UNIVERSITA DEGLI STUDI DI MILANO I.R.C.C.S POLICLINICO SAN DONATO

CENTRO PER LO STUDIO E LA TERAPIA DELLLE MALATTIE CARDIOVASCOLARI

“E. MALAN”

Electrophysiology Workshop 1-SVT

Atrial Fibrillation

Riccardo Cappato, MD

Mechanisms

Multiple wavelet hypothesis

Mechanisms of AF (Substrate)

Moe Arch Int Pharm

Ther 1962

Micro-reentry (Multiple)

Focal aconitine model

Focal activity (Aconitine model)

Mechanisms of AF (Trigger)

Focal trigger (in humans)

Transcatheter Ablation of AF

Focal origin of AF

Haissaguerre et al, 1994

Haissaguerre et al, 1994

Transcatheter Ablation of AF

Focal origin of AF

Experimental Mechanisms of Atrial Fibrillation

Automatic Focus Fixed Rotor Moving Rotor Mother Wave

Multiple Foci Unstable Circuits Multiple Wavelets

Focus +

Multiple Wavelets

Courtesy from Dr. Allessie

Focal pulmonary vein trigger (in humans)

Foci within PV

Mechanisms of AF (Trigger)

Haissaguerre et al, 1998

Transcatheter Ablation of AF

Focal origin of AF

Anatomiac substrate for PV triggers

Hocini et al, 2002

Anatomy of Pulmonary Veins

Electrophysiological substrate for PV triggers

(in dogs)

Hocini et al, 2002

Hocini et al, 2002

Fig. 2

Role of PVs in the Pathophysiology of AF

Oral et al, 2002

Role of PVs in the Pathophysiology of AF

PV mapping

Dominance ratio:

PV : LA = 7 : 3

Paroxysmal and Persistent AF

Permanent AF

A Large Data Base of Fibrillation Maps

from the Left and Right Atrium:

Acute AF Persistent AF

PV-area (seconds/patient): -

Total Seconds Analyzed:

LA (seconds/patient): -

312.8

Nr Patients: 24 25

12.0±4.1 RA (seconds/patient): 8.2±3.6

606.3

10.1±7.1

10.5±7.0

Total Nr of Maps: > 2.200 > 4.400

In More than 4.400 Maps of 24 Patients with Longstanding Persistent AF

NOT A SINGLE

Reentrant Circuit could be Detected

on the Epicardial Surface of

the Right or Left Atria

Big Surprise

Allessie et al, Circ Arrith Electr

Allessie et al, Circ Arrith Electr

Allessie et al, Circ Arrith Electr

0

Longitudinal Dissociation (mm/cm2)

0 10 20 30 40 50

0.5

1

1.5

2

Epicardial

Breakthrough

(# per cycle/cm2)

Diagnosis of the Substrate of AF?

'Focal' Fibrillation Waves

3cm de Groot et al. Circulation 2010

Two Recent Examples of Basket Maps

MV Anterior

MV Posterior

Sep

tal

Narayan et al. CircAE 2013

Diameter: 4.8 - 6.0cm

Perimeter: 15.0 - 18.8cm

Lat

eral

4.8 - 6 cm 4.8 - 6 cm

15 - 18.8 cm

Can We Trust the Maps?

Single Rotor ...Or Multiple

Breakthroughs?

Allessie et al. Circ Res 1978 Allessie et al. Circ Res 1978

Epi

Endo

de Groot et al. Circulation 2010

40 35 30 30 35 40ms

0 5 10 20 25 30ms 15

A Double Layer of Narrow Dissociated Wavelets that

Constantly 'Feed' Each Other.

Courtesy of Dr. Allessie

• Triggered activity, high-frequency local reentry and rapidly expiring

multiple multi-layer sleeves of electrically excited tissue have been

proven as possible mechanisms of unsustained or sustained fibrillatory

activity in animals and humans

• Stable rotor activity has been suggested as a possible mechanism of AF,

but the indirect nature of ist assessment requires more careful evaluation

before conclusive evidence is confirmed

Electrophysiology of Atrial Fibrillation

Conclusions

Mechanisms of AF (Excitation of gangionated plexi)

Ganglionated plexi

Mechanisms of AF (Excitation of gangionated plexi)

Ganglionated plexi

Mechanisms of AF (Excitation of gangionated plexi)

Ganglionated plexi

Focal trigger from other veins! (in humans)

Transcatheter Ablation of AF 2006

Focal origin of AF

Chen et al, 2002

Clinical models of isolation

Transcatheter Ablation of AF 2006

Haissaguerre et al, 2000

?

PV electrical disconnection

Isolation of Superior Vena Cava

Chen et al, 2002

Electrophysiological insights

(in humans)

Mechanisms of AF (Excitation of gangionated plexi)

Multiple PV isolation as therapeutic model

(for both initiation and perpetuation)

AF: Classification, Mechanisms & Hemodynamic Consequences

• Mechanisms other than PV trigger in play

• Loss of effectiveness over time

• Different mechanisms in paroxysmal vs. persistent AF

Why efficacy on short-term is lost at FU?

Surgical linear ablation

Cox et al, 1993

Transcatheter Ablation of AF 2006

at 1-yr FU, ca. 90%

of pts in SR!

Catheteter induced multiple PV isolation:

Drawbacks

Clinical Outcome at Different Steps (free of AADs)

Paroxysmal AF

(pts= 73)

Persistent AF

(pts= 47)

Asymptomatic after Step I 37 (50.1%) 11 (23.4%)

Asymptomatic after Step II 21 (28.8%) 27 (57.4%)

Asymptomatic after Step III 8 (10.9%) 5 (10.7%)

All asymptomatic at EoP 66 (89.8%) 43 (90.5%)

Outcome

Catheter Ablation of Paroxysmal vs Persistent AF

1.00

0.10

0.00

0 5 10 15 20

months FU

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

57 51 38 31 23 Pts at risk

Survival free of AF off AADs

Paroxysmal AF

Persistent AF

35 33 25 20 11

25

11

4

Catheter Ablation of Paroxysmal vs Persistent AF

Paroxysmal AF

(pts= 73)

Persistent AF

(pts= 47)

Age (yrs) 52.8±10.3 52.4±10.3 0.8

Male sex 61 (83.6%) 27 (76.6%) 0.7

Pts with AF duration longer than 5 yrs 4 (3.3%) 15 (31.9%) <0.01

Number of AA drugs 3.7±1.5 4.2±1.7 <0.05

Atrial flutter 22 (30.1%) 12 (25.5%) 0.6

Heart disease

- coronary artery 5 (6.8%) 2 (4.7%) 0.9

- valvular 9 (12.3%) 6 (12.7%) 0.9

Hypertension 15 (20.5%) 15 (34.0%) 0.6

Left atrium max TD (mm) 42.9±5.3 44.7±6.9 0.1

EF 0.51±0.09 0.53±0.08 0.8

FU duration (mos) 17.5±8.9 17.1±6.9 0.9

Pt characteristics P

longest A-PV 60 ms 80 ms 115 ms

pre-ABL1 pre-ABL2 pre-ABL3 post-ABL1 post-ABL2 post-ABL3

First procedure (day 1) Second procedure (day 93) Third procedure (day 234)

I

III

V1

ABL d

ABL p

Lasso 9 - 10

Lasso 8 - 9

Lasso 7 - 8

Lasso 6 - 7

Lasso 5 - 6

Lasso 4 - 5

Lasso 3 - 4

Lasso 2 - 3

Lasso 1 - 2

HIS

CS

shortest A-PV 50 ms 65 ms 105 ms 100 ms

A PV

A

A

A

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PV

PV

PV

PV

PV

PV

PV

PV

PV

PV

PV

PV

PV

PV

PV

PV

PV

PV

PV

Modifiche della Ablazione sulla Durata della FA

Da prima a seconda

procedura

LSPV A-PV più breve (ms) 32 44.8 to 64.5 13 63.6 to 77.7

A-PV più lungo (ms) 67.3 to 98.0 98.0 to 100.0

RSPV A-PV più breve (ms) 29 26.5 to 45.5 14 44.8 to 57.1

A-PV più lungo (ms) 44.5 to 74.0 72.9 to 91.1

Pz Pz Da seconda a terza

procedura

LIPV A-PV più breve (ms) - - 20 41.8 to 52.8

A-PV più lungo (ms) - - 63.4 to 78.5

RIPV A-PV più breve (ms) - - 7 25.6 to 37.1

A-PV più lungo (ms) - - 45.6 to 64.3

AF: Classification, Mechanisms & Hemodynamic Consequences

• In pts with paroxysmal and persistent AF associated

with no heart disease or in the presence of mild heart

disease, multiple PV isolation is effective to reduce

precipitation and perpetuation of clinical arrhythmias

Pathophysiology

Mechanisms of AF in association

with complex substrate

Allessie et al, Circ Arrith Electr

Allessie et al, Circ Arrith Electr

AF: Classification, Mechanisms & Hemodynamic Consequences

• In pts with persistent or permanent AF and significant co-

morbidity,

– reentry does not appear to be the underlying mechanism

– focal activity may represent a surrogate of layer

breakthrough from electrical strings with short-life and

dynamic paths

Pathophysiology

substrate poorly amenable to catheter ablation!

What is Atrial Fibrillation?

• A symptom

• A disease

AF: Classification, Mechanisms & Hemodynamic Consequences

What is AF?

• It is intuitive to believe that it starts as an

epiphenomenon (caused by concomitant conditions,

sometimes difficult to be identieid)

• It has the potential to „take off and fly“ independently,

as a separate disease

– pathophysiologically

– clinically

AF: Classification, Mechanisms & Hemodynamic Consequences

What is AF?

Classification

• First detected AF

• Recurrent AF

– Paroxysmal

– Persistent

– Permanent (Long-standing persistent)

AF: Classification, Mechanisms & Hemodynamic Consequences

Classification

Fuster et al., 2001

ACC / AHA / ESC Guidelines

• Self-terminating within 1 week (usually 24-48 hours)

AF: Classification, Mechanisms & Hemodynamic Consequences

Paroxysmal AF

• Requires AADs or electrical cardioversion to restore

sinus rhythm

• Duration of less than one year

AF: Classification, Mechanisms & Hemodynamic Consequences

Persistent AF

• Does not resume sinus rhythm despite pharmacological

/electrical attempts or cardioversion not attempted based

on clinical judgement

• Longer than 1 year in duration

AF: Classification, Mechanisms & Hemodynamic Consequences

Permanent (long-standing persistent) AF

Assigned title in clinical perspective

Atrial Fibrillation: A Cardiologist’s Perspective

1. To interpret patient symptoms, fears and expectations

2. To put them into clinical perspective

3. To provide relief through appropriate treatment of

arrhythmia and precipitating cause(s)

4. To prevent from relapses of disease

Missions

Understanding of mechanisms and hemodynamic consequences

helps to prevent or mitigate symptoms and impact on prognosis!

Epidemiology

AF: Classification, Mechanisms & Hemodynamic Consequences

• Pts with younger age present more often with

paroxysmal AF

• Pts with longer hx of AF onset have a higher probability

to be in persistent / permanent AF

Epidemiology

Allessie et al, Circ 2001

AF: Classification, Mechanisms & Hemodynamic Consequences

I 4%

II-III 10%-26%

II-IV 12%-27%

III-IV 20%-29%

IV 50%

Prevalence of AF in pts with HF

Predominant

NYHA Class

Prevalence

of AF

Hemodynamic consequences of AF

AF: Classification, Mechanisms & Hemodynamic Consequences

• Low ventricular rate

• High heart rate

Hemodynamic consequences

Atrial Fibrillation: A Cardiologist’s Perspective

• Associated with atrial fibrillation

• Associated with precipitating events

• Subsequent to fibrillatory activity

Interpreting patient symptoms

AF: Classification, Mechanisms & Hemodynamic Consequences

• Major challenges are

– control of symptoms

– reduction of thromboembolic risk

Clinical approach

Atrial Fibrillation: A Cardiologist’s Perspective

• Palpitations

• Weakness

• Shortness of breath

• Dizziness

• Syncope

Interpreting patient symptoms

Associated with atrial fibrillation (classic)

Atrial Fibrillation: A Cardiologist’s Perspective

• Absence of symptoms

Interpreting patient symptoms

Associated with atrial fibrillation

not necessarily advantageous!

AF: Classification, Mechanisms & Hemodynamic Consequences

• Recent discoveries have led to improvement of our

understanding with regards to the mechanisms of AF in the

different clinical settings

• Improved knowledge has guided changing of diagnostic and

therapeutic approaches, also enabling non-surgical curative

therapy of this arrhythmia in selected pts

Conclusions

AF: Classification, Mechanisms & Hemodynamic Consequences

• Despite improvements in the understanding of AF

pathophysiology, treatment of symptoms associated with this

arrhythmia remains a delicate art incorporating overall clinical

judgement, identification and resolution, whenever possible,

of co-morbidity and precipitating conditions, re-assuring and

fine-tuning with patients expectations

Conclusions

Oral et al, 2002

Role of PVs in the Pathophysiology of AF

PV mapping

Dominance ratio:

PV : LA = 7 : 3

RAO view

Transcatheter Ablation of AF 2006

PV electrical disconnection

longest A-PV 60 ms 80 ms 115 ms

pre-ABL1 pre-ABL2 pre-ABL3 post-ABL1 post-ABL2 post-ABL3

First procedure (day 1) Second procedure (day 93) Third procedure (day 234)

I

III

V1

ABL d

ABL p

Lasso 9 - 10

Lasso 8 - 9

Lasso 7 - 8

Lasso 6 - 7

Lasso 5 - 6

Lasso 4 - 5

Lasso 3 - 4

Lasso 2 - 3

Lasso 1 - 2

HIS

CS

shortest A-PV 50 ms 65 ms 105 ms 100 ms

A PV

A

A

A

A

A

A

A

A

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PV

Tops et al 2010

Tops et al 2010

Tops et al 2010

Tops et al 2010

Oral et al, 2002

Catheter Ablation of AF

Ouyang et al, 2004

PV and Posterior Wall Ablation

Examples of Lesion Sets LSPV

LIPV

RSPV

• ECG, including intracardiac EG, still most important imaging

tool after one hundred years

• Computer-assisted 3D mapping highly valuable for recognition

of target substrates

• New imaging technology may assist in energy delivery

Imaging and Atrial Fibrillation

Conclusions

Tops et al 2010

Atrial Fibrillation: A Cardiologist’s Perspective

• “Flying bird trying to get out of my thoracic cage”

• “Internal enemy attempting at my psycological integrity”

• “An alien heart beating with alien rhythm”

• “The falling in love feeling that takes you when you meet

your lover at first dates”

Interpreting patient symptoms

Associated with atrial fibrillation (unusual)

Atrial Fibrillation: A Cardiologist’s Perspective

• “…I cannot plan my holidays any longer, what to do if I

experience AF when far away from home?...”

• “…What if I get stroke?...”

• Gerrard, last year at Europe AF:

“…Because of my AF, my career is in danger. Will I be

able to secure my son’s future?....”

Interpreting patient fears

Atrial Fibrillation: A Cardiologist’s Perspective

• Relief from symptoms

– with drugs

– with pace-maker implant

– with ablation

• Freedom from oral anti-coagulants

• Freedom from risk of stroke

• Healing of underlying heart disease

Interpreting patient expectations

Atrial Fibrillation: A Cardiologist’s Perspective

• While sleeping

• After dinner

• Coffee

• Alcohol

• During effort

• Others

Interpreting patient symptoms

Associated with precipitating events

impairing quality of life and life style!

Atrial Fibrillation: A Cardiologist’s Perspective

• Weakness for hours or days

• Fear of new relapses

• Fear of stroke

• Impact on life style perspective

Interpreting patient symptoms

Subsequent to fibrillatory activity (in pts with AF)

Atrial Fibrillation: A Cardiologist’s Perspective

• Are symptoms associated with AF?

• If not, what is the cause of symptoms?

– co-morbidity? (heart disease - type and degree - ,

gastro-esophageal disease, others)

– psycological instability? (primary - mental

conflicts or imbalancement - ? secondary to AF?)

Symptoms in clinical perspective

correct diagnosis drives appropriate treatment and sets

reliable therapeutic expectations!

Atrial Fibrillation: A Cardiologist’s Perspective

• Drugs

– rhythm control

– rate control

– prevention of thromboembolic risk

• AV nodal modulation

• AV nodal ablation and pace-maker implantation

• Catheter ablation of arrhythmic substrate

Treatment of arrhythmias

Atrial Fibrillation: A Cardiologist’s Perspective

• Withdrawal of stimulating factors

– coffee, tee, alcohol

• Light and frequent meals

• Control of esophageal reflux

• Use of hypotensive agents, if hypertension (including

“borderline”?) is diagnosed

• Compensation for hormone imbalances (thyroid, supra-

renal, others)

Treatment of precipitating cause

Atrial Fibrillation: A Cardiologist’s Perspective

1. “…I am the doctor, I know what is best for you!...”

2. “…Here are the options, here are the pros and cons for each

of the choices available. What would you prefer?…”

Treatment of arrhythmias

Methodology

Atrial Fibrillation: A Cardiologist’s Perspective

• Drugs (palliative)

– rhythm control

– rate control

– prevention of thromboembolic risk

• AV nodal modulation (palliative)

• AV nodal ablation and pace-maker implantation (palliative)

• Catheter ablation of arrhythmic substrate (curative)

The paradigm of catheter ablation

Atrial Fibrillation: A Cardiologist’s Perspective

• Atrial fibrillation is frequent, mode of presentation

varies among pts and within pt, unpredictable,

invalidating, refractory to therapy, does not

disappear once for ever, carries a risk for stroke

Introduction

pts dream of a curative treatment, but know it will not be easy!

Atrial Fibrillation: A Cardiologist’s Perspective

Access of patients to therapy

Patients

Referring physicians Patients w/

previous experience

Internet

Catheter ablation

Atrial Fibrillation: A Cardiologist’s Perspective

Access of patients to therapy

Patients

*Referring physicians *Patients w/

previous experience

Internet

Catheter ablation

* “Peer-reviewed”-like modality of access!

Atrial Fibrillation: A Cardiologist’s Perspective

Access of patients to therapy

Patients

Referring physicians Patients w/

previous experience

*Internet

Catheter ablation

* “Abstract”-like (non-peer-reviewed) modality of access!

Transcateter Ablation of Atrial Fibrillation

Schwartz 1994 Left atrium (Maze-like) linear ablation

Haissaguerre 1996 Right (+ left) multiple linear ablation

Haissaguerre 1998 Focal triggering PV ablation

Pappone 2000 Left atrial circumferential PV ablation

Haissaguerre 2000 PV electrical disconnection

Ouyang 2004 Left atrial circumferential electrical disconnection

Nademanee 2004 Fragmented complex (left atrial) potential ablation

Jais 2004 PV electical disconnection + linear mitral isthmus block

Hocini 2005 PV electrical disconnection + LA roof linear block

Haissaguerre 2005 PV electrical disconnection + multiple linear ablation

Nakagawa 2007 Ganglionated plexi ablation

Author Year Technique

Transcateter Ablation of Atrial Fibrillation

• Referring physicians and communication with other patients

with previous experience on CA of AF provide a reasonable

level of filtering with regard to the quality of “sensible

information” released

• Self-promotion through Internet (or similar modes of

advertisement) is out of control in terms of quality and

reliability of “sensible data” released

Access of patients to therapy

Pros and cons

Transcateter Ablation of Atrial Fibrillation

• Relative proportion of different modalities used by patients for

access to catheter ablation of AF unknown and likely variable

from one center to another

• Prevalent distribution of modality of access according to self-

promoting models should raise concern in regulatory authorities,

at least with regard to verification of officially released data

Access of patients to catheter abaltion

Atrial Fibrillation: A Cardiologist’s Perspective

• First curative treatment of AF

• Variable success rates depending on type of AF, co-morbidity,

and investigator experience

• Setting pt expectations beyond the limit of objective evidence

causes additional discomfort

The paradigm of catheter ablation

Atrial Fibrillation: A Cardiologist’s Perspective

• Establishing a strong faithful relationship with these pts is the

very priority; this will help guiding pts through obtacles and

relapses

• Cure is a real possibility, but limits and concomitant therapies

should be discussed and integrated in the global scheme

The paradigm of catheter ablation

RAO view

Transcatheter Ablation of AF 2006

PV electrical disconnection

• Cicli di attività fibrillatoria più brevi nelle VP che nel tessuto

atriale adiacente

• L‘aumento progressivo nel no. di VP isolate associato a

– prolungamento consensuale del ciclo di FA

– interruzione della FA in corso (fino al 75% dei pz!)

Modifiche della Ablazione sulla Durata della FA

Evidenze elettrofisiologiche nell‘uomo

Studi in acuto

Evidenze cliniche

Oral et al, 2002

ULVP

LLPV

USPV

Ablation design

= electrical

disconnection

Catheter Ablation of AF

Fig. 1

• La maggior parte delle VP mostra recidive di conduzione 3-5

mesi dopo isolamento condotto con ablazione mediante RF

• In pz con FA PERS e nessuna o minima CP

– simile efficacia a quella ottenuta nella FA PAR con

isolamento puro di tutte le VP (about 90% success)

– dopo esclusivo isolamento delle VP, evidenza di

trasformazione da FA PERS a FA PAR

Modifiche della Ablazione sulla Durata della FA

Evidenze cliniche

Studi in cronico

• In pz con FA PAR, recidiva di FA e recidiva di conduzione VP

– l‘aumento dell‘intervallo A-PV correla in modo inverso

con la durata delle recidive di FA dopo ablazione della FA

Modifiche della Ablazione sulla Durata della FA

Evidenze cliniche

Studi in cronico

• Studi in acuto nell‘animale ed in acuto e cronico nell‘uomo

suggeriscono in modo indiretto il ruolo delle VP nella

perpetuazione della FA clinica

Modifiche della Ablazione sulla Durata della FA

Conclusioni

Mechanisms of AF (Excitation of gangionated plexi)

Efficacia cululativa in assenza di farmaci AA

FA parossistica

(pts= 72)

FA persistente

(pts= 47)

- Asintomatico dopo isol VP sup 31 (43.1%) 11 (23.4%)

- Asintomatico dopo isol tutte VP 57 (79.2%) 36 (76.6%)

- Asintomatico dopo consolidamento 65 (90.3%) 40 (85.1%)

Risultato

Modifiche della Ablazione sulla Durata della FA

IPOTESI:

•I trigger innescano multipli

circuiti da rientro

•Necessaria una certa quantità

di MASSA CRITICA per il

mantenimento dell’FA

MICROCIRCUITI DA RIENTRO

Moe Arch Int Pharm Ther 1962

… al concetto di massa critica

Sueda

Ann Thorac Surg 1997

circuiti di microrientro

Haissaguerre

NEJM 1998 foci delle

VP

L di M

Hwang

Circulation 2000

meccanismi necessari perFA