Reappraisal of Atrial Fibrillation: Interaction between HyperCoagulability, Electrical Remodeling, and Vascular Destabilisation in the Progression of AF - An observational exploratory study on pathophysiological mechanisms of AF progression AND on the role of LinQ/ CareLink guided patient tailored therapy in patients with AF (RACE V)

Atrial fibrillation (AF) commonly progresses from paroxysmal self-terminating
to non-self-terminating persistent and permanent AF, which we call AF
progression. The importance of AF progression is that it is associated with a
significant disease burden, including increased cardiovascular hospitalisation
and mortality due to heart failure, stroke and myocardial infarction. In order
to find new strategies to prevent AF progression and to reduce major adverse
cardiac and cerebrovascular events (MACCE), we aim to elucidate the prevalence,
mechanisms and markers of AF progression. The core hypothesis of our proposal
links AF progression to vascular risks via hypercoagulability, i.e. activation
of blood coagulation through thrombin. Hypercoagulability is an obvious, yet
largely unexplored, disease mechanism in a disease like AF, with its well-known
predisposition for stroke and other thromboembolic complications.

2.2 Primary Objective
To study clinical factors, (blood) biomarkers and genetic markers related to AF
progression in patients diagnosed with recent onset self-terminating AF with
special reference to hypercoagulability.

2.3 Secondary Objectives
1. To study the feasibility of implementing changes in therapy in patients with
selfterminating AF using the LinQ/ Carelink system
2. To study the number of patients with change in rate or rhythm control
therapy because of an increase in AF burden (sum of all episodes X duration per
episode) by 30% as assessed over successive 3 months periods.
3. To study the number of patients with change in rate or rhythm control
therapy because an increase in number or duration of episodes of AF by more
than 30% as assessed over successive 3 months periods.
4. To study the number of patients with short SCAF at baseline who show
progression to SCAF/AF > 24 hours in whom anticoagulation is initiated.
5. To study the incidence of AF progression in patients diagnosed with
self-terminating AF;
6. To study the cross-sectional relation between hypercoagulability and the
cardiovascular and arrhythmia profile at inclusion;
7. To study changes in hypercoagulability between baseline and 2.5 years
follow-up and relate these to cardiovascular and arrhythmia profiles at various
time points in the study;
8. To study the clinical impact of AF progression on MACCE incidence;
9. To study gender differences in incidence of AF progression, clinical factors
and (blood) biomarkers related to AF progression and occurrence of MACCE;
10. To study differences between systemic markers of hypercoagulability
assessed at the moment of an acute episode of AF compared to remote from an AF
episode during sinus rhythm;
11. To study differences between other biomarkers in acute AF versus sinus
rhythm;
12. To study the cross sectional relation between biomarkers, the
cardiovascular risk profile and arrhythmia profile at inclusion assessed at the
moment of an acute episode of AF compared to remote from an AF episode in sinus
rhythm;
13. To study differences between hypercoagulability assessed locally in the
atria at the moment of an acute episode of AF as compared to sampled
peripherally (femoral vein);
14. To study differences between other biomarkers assessed locally in the atria
at the moment of AF as compared to sampled peripherally;
15. To study the cross sectional relation between biomarkers and the
cardiovascular risk profile and arrhythmia profile at inclusion assessed
locally in the atria at the moment of an acute episode of AF compared to
sampled peripherally;
16. To study in patients included in the scene of calamity substudy the
electrophysiological properties of the atria using an electro-anatomical
mapping system.
17. To study the association between the electrophysiological properties of the
atria with hypercoagulability, clinical characteristics, echocardiographic
parameters of atrial remodeling, AF burden and other phenotypic information.
18. To study differences in AF progression rate and MACCE in patients on
dabigatran, FXa inhibitors and VKA versus controls;
19. To study hidden associations between hypercoagulability, atrial
remodelling, vascular disease and AF progression, using unbiased,
hypothesis-free latent class clustering modelling;
20. To construct a novel risk prediction model for AF progression based on the
most important phenotypic information (clinical and biomarker data) using data
from the latent class clustering modelling;
21. To construct a multimarker genetic risk score with the independently
associated genetic mechanisms, and study whether the multimarker genetic risk
score is associated with progression of AF.

This study is a multi-center, prospective registry. A total of 750 patients
with paroxysmal AF will be included. In addition to routine clinical practice,
we will perform deep phenotyping and continuous rhythm monitoring. Eligible
patients will be asked to participate in two substudies. In the *time of
calamity* (TOC) substudy, patients with an acute episode AF will undergo one
extra vena puncture. In the *scene of calamity* (SOC) substudy, extra blood
collections in the left atrium will be performed in patients who undergo
catheter ablation of AF as part of their clinical care.
For the HBC-x substudy, an MRI will be taken from the brain for the patients to
be included, and an extensive NPO examination will be done. At the end of the
study all patients will receive a shortened version of the NPO.

AF progression is a harbinger of MACCE. By continuous atrial monitoring AF
progression can be carefully assessed. We expect our approach to change the
clinical diagnostic approach towards patients with AF. Using continuous atrial
rhythm monitoring, the early detection of AF and of AF progression will become
primary diagnostic goals. Biomarking in patients reporting with an acute AF
episode will emerge, comparable to the clinical routine in acute coronary
syndrome (*diagnosis before shock*). Our research will also generate new
prediction rules, which should distinguish susceptible patients from resilient
patients more efficiently in terms of AF progression. These results will be
generated through robust clinical-epidemiological techniques, but also through
cutting-edge novel analysis techniques that are able to find the hidden
associations between hypercoagulability, atrial remodelling, vascular disease,
and AF progression.
Risks include complications associated with implantation of the ILR, being
extremely low (i.e. <0.3%) and include infection and bleeding. These potential
complications are easily treatable. No additional study visits are necessary.
Patients will be seen according to routine follow-up protocols. Blood sampling
via vena punctures will be performed twice (at baseline and 2.5 years of
follow-up), and one phone call at the end of life of the device. Complications
of vena punctures are rarely reported.

In a subgroup of 100 patients blood sampling will be performed at the moment of
an episode of AF (*time of calamity* or TOC). This requires one extra vena
puncture. In another group of 100 patients undergoing pulmonary vein isolation,
blood sampling will be performed in the atria, at the *scene of
calamity* (SOC). This requires no extra puncture, will be done via catheters in
situ during the procedure.

In another subgroup of 150pts (with early onset self-terminating AF) and 50pts
(which also undergo CABG), a MRI scan of the brain will be made at baseline and
an extensive NPO examination will be conducted. At the end of the study, all
patients will be asked whether they want to take a shortened NPO. The aim of
this research is to see whether atrial fibrillation leads to reduced blood flow
to the brain and to problems with memory and other psychological symptoms.