'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: