'AF Begets AF' The Role of Early Action
Maurits A. Allessie Department of Physiology
Cardiovascular Research Institute Maastricht, The Netherlands
1995 Atrial Remodeling
•Morillo et al. Circulation 1995; 91: 1588-1595 Chronic Rapid Atrial Pacing Structural, functional, electrophysiological characteristics of a new model of sustained atrial fibrillation (dog) •Wijffels et al. Circulation 1995; 92: 1954-1968 Atrial Fibrillation Begets Atrial Fibrillation A study in awake chronically instrumented goats
The Goat model of AF
LA RA
BB
PV SCV
50 Hz 50 Hz 50 Hz AF AF AF
SR SR Wijffels et al.Circulation 1995
Paroxysmal → Persistent AF
Wijffels et al. Circulation 1995
5 sec
20 sec
Chronic AF
Sinus Rhythm
After 24 h
After 1 week
Control
Sinus Rhythm
burst
The 3 Wheels of Atrial Remodeling
AF Electrical
(days)
Contractile (days)
Structural (months)
Allessie et al. Cardiovasc Res 2002
Pacing Interval (ms)
110
130
150
100 200 300 400 500
AERP (ms) Control
After 24 hours of AF
Control
AF
Wijffels et al. Circulation 1995
The First Days….
Shortening of the Wavelength
WAVE LENGTH
WL = RP * CV
Increased Number of Wavelets Acute AF
Persistent AF
Van Wagoner et al. Circ Res 1999 Bosch et al. Cardiovasc Res 1999
Downregulation of L-type Ca++ in Human AF
Control
AF Control
AF
Sinus Rhythm
Chronic
AF
mV
pA/pF
Electrical Remodeling:
Wavelength
θ Frequency AF
Duration AP AF
‘AF Begets AF’
Less L-type
Ca++ Current
More Fibrillation
Waves
Contractile and Electrical Remodeling ‘Go Hand in Hand’
0 1 2 3 4 5 6 7 8 9 10
80
100
120
140 Refractory Period
Work Index
0
5
10
15
Refractory Period (ms)
Atrial Work Index
(mm2Hg)
Time (days)
AF Conversion SR
Schotten et al. Circulation 2003
...But Both Are Completely Reversible
Electrical Remodeling is Forgiving
However ... There Must be a 'Second Factor'
Within 4 Months of AF the Succes Rate of Cardioversion Drops to 0%!
(3/6)
(2/6)
(0/7) (0/7) (0/7)
Succes Rate Pharmacologic Cardioversion
(14/15)
0
25
50
75
0 1 2 3 4 5 6
AF Duration (months)
100 %
Verheule et al. Circ AE 2010
AF-Induced Structural Remodeling Sinus Rhythm 16 Weeks AF
Ausma et al. Circulation 2000
Cx40
Cx43
Down Regulation of Connexin 40 Sinus Rhythm 4 Months AF
Structural Remodeling is a Slow Process
Duration of AF 0 2 4 8 16 Weeks
Myolysis in
Right Atrium 1.3 3.9 4.2 10.0 12.2 %
Myolysis in
Left Atrium 2.0 2.7 4.9 7.6 10.2 %
Ausma et al. Circulation 2000
Reversibility Slow and Incomplete
Total:
Control
7.9±6.0
16 weeks of AF
Mild:
Severe:
36.7±12.3
27.8±12.1
8.9±7.2
37.7±4.7
34.2±4.6
3.5±3.1
27.1±7.7
25.4±6.2
1.8±1.6
Myolysis (% of cells)
2 months of SR
6.5±5.1
1.4±1.6
4 months of SR
Ausma et al. JMCC 2002
Structural Remodeling is NOT Forgiving
Architecture?
Connexins?
Amyloidosis?
Structural Proteins?
Fatty Infiltration?
Fibrosis?
Myolysis? Dilatation?
Hypertrophy?
Anisotropy?
Who Are the Players?
Many Structural Changes
What Makes the Atria Such a Perfect Host
for AF?
Is It Small Islands without Connexins? AF More Complex
Kanagaratnam al. JCE 2004
Simple Complex
Type of AF Simple Complex
Cx40 P = 0.018
0.00
0.01
0.02
0.03
0.04
Average Complexity
0.00
0.25
0.50
0.75
Cx4
0/C
x43
Rat
io
1.0 1.5 2.0 2.5 3.0
P = 0.013 R = -0.74
Is It Conduction Defects due to Stretch?
Houben et al. Heart Rhythm 2005
Is it Atrial Fibrosis?
Anné et al. Cardiovasc Res 2005
CABG SR MVS AF MVS SR
RA RA RA
LA LA
LA
Mitral Valve Disease
Left Atrial Size: 59±9 mm
Persistent AF > 1 Year
Age: 64±9
24 Patients
♂15 ♀9
Epicardial Mapping of Longstanding Persistent AF during Cardiac Surgery
Allessie et al. Circulation AE 2010
LA RA PV
>1.400
# of Epicardial Maps
>1.100 >1.800
Wave Mapping of Human AF
3 cm
17 Waves Acute AF Persistent AF 3 Waves
3 cm
Fibrillation Waves Fuse and Collide
Waves are Separated by Lines of Block
Allessie et al. Circ AE 2010
6-10 Times More Intra-atrial Block in Patients with Persistent AF
Acute AF (25 patients)
RA
3.4
RA LA PV
Persistent AF (24 patients)
33.0
21.0
0
10
20
30
40
50
Length of lines of block (mm/cm2/AF-cycle)
21.1
Narrow Multiple Wavelets Separated by Long Lines of Conduction Block
Macroscopic Longitudinal Dissociation of Atrial Muscle Bundles
43 ms
171 ms
31 ms
149 ms
Epicardial Breakthroughs
3cm
de Groot et al. Circulation 2010
4-fold Higher Incidence of Epicardial Breakthroughs
25 Pts with Acute AF (Right Atrium)
Median: 0.11
2 1 0
1
2
% 3
4
Median: 0.47
2 1 3 0
1
2
24 Pts with Persistent AF (Right Atrium)
3
4
Number of Epicardial Breakthroughs per AF-cycle/cm2
As Many as 115 Epicardial Breakthroughs
during 8 seconds of AF
3cm
Epicardial Breakthrough in the Right Atrium in a Patient with
Longstanding Persistent AF
de Groot et al. Circulation 2010
Right Atrium
Median: 0.47
2 1 3 0
1
2
3
4
% Left Atrium
Median: 0.45
2 1 3 0
1
2
3
4
%
1
PV-Area
Median: 0.54
2 1 3 0
2
3
4
%
Number of Epicardial Breakthroughs per AF-cycle/cm2
In 24 Patients with Longstanding Persistent AF, on Average 3-4 Breakthroughs per second
in Each Square cm of the Atrial Wall
This Means a Total of > 200 Breakthroughs
per Second
Breakthrough Sites Are Multiplication Sites
Endo-Epicardial Junction
40 30 30 40 ms
EPI
ENDO
0 10 20 30 ms
ENDO
EPI
15 5 25
35 35
They Form a Constant Source of 'New' Fibrillation Waves
The 'Hidden' Reservoir of AF-Sources is Right Under Your Feet!
Simultaneous
Endo-Epicardial
Mapping of
Persistent AF in
the Goat
Eckstein et al. Cardiovasc Res 2011
Epicardial Layer
Endocardial Layer
18
21
20
35
10
0
44
18ms
8ms
Eckstein et al.Cardiovasc Res 2011
Acute AF
3 Weeks of AF
6 Months of AF
Low High
Goat 1 Goat 2 Goat 3 Goat 4 Goat 5 Goat 6 Goat 7
Degree of Endo-Epicardial Dissociation
Progressive Endo-Epicardial Dissociation in the Goat
In Patients with Longstanding AF the Atria have been Transformed
into a Double Layer of Dissociated Muscle Bundles
Two Layers of Dissociated Fibrillation Waves that Constantly
'Feed' Each Other
de Groot et al. Circulation 2010
Perpetuation of AF Independent of Presence of Rotors or Rapid Foci
Each Layer of Dissociated Wavelets Serves as a Multi-Site Generator for the Other Layer
Will Not Be Easy to Ablate
Double Layer AF:
1) Prevention of Structural Remodeling
The Role of Early Action:
But How? Advancing Age, Hypertension, Valvular Disease,
Left Ventricular Dysfunction ..... Years
AF (Months)
Atrial Ischemia?
Neurohumoral?
Atrial Stretch?
1) Prevention of Structural Remodeling
2) Diagnosis of the Stage of the
Electropathological Substrate of AF
3) Don't Ablate When it is Too Late
The Role of Early Action: