a consequence ofatrial fibrillation.

A correlation between circulation level of inflammation biomarkers,like: C-reactive protein (CRP), cytokines, interleukin, complement andactivation state of leukocytes and atrial fibrillation has been documented.19,20The link between inflammation and AF is represented by atrial fibrosis.Inflammation increases the level of pro-inflammation cytokines in the blood,such as IL 1, 2, 6, 8, CRP, tumour necrosis factor ?, monocyte, chemoattractantprotein 1, which stimulate endothelial and other cells19. Anindependent correlation between the level of inflammation biomarkers and AF wasdescribed, the level of CRP and IL 6 correlating with structural remodelling (LAenlargement) and with impaired LA function.21 Furthermore, the levelof CRP is an independent predictor of AF, and this level is higher in patientswith persistent AF19. Inflammation also has an important role inthrombus formation and ischemic events, this correlation being mediated byendothelial injury, platelet activation, tissue factors, Von Willebrand factor,fibrinogen, P-selectin.22,23  Therefore,CRP can become a useful biomarker to assess the risk of thromboembolic eventsin patients with AF.

12  Pericardial adipose tissue is a highly metabolicallyactive tissue that can predispose to AF, involving inflammatory cytokines andoxidative stress. Furthermore, it has a quantitatively association with AFseverity.24,25AF produces a hypercoagulable state. Thrombincan initiate a pro-fibrotic, pro-inflammatory and pro-hypertrophic state viastimulation of protease activated receptors.26 New anticoagulanttherapy can inhibit PAR1 activation and through it can prevent the developmentof a substrate for atrial fibrillation.27 Figure 1. Causes and consequence of atrialfibrillationA CHADS2 and CHA2DS2-VASCscore of 0 may be insufficient to avoid in totality thromboembolism events inpatients with AF.

28 More information about thromboembolic risk canbe obtain by determination of the level of troponin I, CRP, NT-pro BNP.29 However,even these haematological biomarkers fail to fully predict the risk of thromboembolism.28Novel studies demonstrated that AF and atrial fibrosis are independentlyrisk factors for stroke, even after the sinus rhythm was restored. A IV degree (>75%)of atrial fibrosis can have a huge impact on the risk of STROKE, and may be includedin the new stroke prediction index.13POTENTIALCONTRIBUTIONS OF THE STUDY The phenomenon of atrial fibrosis as apathogenic mechanism of atrial fibrillation has been described in theliterature, however its role in atrial thrombosis has not been elucidated sofar. The originality of the present study consists inbuilding an algorithm of investigation by which high-quality imaging data willbe correlated with haematological markers of inflammation, platelet aggregationand clotting. A model of complex investigations will be developed to identifypatients with increased thromboembolic risk and thus a large number ofcardio-embolic events will be prevented.    STUDY HYPOTHESISThe degree of atrial fibrosis and the level ofinflammatory markers in the blood can predict the risk of thromboembolic eventsin patients with atrial fibrillation.

STUDY OBJECTIVESPrimary objectiveThe primary objective of this study is to identify newimaging-derived biomarkers provided by modern imaging technologies, such as CardiacComputed Tomography Angiography (CCTA), Delayed Enhancement MR Imaging (DE-MRI)or Speckle Tracking Echocardiography (STE), as well as haematological biomarkers,associated with the risk of intracavitary thrombosis in patients with AF, inorder to identify the characteristics associated with an increased risk ofcardio-embolic events.Secondary objectivesThis study also aims to evaluate the correlationbetween structural remodelling of the left and right atria and the amount ofmyocardial fibrosis of the left atrium by DE-MRI. We will determine thefunction of LA with EST, and will be performed automated quantification ofatrial fibrosis. At the same time, volumetric assessment of epicardialadipose tissue will be performed in each patient undergoing CCTA and MRI. Besides this we will also look for identification of haematologicalbiomarkers of predisposition for thrombosis and platelet aggregation. We willalso evaluate the differences in these biomarkers in blood samples collected froma peripheral line and from the left atrium during interventional ablationprocedures.

Another important part of this study is to analyse the electrical remodellingof the atrium by three-dimensional electro-anatomic mapping system and tocorrelate these findings with the rate of thrombosis and with the level oflocal haematological markers. We will determine the rate of recurrence of AF, therate of thromboembolic events and the rate of MACE, in every 3 months duringthe follow up. METHODSStudy designThis is a prospective, descriptive, cohort study andis composed of two major parts. In the first part of the study, laboratorytests and necessary interventions will be performed. The second part is represented by the follow-up of patientsfor 2 years and will contain the analysis of the data obtained during the firstpart of study. Before startingthe study all patients will sign an informed consent.

After evaluatingeligibility for the screening process, patients who meet the inclusion criteriawithout exclusion criteria will be included in the study. All study proceduresare in line with the principles in the Declaration of Helsinki. The studypopulation will be comprised by minimal 50 patients. Each patient included instudy need to be eligible to catheter ablation.

The study population based onthe degree of atrial remodelling (size, wall thickness and function) assessedwith CCTA, will be divided in 2 groups. Patients with a mild atrial remodellingwill be enrolled in the first group, while the second group will containpatients with moderate or severe atrial remodelling.   Personal data of patients will be collected atthe start of study. Anamnesis, physical examination, ECG, evaluation of riskfactors and comorbidities will be performed in each case. Lab tests willinclude the level of leukocytes, hs-CRP, and the erythrocyte sedimentationrate. In each case we will exclude the presence of intracavitary thrombus usingtransthoracic and transesophageal echocardiography. The structure of atrial anatomyand the level of epicardial adipose tissue will be examined with echocardiographyand CCTA. EST will be used for the assessment of cardiac function.

Electrophysiologicalstudy will be performed in each patient included in the study and the imagesobtained with CCTA will be merged with the electrical map of the heart. After trans-septalpuncture, but before pulmonary veins isolation, we will harvest blood from theleft atrium to determine the level of pro-inflammatory and pro-coagulationfactors. We will quantify the level of hs-CRP, IL-1,6, fibrinogen, tumournecrosis factor, the erythrocyte sedimentation rate, INR, PT, PT%. At the sametime, we will harvest blood again to determine these factors but this time fromthe peripheral blood.

The grade of atrial fibrosis will be assessedwith DE-MRI. Upon discharge, we will re-perform a new ECG to confirm thesuccess of cardioversion. All patients without atrial fibrillation at dischargewill be followed for 2 years. Patients will be recalled for periodicinvestigations (anamnesis, physical examination, ECG, echocardiography) in the3rd, 12th and 24th month and contacted by phone in the6th and 9th month after cardioversion. At the last session (month 24), magneticresonance, EST will be performed to assess the progression of atrial fibrosisand the changes in atrial function.INCLUSION AND EXCLUSION CRITERIAPatients are eligible if they had non-valvularparoxysmal or persistent AF. All patients need to be adults and to be able toread and understand the informed consent document.

Also, only patients who havesigned informed consent will be enrolled in the study.The study cannot be realized without imaging technicsin consequence patients who present contraindications to imaging tests will beexcluded from the study. These conditions are represented by claustrophobia,hypersensitivity to contrast agents (gadolinium, CT contrast agents),pregnancy, acute or chronic kidney failure (Stage 3a, 3b, 4, 5), anddecompensated cirrhosis.

Presence of metallic foreign bodies, cardiac rhythmdevice are contraindications for magnetic resonance imaging and therefore for thestudy. Patients receiving any drug that may affect thelevel of haematological markers will be excluded from the study. Terminally illpatients and those who may not adhere or may not complete follow up or do nothave reliable information will be also excluded from the study.END-POINTSThe primary end point of the study is represented bythe rate of thromboembolic events. Besides this, the rate of cardiovascular death,the rate of MACE and the rate of the AF recurrence will be determined.DATE STORAGE AND ANALYSES A dedicated database with the patient’s data andimaging tests will be created and handled with the utmost accuracy andconfidentiality, only the staff involved in the research having access to thisdatabase. Imaging data stored in the database will undergo complex post-processingin the computational medicine laboratory, using computational simulations andadvanced imaging techniques processing.

The merging of images obtained with CTscanner with the electro anatomical map of the left atrium will be performed inreal time during the catheter ablation procedure. The quantification of the leftatrium fibrosis will be performed by a radiologist.The statistical analysis will be performed in themedical statistics laboratory of the Center of Advanced Research in Multimodal CardiacImaging of S.

C. Cardio Med SRL.CONCLUSIONIn AF undergoing complex ablation procedures,the rate of recurrence and the cardioversion succession rate are influenced byseveral intra and extra-cardiac factors. Novel studies have shown that inaddition to atrial stasis, many factors are involved in the appearance ofintra-atrial thrombosis. Patients with positive history of atrial fibrillationhave also an increased risk for stroke than those who never had atrialfibrillation. It is known that atrial fibrosis, inflammation andhypercoagubility have an important role in the appearance of intracavitarythrombosis but the exact mechanisms involved in this correlation has not been elucidatedso far. This study will characterize new imaging-derived biomarkers tocorrelate the structural remodeling and fibrosis of the left and right atrium withthe hematological parameters reflecting a high coagulability in the atria, inorder identify new tools for predicting the risk of thromboembolic events inthis group of patients.

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