Reappraisal of Atrial Fibrillation: Interaction between HyperCoagulability, Electrical Remodeling, and Vascular Destabilisation in the Progression of AF (RACE V) - Workpackage 5

Although the socio-economic burden of AF is growing steadily and significant
progress has been made in understanding the pathophysiology of this arrhythmia,
treatment of AF patients is still far from satisfactory. The success rate of
cardioversion is still limited and anti-arrhythmic drugs are unable to prevent
recurrences of AF. Prevention of thromboembolic events still requires
anticoagulation therapy with all the associated risks. Radio-frequency
ablation, originally developed for treatment of paroxysmal AF, varies in its
efficacy to cure persistent AF and is afflicted with a number of potentially
serious side-effects.
AF is a progressive arrhythmia. With time, paroxysmal AF becomes persistent and
the success rate of cardioversion declines. This progressive nature of AF is
presumably related to a slow but steady process of structural remodeling in the
atria characterized by hypertrophy, activation of fibroblasts and enhanced
collagen deposition. Also the distribution and function of gap junctions
undergoes changes, which are important for the development of intra-atrial
conduction disturbances. Since these structural and electrophysiological
alterations form the basis for initiation and perpetuation of AF,
characterization of the atrial substrate is essential to develop better
strategies for prevention and treatment of the arrhythmia.
Clearly, the mechanisms underlying the progression of AF are multifactorial.
Atrial fibrosis, vascular rarefaction, inflammation, abnormalities in atrial
Ca2+ handling and atrial adipose tissue infiltration as well as
hypercoagulability appear to play a role in the progression of AF.
An area logically effected by AF seems to be the left and right ventricle. A
well described pathology correlated to AF is tachycardia-induced myopathy where
there is a significant decrease in left ventricular function. Recent evidence
correlates atrial fibrillation to structural changes as well as overall loss of
function of both ventricles.
Despite new insights on electrical mechanisms leading to AF initiation and
progression, it is still unclear which electrical properties are associated
with lower probability of successful ablation or poorer long-term outcomes.
Detailed analysis of electrical conduction patterns using epicardial mapping in
patients with and without a history of AF provides unique information about
complexity and sources of AF. This information will be used to develop new
ablation strategies in patients with AF.

1. find out the true time-in-AF per AF category and identify progression of AF,
2. uncover genetic predisposing patterns for AF and AF progression,
3. find out electrical basis of AF,
4. investigate the relationship between genetic changes, electrical adaptations
and structural properties in the atria,
5. to unravel the role of coagulation in AF progression,
6. uncover molecular mechanism in cardiac tissue and detect specific biomarkers
to recognize the severity of AF or AF-prone patients.

Before the operation:
1. CT scan of the heart,
2. Taking questionnaires,
3. Blood collection,
4. Digital electrocardiogram (EKG),
5. OPTIONAL: MRI brain and neuropsychological testing.

During the operation
1. Taking small biopsies
2. OPTIONAL: Epicardial Mapping of the Atria
3. OPTIONAL: insertion of a rhythm monitor under the skin.

After 1 year on the control appointment
1. Physical examination,
2. Taking questionnaires,
3. Digital electrocardiogram (EKG),
4. Duplex carotides,
5. OPTIONAL: neuropsychological testing.

After 2.5 years at the control appointment
1. Sound examination (USG) of the heart,
2. Blood collection,
3. Digital electrocardiogram (EKG);
4. OPTIONAL: neuropsychological testing.
5. OPTIONAL: Remove the rhythm monitoring device

- Rhythm monitoring: this will no longer be done with implanted recorders, but
with non-invasive techniques. This will reduce the burden on the patients.
Patients will no longer have to return for a recorder explant and they will no
longer have to make weekly transfers with their home monitors. Previous
research has shown that non-invasive techniques are effective for detecting
symptomatic AF that also plays a greater role with poorer long-term outcomes.
Study subjects can easily and quickly make transfers with the non-invasive
recorder, which means that these results will also be translated more quickly
into future clinical practice.
- Epicardial mapping: in this study epicardial mapping electrodes will be used
that will allow to map electrical conduction in the atria. An extensive
analysis of the electrodes has taken place and they can be used safely in
patients.

The important benefits for the understanding of AF pathophysiology and also for
the patient themselves will certainly outweigh the above mentioned risks.