Fibrillation Auriculaire: Thérapies en AmontFibrillation Auriculaire: Thérapies en Amont

Gerald V. Naccarelli M.D.Gerald V. Naccarelli M.D.

Research support:Research support: Boston-Scientific, Sanofi-Aventis, Boston-Scientific, Sanofi-Aventis, Boehringer-Ingelheim, Glaxo-Smith-KlineBoehringer-Ingelheim, Glaxo-Smith-Kline

Consultant:Consultant: Glaxo-Smith-Kline, Medtronic, Boston- Glaxo-Smith-Kline, Medtronic, Boston-Scientific, Pfizer, Xention, Sanofi-Aventis, Biocritique, Scientific, Pfizer, Xention, Sanofi-Aventis, Biocritique, Novartis, Astellas, Cardiome, Paracor, Gilead, Astra- Novartis, Astellas, Cardiome, Paracor, Gilead, Astra- Zeneca, Boehringer-IngelheimZeneca, Boehringer-Ingelheim

Effets du RAAS sur l’AFEffets du RAAS sur l’AF

In human AF, tissue ACE is up-regulated correlating with increased In human AF, tissue ACE is up-regulated correlating with increased atrial angiotensin II productionatrial angiotensin II production11

ACE inhibition has been shown to attenuate atrial structural ACE inhibition has been shown to attenuate atrial structural remodeling (interstitial fibrosis) in a canine rapid ventricular pacing remodeling (interstitial fibrosis) in a canine rapid ventricular pacing modelmodel2 2 and reduce AF in post-MI LVD patientsand reduce AF in post-MI LVD patients33

There is an association of RAAS gene polymorphisms in patients There is an association of RAAS gene polymorphisms in patients with non-familial structural AFwith non-familial structural AF44

– Are such patients more likely to benefit from ACEI and ARBs?Are such patients more likely to benefit from ACEI and ARBs?

1. Goette A, et al. J Am Coll Cardiol 2000;35:1669-16772. Li D, et al. Circulation 1999;100:87-952. Li D, et al. Circulation 1999;100:87-953. Pedersen et al. Circulation 1999:100:376-3803. Pedersen et al. Circulation 1999:100:376-3804. Tsai CT, et al. Circulation 2004;109:1640-16464. Tsai CT, et al. Circulation 2004;109:1640-1646

Mécanismes Possibles des ARBs dans la Mécanismes Possibles des ARBs dans la Prévention de l’AFPrévention de l’AF

Aksnes TA, et al J Hyperten 2007;25:15-23Aksnes TA, et al J Hyperten 2007;25:15-23

Les Antagonistes de l’Angiotensine II Les Antagonistes de l’Angiotensine II Attenuent le Remodelage Électrique Attenuent le Remodelage Électrique

dans l’AFdans l’AF

Nakashima H, et al. Circulation. 2000;101:2612-2617

AE

RP

, % c

han

ge

Captopril

Candesartan

ControlControl

120

110

100

90

80

0 30 60 120 180 30R Time (min)InfusionInfusion

PacingPacing

ACEI: Prévention du Remodelage StructuralACEI: Prévention du Remodelage Structural

Fibrosis AF Duration

0

100

200

300

400

500

600

700

800

900

CT

L

CH

F

CH

F+

E

**

* #

Li D, et al. Circulation 1999;100:87-95Li D, et al. Circulation 1999;100:87-95Kumagai K, et al. JACC 2003;41:2197-2204Kumagai K, et al. JACC 2003;41:2197-2204

0

3

CT

L

CH

F

CH

F+

E

**

**##

6

9

12

15

Control

CHF

CHF +Enalapril

% sec

In another study, candesartan decreased duration In another study, candesartan decreased duration of AF (4-5 weeks) (p<.05) and % atrial fibrosis in atrialof AF (4-5 weeks) (p<.05) and % atrial fibrosis in atrial paced dog model (p<.001)paced dog model (p<.001)

Le RAAS a-t-il des Effets Le RAAS a-t-il des Effets Électrophysiologiques Directs?Électrophysiologiques Directs?

In a canine RVP model, AF duration increases compared to In a canine RVP model, AF duration increases compared to controls both before and following recovery of pacing-controls both before and following recovery of pacing-induced atrial electrical remodelinginduced atrial electrical remodeling

– Tissue fibrosis creates a substrate for increased Tissue fibrosis creates a substrate for increased arrhythmia persistence independent of action potential arrhythmia persistence independent of action potential durationduration

Although enalapril attenuated the development of interstitial Although enalapril attenuated the development of interstitial fibrosis, it had no impact on the AERP, conduction velocity fibrosis, it had no impact on the AERP, conduction velocity or wavelength of conductionor wavelength of conduction

Angiotensin II may contribute to the development of atrial Angiotensin II may contribute to the development of atrial fibrosis, fibrosis, but with minimal electrophysiologic effectsbut with minimal electrophysiologic effects

Shi Y, et al. Cardiovasc Res 2002;54:456-461Shi Y, et al. Cardiovasc Res 2002;54:456-461Ram R, Van Wagoner D. JCVEP 2006;17:42-543Ram R, Van Wagoner D. JCVEP 2006;17:42-543

Losartan Évite le Remodelage Auriculaire Losartan Évite le Remodelage Auriculaire Induit par la tension Induit par la tension Chez des Myocites Chez des Myocites

Néonatales Auriculaires CultivésNéonatales Auriculaires Cultivés

Saygili E, et al. Am J Physiol Heart Circ Physiol 2007;292:H2898-H2995Saygili E, et al. Am J Physiol Heart Circ Physiol 2007;292:H2898-H2995

*p<.05 vs. control*p<.05 vs. control**p<.05 vs. stretched**p<.05 vs. stretched

•Losartan prevented stretch -induced increases in the protein to Losartan prevented stretch -induced increases in the protein to DNA ratio, ANP mRNA expressionDNA ratio, ANP mRNA expression•Attenuated stretch-induced expression of IK1,IKur and Ito Attenuated stretch-induced expression of IK1,IKur and Ito •Thus preventing the stretch-induced abbreviation of atrial APDThus preventing the stretch-induced abbreviation of atrial APD

Amiodarone + Losartan ou Perindopril Maintient Amiodarone + Losartan ou Perindopril Maintient mieux NSR Post-CV que l’Amiodarone Seulementmieux NSR Post-CV que l’Amiodarone Seulement

0

10

20

30

40

50

60

70

80

90

Amio Amio + Losartan Amio + Perindopril

% in NSR% in NSR P=.006P=.006

Yin Y, et al. Eur Heart J 2006;27:1841-1846Yin Y, et al. Eur Heart J 2006;27:1841-1846

59 pts in each group59 pts in each group

pNSpNS

P=.04P=.04

ACEI et ARB Attenuent l’Augmentation ACEI et ARB Attenuent l’Augmentation Dépendant du Temps dans le Diamètre LA Dépendant du Temps dans le Diamètre LA

dans l’AFdans l’AF

Yin Y, et al. Eur Heart J 2006;27:1841.

p < 0.001 for trendAmiodaroneAmiodarone + LosartanAmiodarone + perindopril

p < 0.001 for trend

p < 0.052 for trend

Baseline 6 months 12 months 18 months 24 months

33

34

35

36

37

38

39

LA Diameter in mmLA Diameter in mm

Prévention de l’AF: ARBs Vs. ACEI? Prévention de l’AF: ARBs Vs. ACEI?

Salehian et al. Am Heart J 2007;154:448-453Salehian et al. Am Heart J 2007;154:448-453

Losartan Est-il Supérieur à Atenolol pour Losartan Est-il Supérieur à Atenolol pour Supprimer l’AF dans l’Étude LIFE?Supprimer l’AF dans l’Étude LIFE?

Losartan reduced AF compared to atenolol (HR 0.67; Losartan reduced AF compared to atenolol (HR 0.67; PP.001) in 342 .001) in 342 hypertensive patients with LVH and AFhypertensive patients with LVH and AF

Losartan also reduced stroke (HR 0.49; CI 0.29-0.86; Losartan also reduced stroke (HR 0.49; CI 0.29-0.86; PP=.01)=.01)

Wachtell et al. J Am Coll Cardiol. 2005;45:712-719Wachtell et al. J Am Coll Cardiol. 2005;45:712-719

Time (Months)Time (Months)

Pro

po

rtio

n o

f P

atie

nts

Pro

po

rtio

n o

f P

atie

nts

Wit

h F

irst

Eve

nt

(%)

Wit

h F

irst

Eve

nt

(%) HR: 0.67 (95% CI: 0.55-0.83), HR: 0.67 (95% CI: 0.55-0.83), PP.001..001.

Adj. HR: 0.67 (95% CI: 0.55-0.83), Adj. HR: 0.67 (95% CI: 0.55-0.83), PP.001..001.Log rank Log rank PP=.0001=.0001

88

77

66

55

44

33

22

11

0000 66 1212 1818 2424 3030 3636 4242 4848 5454 6060 6666

LosartanLosartan

AtenololAtenolol

Pour Quel Groupe de Patients le Blocage du Pour Quel Groupe de Patients le Blocage du RAAS est-il efficace pour éviter l’AF?RAAS est-il efficace pour éviter l’AF?

Hypertension Hypertension ++ LVH LVH– In In LIFELIFE, losartan reduced AF compared to atenolol (HR 0.67; , losartan reduced AF compared to atenolol (HR 0.67; PP.001) in 342 .001) in 342

hypertensive patients with LVH and AF hypertensive patients with LVH and AF (Wachtell et al. J Am Coll Cardiol. 2005;45: (Wachtell et al. J Am Coll Cardiol. 2005;45: 712-719)712-719)

Diastolic DysfunctionDiastolic Dysfunction– In CHARM, HR =0.894 (0.618-1.295) In CHARM, HR =0.894 (0.618-1.295) ((Ducharme et al. Am Heart J. 2006;152:86-92)

Systolic DysfunctionSystolic Dysfunction– InIn TRACE, TRACE, 5.3% of placebo vs. 2.8% of trandolopril group developed AF (p<.05)5.3% of placebo vs. 2.8% of trandolopril group developed AF (p<.05)(Pedersen et al. Circulation 1999:100:376-380)(Pedersen et al. Circulation 1999:100:376-380)– InIn SOLVD, SOLVD, 5.4% enalapril vs. 24 placebo developed AF (p<.0001)5.4% enalapril vs. 24 placebo developed AF (p<.0001) ((Vermes et al. Circ 2003; 107:2926-2931) – InIn VAL-HeFT, VAL-HeFT, Valsartan added to ACEI (93%) reduced AF by 35% (7.86% to Valsartan added to ACEI (93%) reduced AF by 35% (7.86% to

5.27%) 5.27%) (Maggioni AP, et al. Circ 2003;24:504)(Maggioni AP, et al. Circ 2003;24:504) DiabetesDiabetes

– In hypertensive/diabetic patients, valsartan-amlodipine lowered 1 year AF to 14% In hypertensive/diabetic patients, valsartan-amlodipine lowered 1 year AF to 14% from 41% with atenolol-amlodipine from 41% with atenolol-amlodipine ((Fogari R, et al. Circulation 2006;114: II)-789)

Post-AF ablationPost-AF ablation– No benefitNo benefit ((Richter et al. Am Heart J 2007;153:113-119)Richter et al. Am Heart J 2007;153:113-119)

All patientsAll patients– No benefit in HOPE if LVEF No benefit in HOPE if LVEF >> 40% with only a 2% development of AF overall 40% with only a 2% development of AF overall

(HR 0.92, pNS)(HR 0.92, pNS) (Salehian et al. Am Heart J 2007;154:448-453)(Salehian et al. Am Heart J 2007;154:448-453)

Essais en Cours pour Évaluer les ARBs Essais en Cours pour Évaluer les ARBs dans l’AFdans l’AF

ACTIVE-I ACTIVE-I (Irbesartan vs. placebo) - 9018 patients(Irbesartan vs. placebo) - 9018 patients– Primary outcome: stroke, MI, vascular death + CHF Primary outcome: stroke, MI, vascular death + CHF

hospitalizationhospitalization ANTIPAFANTIPAF (Olmesartan vs. placebo in PAF) (Olmesartan vs. placebo in PAF) CAPRAFCAPRAF (Candesartan vs. placebo) (Candesartan vs. placebo) DRAFTDRAFT (Diovan to Reduce post-CV recurrence of AF (Diovan to Reduce post-CV recurrence of AF

Trial)Trial) GISSI-AFGISSI-AF (Valsartan vs. placebo) – 1442 patients (Valsartan vs. placebo) – 1442 patients

– Primary endpoint: Time to 1Primary endpoint: Time to 1stst AF; total # AF episodes AF; total # AF episodes I-PACEI-PACE (Irbesartan vs. placebo) (Irbesartan vs. placebo) ON TARGET/TRANSCENDON TARGET/TRANSCEND (Telmisartan vs. ramipril (Telmisartan vs. ramipril

vs telmisartan + ramipril vs. placebo)vs telmisartan + ramipril vs. placebo)Connolly S, et al. Am Heart J 2006;151:1187-1193Connolly S, et al. Am Heart J 2006;151:1187-1193Disertori m, et al. J Cardiovasc Med 2006;7:29-38Disertori m, et al. J Cardiovasc Med 2006;7:29-38Teo K, et al. Am Heart j 2004;148:52-61Teo K, et al. Am Heart j 2004;148:52-61Aksnes TA, et al J Hyperten 2007;25:15-23Aksnes TA, et al J Hyperten 2007;25:15-23

Some of the above studies will tell us if Some of the above studies will tell us if ARBs will prevent AF on top of ACEIARBs will prevent AF on top of ACEI

Données Préliminaires ACTIVE-IDonnées Préliminaires ACTIVE-I

9018 patients (Irbesartan vs. placebo)9018 patients (Irbesartan vs. placebo) Primary outcome: stroke, MI, vascular death + CHF Primary outcome: stroke, MI, vascular death + CHF

hospitalizationhospitalization 65.2% permanent AF, 20.1 % PAF, 14.5% persistent 65.2% permanent AF, 20.1 % PAF, 14.5% persistent

AFAF 60.4% already on ACEI60.4% already on ACEI Largest trial of BP lowering in AF Largest trial of BP lowering in AF

– 88.7% hypertensive88.7% hypertensive– 4-7 mm Hg decrease in SBP over course of study4-7 mm Hg decrease in SBP over course of study

Follow-up complete 5/08Follow-up complete 5/08– Mean follow-up 3 yearsMean follow-up 3 years

Connolly S. Venice 10/07Connolly S. Venice 10/07

0

12

Pro

bab

ilit

y o

f Fir

st

Recu

rren

ce o

f A

F

GISSI AFGISSI AFRésultats de l’Étude: Probabilité de Première Récurrence d’AFRésultats de l’Étude: Probabilité de Première Récurrence d’AF

Valsartan

Placebo

Log-rank testp=0.829

Patients at Risk0 1 2 3 4 5 6 7 8 9 10 11

Time Since Randomization (Months)

ValsartanPlacebo

722720

586589

524520

491484

465454

445435

423407

398387

383377

368359

356344

343334

260254

0.1

0.2

0.3

0.4

0.5

0.6

Maggioni A. AHA 2008 Scientific Sessions, Abstract Oral Session 4096, Nov. 11, 2008

Valsartan: 371/722 (51.4%)

Placebo: 375/720 (52.1%)

Adjusted* HR 0.9996%CI 0.85-1.15

P value 0.84

Effets des Antagonistes de l’Aldosterone sur Effets des Antagonistes de l’Aldosterone sur l’AFl’AF

Serum aldosterone levels have been reported to be Serum aldosterone levels have been reported to be elevated in AF patients with levels returning to elevated in AF patients with levels returning to normal with restoration of sinus rhythmnormal with restoration of sinus rhythm11

In a rat model of heart failure following MI, In a rat model of heart failure following MI, spironolactone decreased atrial fibrosis and atrial P-spironolactone decreased atrial fibrosis and atrial P-wave duration but ACEI and beta-blockers did notwave duration but ACEI and beta-blockers did not22

In the RVP heart model, eplerenone further In the RVP heart model, eplerenone further prolonged right atrial appendage and left posterior prolonged right atrial appendage and left posterior AERP but no effect in Bachmann’s bundleAERP but no effect in Bachmann’s bundle– No effect of Angiotensin II blockadeNo effect of Angiotensin II blockade33

1. Goette A et al. Am J Cardiol 2001;88:906-9091. Goette A et al. Am J Cardiol 2001;88:906-9092. Milliez P, et al. Eur Heart J 2005;26:2193-21992. Milliez P, et al. Eur Heart J 2005;26:2193-21993. Schroff SC, et al. JCVEP 2006;17:534-5413. Schroff SC, et al. JCVEP 2006;17:534-541

Statines et AFStatines et AF

In a tachycardia induced AF dog model,simvastatin In a tachycardia induced AF dog model,simvastatin suppressed RAP remodeling effects (shortening of suppressed RAP remodeling effects (shortening of atrial ERP) and induced AF duration (>1000 sec with atrial ERP) and induced AF duration (>1000 sec with placebo vs 40 sec with statin)*placebo vs 40 sec with statin)*

Tachy-pacing downregulated L-type calcium channel Tachy-pacing downregulated L-type calcium channel alpha subunit expression was greatly attenuated by alpha subunit expression was greatly attenuated by simvastatin.simvastatin.

Retrospective meta-analysis have suggested a Retrospective meta-analysis have suggested a beneficial effect in AF in manbeneficial effect in AF in man

Statin therapy has also been found to reduce the risk Statin therapy has also been found to reduce the risk for first ventricular arrhythmia in pts with CAD and for first ventricular arrhythmia in pts with CAD and an ICD.**an ICD.**

* Shiroshita-Takeshita et al. Circulation 2004; 110:2313-19** Chiu et al. Am J Cardiol 2005; 95:490-91

Les Statines Peuvent Réduire l’AF dans Les Statines Peuvent Réduire l’AF dans la CADla CAD

449 pts (age 40-87 yrs) with chronic stable CAD without 449 pts (age 40-87 yrs) with chronic stable CAD without AF were followed prospectively for an average of 5 yrs in AF were followed prospectively for an average of 5 yrs in a large out-patient cardiology practicea large out-patient cardiology practice

The association between statin use and the development of The association between statin use and the development of AF was evaluatedAF was evaluated

52 pts (12%) developed AF52 pts (12%) developed AF Statins, used by 59% of the subjects, reduced the Statins, used by 59% of the subjects, reduced the

probability of developing AF (HR 0.49; CI 0.28-0.83; probability of developing AF (HR 0.49; CI 0.28-0.83; p<0.05)p<0.05)

This remained significant after adjustment for age, HTN, This remained significant after adjustment for age, HTN, LVEF, CHF, ACU, baseline TC, change in TC (HR 0.37; LVEF, CHF, ACU, baseline TC, change in TC (HR 0.37; CI 0.18-0.76)CI 0.18-0.76)

Young-Xu et al. Am J Cardiol 2003; 92:1379-1383Young-Xu et al. Am J Cardiol 2003; 92:1379-1383

Effet de l’Atorvastatine 10 mg/jour Effet de l’Atorvastatine 10 mg/jour dans l’AF Persistantedans l’AF Persistante

05

101520

25303540

4550

Conversion Recurrence

Ozaydin M, et al. Am J Cardiol 2006:97:1490-1493Ozaydin M, et al. Am J Cardiol 2006:97:1490-1493

%%

ControlControl

AtorvastatinAtorvastatin

0

20

40

60

80

100

1 2 3 7 14 21 30

Atr

ial f

ibri

llati

on

-fre

e s

urv

ival

(%

)

Atorvastatin Placebo

ARMYDA-3 (Atorvastatine pour la Réduction de la Dysrythmie du Myocarde après la Chirurgie Cardiaque):: SSurvie Libre d’AF

Patti, G. et al., Circulation 2006;114:1455-1461

P = 0.003

Post-operative daysDaysDays

•Atorvastatin significantly reduced the incidence of AF versus placebo (35% versus 57%, P = 0.003)•Length of stay was longer in the placebo versus atorvastatin arm (6.9 + 1.4 versus 6.3 + 1.2 days, P = 0.001)

Statines: Récurrence de l’AF Après la Statines: Récurrence de l’AF Après la CardioversionCardioversion

62 patients with lone, persistent AF underwent 62 patients with lone, persistent AF underwent successful DC cardioversion.successful DC cardioversion.

10/62 were on statin therapy for hyperlipidemia 10/62 were on statin therapy for hyperlipidemia (starting pre-CV). They were also older but had no (starting pre-CV). They were also older but had no difference in SHD or AF therapy.difference in SHD or AF therapy.

In a follow up of 44 months on average the use of In a follow up of 44 months on average the use of statins in a retrospective analysis was found to statins in a retrospective analysis was found to significantly decrease the number with recurrent AF:significantly decrease the number with recurrent AF:– 40% vs 82%, p=0.00740% vs 82%, p=0.007

Siu et al. Am J Cardiol 2003; 92:1343Siu et al. Am J Cardiol 2003; 92:1343

Résumé des Effets Essentiels EP de l’Huile de Résumé des Effets Essentiels EP de l’Huile de PoissonPoisson

EPA prolongs the QTc in the Langendorff rabbit modelEPA prolongs the QTc in the Langendorff rabbit model Fish oils block L-type calcium channelsFish oils block L-type calcium channels EPA and DHA suppress Na channels in cardiomyocytes and DHA EPA and DHA suppress Na channels in cardiomyocytes and DHA

slows Na channel dependent longitudinal conduction in the slows Na channel dependent longitudinal conduction in the perfused heart modelperfused heart model

DHA and EPA raise the threshold to elicit an extrasystoleDHA and EPA raise the threshold to elicit an extrasystole In humans, fish oils slow heart rate, increase the PR and decrease In humans, fish oils slow heart rate, increase the PR and decrease

the likelihood of a prolonged QTcthe likelihood of a prolonged QTc Ninio et al noted that feeding rabbits 5% tuna oil for 12 weeks Ninio et al noted that feeding rabbits 5% tuna oil for 12 weeks

significantly increased the atrial pressure necessary to induce significantly increased the atrial pressure necessary to induce sustained AF compared to controlssustained AF compared to controls– The decline in AERP produced by increasing atrial pressure was The decline in AERP produced by increasing atrial pressure was

less attenuated in the tuna oil groupless attenuated in the tuna oil group Mozzaferian et al showed that consumption of tuna or other Mozzaferian et al showed that consumption of tuna or other

broiled/baked fish lowered AF by 31% if intake was broiled/baked fish lowered AF by 31% if intake was >> 5 times per 5 times per week compared to < 1 per month (p=.004)week compared to < 1 per month (p=.004)

Dhein, et. al. Arch Phamacol 2005;371:202-211 Xiao, et. al. Proc Natl Acad Sci 1997;94:4182-4187 Ninio DM, et al. JCVEP 2005;16:1189-1194 Mozzaferian D, et al. Circulation 2004;110:368-373

N-3 PUFAs Évitent le Remodelage Électrique Aigu N-3 PUFAs Évitent le Remodelage Électrique Aigu dans le Modèle Canin de Tachy-Stimulation dans le Modèle Canin de Tachy-Stimulation

Auriculaire AiguëAuriculaire Aiguë

Da Cunha DNQ, et al. Br J Pharmacol 2007;150:281-285Da Cunha DNQ, et al. Br J Pharmacol 2007;150:281-285

NSRNSR Atrial PacingAtrial Pacing

Omega 3-PUFA Évite l’AF Associée à l’Insuffisance Omega 3-PUFA Évite l’AF Associée à l’Insuffisance Cardiaque Mais N’Évite Pas le Remodelage de la Cardiaque Mais N’Évite Pas le Remodelage de la

Tachycardie AuriculaireTachycardie Auriculaire

Sakabe M, et al. Circulation 2007;116:2101-2109Sakabe M, et al. Circulation 2007;116:2101-2109

““The beneficial effects of PUFAs on structural remodeling, possibly related to The beneficial effects of PUFAs on structural remodeling, possibly related to prevention of mitogen-activated protein kinase activation, may contribute to prevention of mitogen-activated protein kinase activation, may contribute to their clinical anti-AF potential.”their clinical anti-AF potential.”

Incidence Réduite de l’AF Induite par la Voie Incidence Réduite de l’AF Induite par la Voie Vagale et Expression des Connexines par n-3-Vagale et Expression des Connexines par n-3-

PUFAs chez les ChiensPUFAs chez les Chiens Atrial tissue n-3 PUFA levels increased in oral treatment Atrial tissue n-3 PUFA levels increased in oral treatment

dogs (p<.0001)dogs (p<.0001)

Incidence of AF inducibility decreased from 48.9% in Incidence of AF inducibility decreased from 48.9% in controls to 10.5% in treated dogs using the extrastimulus controls to 10.5% in treated dogs using the extrastimulus technique (p<.003)technique (p<.003)

Both Cx40 and Cx43 levels (primary components of the Both Cx40 and Cx43 levels (primary components of the atrial GAP junctions) were lower in treated dogs (p=.02)atrial GAP junctions) were lower in treated dogs (p=.02)

Conclusion: Oral Rx with fish oils increased atrial n-3 Conclusion: Oral Rx with fish oils increased atrial n-3 PUFA levels and reduced vulnerability to AF induction. PUFA levels and reduced vulnerability to AF induction. Modulation of cardiac connexin expression by n-3 PUFAs Modulation of cardiac connexin expression by n-3 PUFAs may contribute to the antiarrhythmic effect of fish oilsmay contribute to the antiarrhythmic effect of fish oils

Sarrazin JF, et al. J Am Coll Cardiol 2007;50:1505-1512Sarrazin JF, et al. J Am Coll Cardiol 2007;50:1505-1512

Calo L et al. J Am Coll Cardiol. 2005;45:1723-1728

Control Control (n=81)(n=81)

N-3 FA N-3 FA (n=79)(n=79)

PP

Post Post CABG AFCABG AF

33%33% 15%15% 0.0130.013

Hours of Hours of AFAF

2424 1616 0.120.12

Length of Length of StayStay

8.2 days8.2 days 7.3 days7.3 days 0.0170.017

Omega-3 pour la Prévention de la Fibrillation Omega-3 pour la Prévention de la Fibrillation Auriculaire Post-CABGAuriculaire Post-CABG

• 160 patients awaiting CABG

• Randomized to usual care or EPA+DHA(1.7 g/d)

• From 5 days pre-surgery through hospitalization

• Endpoint was AF detected by ECG during hospitalization. AF >5 min or requiring intervention

Pat

ien

ts f

ree

of A

tria

l Fib

rill

ati

on

(%

)

Days after Surgery0 1 2 3 4 5 6 7 8 9

100%

90%

80%

70%

60%

50%

N-3 FA Group

Log-rank P=0.009 PUFAs Group

Control Group

10 11 12 13 14 15 16 17 18

Réduction de l’AF chez des Patients Portant Réduction de l’AF chez des Patients Portant des Stimulateurs I Double Chambredes Stimulateurs I Double Chambre

Number of atrial tachyarrhythmia episodes

Atrial tachyarrhythmia burdern

444181

552

3.89%

1.06%2.69%

•N=46 (6 not analyzed) with dual chamber PM •Design—OLX, received 1gm N-3 or nothing for treatment periods of 4 months•Results

•59% reduction in AFib episodes (P=0.037); 67% reduction in AFib burden (P=0.029)•P=0.065 and 0.003 for increase in AFib episodes and AFib burden following cessation of therapy•For patients with sustained AFib there were similar significant reductions in AFib episodes and AFib burden.

Biscione, et. al, Ital Heart J Suppl Vol 6 Gennaio 2005 (53-59)

Bénéfice des Huiles de Poisson dans la Bénéfice des Huiles de Poisson dans la Suppresion de la Fibrillation Auriculaire: Suppresion de la Fibrillation Auriculaire:

Mécanismes PossiblesMécanismes Possibles

Direct electrophysiologic effectsDirect electrophysiologic effects

Anti-inflammatory effectsAnti-inflammatory effects

Slow progression of CADSlow progression of CAD

StructuralStructural

MetabolicMetabolic

AutonomicAutonomic

Reiffel JA, McDonald A. Am J Cardiol 2006;98:50i-60i

OM8OM8

Randomized, double blind, placebo controlled, parallel-group Randomized, double blind, placebo controlled, parallel-group trial to assess the efficacy and safety of Lovaza for the trial to assess the efficacy and safety of Lovaza for the prevention of recurrent, symptomatic AFprevention of recurrent, symptomatic AF

Primary Objective: Primary Objective: assess the effect of Lovazaassess the effect of Lovaza on time to on time to the first symptomatic recurrence of AF the first symptomatic recurrence of AF

– Time will be measured as event-free days from the end of Time will be measured as event-free days from the end of the loading period (Week 1) the loading period (Week 1)

Inclusion criteria: Inclusion criteria: >>18 years old, electrocardiographic 18 years old, electrocardiographic evidence of symptomatic paroxysmal AF, no current anti-evidence of symptomatic paroxysmal AF, no current anti-arrhythmic therapy. arrhythmic therapy.

– Rate control and/or anticoagulation therapy or no therapy Rate control and/or anticoagulation therapy or no therapy is permitted. is permitted.

– Approximately 550 subjects (275 per treatment group) will Approximately 550 subjects (275 per treatment group) will be recruitedbe recruited

Quel est le Mécanisme des Thérapies Quel est le Mécanisme des Thérapies En Aval dans la Prévention de l’AF?En Aval dans la Prévention de l’AF?

ACEI, ARBACEI, ARB – Angiotensin II blockade; decreasing – Angiotensin II blockade; decreasing stretch activated channels; slowing progression of stretch activated channels; slowing progression of atrial remodelingatrial remodeling

StatinsStatins – Anti-inflammatory; decrease lipids – Anti-inflammatory; decrease lipids

PUFAPUFA – Anti-inflammatory; decreasing – Anti-inflammatory; decreasing triglycerides; direct channel EP effectstriglycerides; direct channel EP effects

Conclusion: Les Drogues En Amont pour Conclusion: Les Drogues En Amont pour l’AFl’AF

Encouraging data for a number of new concepts Encouraging data for a number of new concepts Proof of efficacy/safety will come from well-done, Proof of efficacy/safety will come from well-done,

adequately powered, controlled, randomized trialsadequately powered, controlled, randomized trials

– Which patient groups will benefit?Which patient groups will benefit? Added benefits of beta-blockers, ACEI, ARB, statins, Added benefits of beta-blockers, ACEI, ARB, statins,

Omega-3 fish oil will have to be considered as part of Omega-3 fish oil will have to be considered as part of any new drug’s efficacy in specific patient populationsany new drug’s efficacy in specific patient populations

Future possibility of drug combinations with Future possibility of drug combinations with antiarrhythmic agentsantiarrhythmic agents