Assessment of the substrate for atrial fibrillation using tissue velocity imaging of the fibrillating wall

Atrial fibrillation (AF) may provoke palpitations, dyspnea, chest pain, fatigue
and syncope, all of which may be relieved by rhythm control. Unfortunately, AF
recurrence is frequent with over 50-70% of patients again in AF within one year
after initial treatment. In addition, rhythm control may not prevent
progression to persistent AF in 8.6-15% of paroxysmal AF patients. Identifying
patients who will respond to rhythm control is worthwhile since it will prevent
unnecessary use of antiarrhythmic drugs, electrical and pharmacological
cardioversions and ablations. Predictors of recurrence or progression include
advanced age, long AF duration, type of underlying heart disease, transient
ischemic attack or stroke, chronic obstructive pulmonary disease, hypertension
and large left atrial size. These predictors are not used in a systematic
fashion in clinical practice because they lack predictive accuracy, conceivably
due to the fact that they only relate indirectly to atrial remodelling. It may
be conjectured that parameters derived directly from the atrial wall are better
predictors.
The atrial refractory period (ARP) is an important parameter of electrical
remodelling and it may predict the response to rhythm control. The shorter the
ARP, the worse arrhythmia outcome, i.e. the higher the risk of progression to
persistent AF. To predict the response to treatment, ideally one needs to
assess the patient before the treatment is given, i.e. during ongoing AF. One
way to do this is to assess the AF cycle length (AFCL) during ongoing AF,
because it represents the ARP. However this measurement is complex and invasive
since it involves the use of catheters which is patient unfriendly and not
without risk .
Current echocardiographic techniques include the option of tissue velocity
imaging (TVI) enabling detailed assessment of the atrial walls. Using this new
technique we recently validated a so-called echoelectrocardiographic method to
assess AFCL using tissue velocity imaging (AFCL-TVI) of the fibrillating atrial
myocardium. We demonstrated that AFCL-TVI matches accurately with the
invasively measured electrophysiological AFCL.[9], and thus also reflects the
ARP. Considering the above, it is reasonable to assume that the AFCL-TVI may be
used to assess atrial electrical remodelling and hence also arrhythmia
prognosis.
Apart from electrical remodelling (i.e. shortening of ARP) also structural
remodelling causes recurrences of AF. The latter is characterised by fibrosis
and loss of contractility of the atrial wall. Clinically, structural
remodelling is assessed only indirectly by measuring atrial size and
transmitral and left atrial appendage flow velocities.
Nowadays, direct information on atrial contractility may be obtained by imaging
the atrial fibrillatory wall motion velocity using TVI (AFV-TVI). Using atrial
TVI we have recently shown that advanced electrical and structural remodelling
in patients with AF is characterized by short AFCL-TVI and low AFV-TVI.
Conceivably this direct information on atrial contractility reflecting
structural remodelling may provide a firmer basis for predicting arrhythmia
outcome after AF treatment compared to conventional echocardiographic and
clinical parameters. However, at present it is unknown whether atrial TVI
focusing on electrical and structural remodelling may be used to predict
arrhythmia prognosis in patients with paroxysmal and persistent AF (primary
objective). In addition, atrial TVI may provide information about the clinical
and electropharmacological response to pharmacological conversion, both during
intravenous and oral administration of the anti-arrhythmic drug (secondary
objectives). Clinically, it is of utmost importance to identify patients who
will not respond to pharmacological rhythm control to avoid unnecessary adverse
drug effects.

Primary Objective:
to show that TVI of the atrial wall during ongoing AF may be used to predict
long-term progression to (or recurrence of) persistent AF in patients with
paroxysmal and persistent AF undergoing rhythm control.

Secondary Objective(s):
(a) in paroxysmal AF patients to show that acute pharmacological cardioversion
may be predicted by atrial TVI before drug treatment
(b) in patients with persistent AF undergoing amiodarone loading, to show that
TVI can reveal electropharmacological and contractility effects of amiodarone
(c) in patients with persistent AF undergoing amiodarone loading, to show that
time-dependent changes in atrial TVI parameters can be used to predict
long-term outcome on amiodarone

This is a multicentre exploratory study to assess the value of
echocardiographic tissue velocity imaging (TVI) in predicting short and long
term arrhythmia outcome in patients with AF undergoing rhythm control
treatment. After obtaining informed consent, patients will undergo complete
trans-thoracic echocardiography while still in AF, including recording of the
novel atrial TVI parameters. All baseline characteristics and echocardiographic
measurements will be noted in a case record form. These include demographic
characteristics, medical history, use of anti-arrhythmic drugs, previous rhythm
control, data on electrocardiogram and echocardiogram. After the baseline
echocardiogram, pharmacological or electrical cardioversion will be performed.
After the cardioversion, patients will be followed in the outpatient clinic at
1 month and at regular intervals thereafter, for a minimum of 1 year. During
follow-up the rhythm as well as major adverse cardiovascular and
cerebrovascular events will be recorded. If AF is continuously present for > 48
hours (Holter) the primary endpoint will be reached. In patients with
paroxysmal AF undergoing pharmacological cardioversion using flecainide or
ibutilide, the rhythm will be continuously monitored for at least 1-4 hours
after ending the intravenous treatment. The time point of conversion to
sustained (>1 minute) sinus rhythm will be noted. If conversion to sinus rhythm
occurs within 60 minutes after start of the infusion, one of the secondary
endpoints (2a) will be reached. In patients with persistent AF
undergoing amiodarone loading, serial follow-up echocardiograms will be taken
at weekly intervals after start of loading and on the day of the electrical
cardioversion (secondary endpoint 2b). After cardioversion all patients will be
followed as mentioned above and recurrence of persistent AF while treated with
amiodarone will be noted (secondary endpoint 2c). See figure with study flow
chart and numbered objectives.

Patients with paroxysmal AF only receive one echocardiography before treatment.
Patients do not have to come for an extra visit. In patients with persistent AF
undergoing amiodarone loading, serial follow-up echocardiograms will be taken
at weekly intervals after start of loading and on the day of the electrical
cardioversion. There is no risk of undergoing an echocardiography. In some
patients , if the heart rate is too high carotid sinus massage will be
performed or patients will receive a low dose of betablocker (metoprolol) or
verapamil. In this way, a heart rate < 80 beats per minute can be achieved to
obtain optimal echocardiographic images. Carotid sinus massage or intravenous
administration of metoprolol or verapamil are frequently used in patients with
supraventricular rhythm disorders. Infusion of these agents in patients with
high heart rate may have beneficial effects by lowering heart rate. If applied
following clinical rules, infusion of these rate slowing drugs is not related
with significant side effects.