ABSTRACT

Recent studies demonstrated that the patients
with a positive history of AF are still at risk of thromboembolic events,
despite restoration of the sinus rhythm. The primary objective of this study is
to identify new imaging-derived biomarkers provided by modern imaging
technologies, such as Cardiac Computed Tomography Angiography, Delayed
Enhancement MR Imaging or Speckle Tracking Echocardiography, as well as
haematological biomarkers, associated with the risk of intracavitary thrombosis
in patients with AF, in order to identify the imaging-derived characteristics
associated with an increased risk of cardio-embolic events. Imaging data
collected will be post-processed using advanced techniques of computational
modelling, in order to fully characterise the degree of structural remodelling
and the amount of atrial fibrosis. The primary end point of the study is
represented by the 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.

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Key words: atrial fibrillation, atrial fibrosis, inflammation, coagulation,
stroke, thrombosis, magnetic resonance, ablation

 

 

 

 

 

 

 

 

Atrial fibrillation (AF) is the most common
sustained arrhythmia that can appear in patients with or without cardiac
comorbidities.1  The
incidences of AF is decreasing, however its  prevalence remained constant, one third of
adult population being affected by this devastating disease.2,3 The
risk of stroke in patients with AF decreased in the last few years, however
this was not accompanied by a decrease in mortality risk.2 Recent
studies have demonstrated that patients with a positive history of AF are still
at risk of thromboembolic events, despite sinus rhythm restoration, therefore
the blood stagnation in the atria is not the only contributor to the
development of intracavitary thrombus.4,5,6 In the ASSERT study only
8% of patients with stroke or systemic embolism had atrial fibrillation in the last
30 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, local
inflammation, hypercoagulability10, endothelial dysfunction,
structural pathologies, neurohumoral and genetics factors.4 It has
been described in the literature that atrial fibrosis significantly increase
the incidence of stroke and that the degree of atrial fibrosis is significantly
higher in patients with stroke17.

Atrial fibrosis plays an important role in the
appearance, maintenance and recurrence of AF and in the effectiveness of
catheter ablation. At the same time, atrial fibrosis is a consequence of AF,
therefore producing a vicious circle in which “AF begets AF”.11 Atrial
fibrosis is caused by: atrial fibrillation, rapid atrial myocyte depolarization13,
inflammation, mechanical stretch, atrial distension13, cardiac
injury11, electrical derangements11, accumulation of
intracellular Ca ions, autocrine and paracrine mediators12, oxidative
stress14, diabetes, obesity15,  hypercoagulability (activation of PAR1
receptors by thrombin)16, genetic factors and systemic autoimmune
disease. Cardiovascular comorbidities and age (75%)
of atrial fibrosis can have a huge impact on the risk of STROKE, and may be included
in the new stroke prediction index.13

POTENTIAL
CONTRIBUTIONS OF THE STUDY

The phenomenon of atrial fibrosis as a
pathogenic mechanism of atrial fibrillation has been described in the
literature, however its role in atrial thrombosis has not been elucidated so
far.

The originality of the present study consists in
building an algorithm of investigation by which high-quality imaging data will
be correlated with haematological markers of inflammation, platelet aggregation
and clotting. A model of complex investigations will be developed to identify
patients with increased thromboembolic risk and thus a large number of
cardio-embolic events will be prevented.

 

 

 

STUDY HYPOTHESIS

The degree of atrial fibrosis and the level of
inflammatory markers in the blood can predict the risk of thromboembolic events
in patients with atrial fibrillation.

STUDY OBJECTIVES

Primary objective

The primary objective of this study is to identify new
imaging-derived biomarkers provided by modern imaging technologies, such as Cardiac
Computed 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, in
order to identify the characteristics associated with an increased risk of
cardio-embolic events.

Secondary objectives

This study also aims to evaluate the correlation
between structural remodelling of the left and right atria and the amount of
myocardial fibrosis of the left atrium by DE-MRI. We will determine the
function of LA with EST, and will be performed automated quantification of
atrial fibrosis.

At the same time, volumetric assessment of epicardial
adipose tissue will be performed in each patient undergoing CCTA and MRI.

Besides this we will also look for identification of haematological
biomarkers of predisposition for thrombosis and platelet aggregation. We will
also evaluate the differences in these biomarkers in blood samples collected from
a peripheral line and from the left atrium during interventional ablation
procedures. Another important part of this study is to analyse the electrical remodelling
of the atrium by three-dimensional electro-anatomic mapping system and to
correlate these findings with the rate of thrombosis and with the level of
local haematological markers. We will determine the rate of recurrence of AF, the
rate of thromboembolic events and the rate of MACE, in every 3 months during
the follow up.

 

METHODS

Study design

This is a prospective, descriptive, cohort study and
is composed of two major parts. In the first part of the study, laboratory
tests and necessary interventions will be performed. The second part is represented by the follow-up of patients
for 2 years and will contain the analysis of the data obtained during the first
part of study. Before starting
the study all patients will sign an informed consent. After evaluating
eligibility for the screening process, patients who meet the inclusion criteria
without exclusion criteria will be included in the study. All study procedures
are in line with the principles in the Declaration of Helsinki. The study
population will be comprised by minimal 50 patients. Each patient included in
study need to be eligible to catheter ablation. The study population based on
the degree of atrial remodelling (size, wall thickness and function) assessed
with CCTA, will be divided in 2 groups. Patients with a mild atrial remodelling
will be enrolled in the first group, while the second group will contain
patients with moderate or severe atrial remodelling.  

Personal data of patients will be collected at
the start of study. Anamnesis, physical examination, ECG, evaluation of risk
factors and comorbidities will be performed in each case. Lab tests will
include the level of leukocytes, hs-CRP, and the erythrocyte sedimentation
rate. In each case we will exclude the presence of intracavitary thrombus using
transthoracic and transesophageal echocardiography. The structure of atrial anatomy
and the level of epicardial adipose tissue will be examined with echocardiography
and CCTA. EST will be used for the assessment of cardiac function. Electrophysiological
study will be performed in each patient included in the study and the images
obtained with CCTA will be merged with the electrical map of the heart.

 After trans-septal
puncture, but before pulmonary veins isolation, we will harvest blood from the
left atrium to determine the level of pro-inflammatory and pro-coagulation
factors. We will quantify the level of hs-CRP, IL-1,6, fibrinogen, tumour
necrosis factor, the erythrocyte sedimentation rate, INR, PT, PT%. At the same
time, we will harvest blood again to determine these factors but this time from
the peripheral blood.

The grade of atrial fibrosis will be assessed
with DE-MRI. Upon discharge, we will re-perform a new ECG to confirm the
success of cardioversion. All patients without atrial fibrillation at discharge
will be followed for 2 years. Patients will be recalled for periodic
investigations (anamnesis, physical examination, ECG, echocardiography) in the
3rd, 12th and 24th month and contacted by phone in the
6th and 9th month after cardioversion. At the last session (month 24), magnetic
resonance, EST will be performed to assess the progression of atrial fibrosis
and the changes in atrial function.

INCLUSION AND EXCLUSION CRITERIA

Patients are eligible if they had non-valvular
paroxysmal or persistent AF. All patients need to be adults and to be able to
read and understand the informed consent document. Also, only patients who have
signed informed consent will be enrolled in the study.

The study cannot be realized without imaging technics
in consequence patients who present contraindications to imaging tests will be
excluded 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), and
decompensated cirrhosis. Presence of metallic foreign bodies, cardiac rhythm
device are contraindications for magnetic resonance imaging and therefore for the
study.

Patients receiving any drug that may affect the
level of haematological markers will be excluded from the study. Terminally ill
patients and those who may not adhere or may not complete follow up or do not
have reliable information will be also excluded from the study.

END-POINTS

The primary end point of the study is represented by
the 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 and
imaging tests will be created and handled with the utmost accuracy and
confidentiality, only the staff involved in the research having access to this
database. Imaging data stored in the database will undergo complex post-processing
in the computational medicine laboratory, using computational simulations and
advanced imaging techniques processing. The merging of images obtained with CT
scanner with the electro anatomical map of the left atrium will be performed in
real time during the catheter ablation procedure. The quantification of the left
atrium fibrosis will be performed by a radiologist.

The statistical analysis will be performed in the
medical statistics laboratory of the Center of Advanced Research in Multimodal Cardiac
Imaging of S.C. Cardio Med SRL.

CONCLUSION

In AF undergoing complex ablation procedures,
the rate of recurrence and the cardioversion succession rate are influenced by
several intra and extra-cardiac factors. Novel studies have shown that in
addition to atrial stasis, many factors are involved in the appearance of
intra-atrial thrombosis. Patients with positive history of atrial fibrillation
have also an increased risk for stroke than those who never had atrial
fibrillation. It is known that atrial fibrosis, inflammation and
hypercoagubility have an important role in the appearance of intracavitary
thrombosis but the exact mechanisms involved in this correlation has not been elucidated
so far. This study will characterize new imaging-derived biomarkers to
correlate the structural remodeling and fibrosis of the left and right atrium with
the hematological parameters reflecting a high coagulability in the atria, in
order identify new tools for predicting the risk of thromboembolic events in
this group of patients.