'AF Begets AF' - GIORNATE CARDIOLOGICHE · Atrial Fibrillation Begets Atrial Fibrillation A study...
Transcript of 'AF Begets AF' - GIORNATE CARDIOLOGICHE · Atrial Fibrillation Begets Atrial Fibrillation A study...
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'AF Begets AF' The Role of Early Action
Maurits A. Allessie Department of Physiology
Cardiovascular Research Institute Maastricht, The Netherlands
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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
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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
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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
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The 3 Wheels of Atrial Remodeling
AF Electrical
(days)
Contractile (days)
Structural (months)
Allessie et al. Cardiovasc Res 2002
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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….
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Shortening of the Wavelength
WAVE LENGTH
WL = RP * CV
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Increased Number of Wavelets Acute AF
Persistent AF
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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
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Electrical Remodeling:
Wavelength
θ Frequency AF
Duration AP AF
‘AF Begets AF’
Less L-type
Ca++ Current
More Fibrillation
Waves
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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
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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
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AF-Induced Structural Remodeling Sinus Rhythm 16 Weeks AF
Ausma et al. Circulation 2000
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Cx40
Cx43
Down Regulation of Connexin 40 Sinus Rhythm 4 Months AF
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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
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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
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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?
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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
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Is It Conduction Defects due to Stretch?
Houben et al. Heart Rhythm 2005
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Is it Atrial Fibrosis?
Anné et al. Cardiovasc Res 2005
CABG SR MVS AF MVS SR
RA RA RA
LA LA
LA
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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
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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
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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
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Narrow Multiple Wavelets Separated by Long Lines of Conduction Block
Macroscopic Longitudinal Dissociation of Atrial Muscle Bundles
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43 ms
171 ms
31 ms
149 ms
Epicardial Breakthroughs
3cm
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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
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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
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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
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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!
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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
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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
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In Patients with Longstanding AF the Atria have been Transformed
into a Double Layer of Dissociated Muscle Bundles
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Two Layers of Dissociated Fibrillation Waves that Constantly
'Feed' Each Other
de Groot et al. Circulation 2010
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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:
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1) Prevention of Structural Remodeling
The Role of Early Action:
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But How? Advancing Age, Hypertension, Valvular Disease,
Left Ventricular Dysfunction ..... Years
AF (Months)
Atrial Ischemia?
Neurohumoral?
Atrial Stretch?
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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: