Anti-remodelling Therapy (cont…)

Early Management of Atrial
Fibrillation to Prevent
Cardiovascular Complications
Supported by an unrestricted
educational grant from Sanofi
Contributing Authors
Stanley Nattel MD1, Eduard Guasch MD1, Irina Savelieva MD2, Francisco G Cosio MD3, Irene
Valverde MD3, Jonathan L Halperin MD4, Jennifer M Conroy MD4, Sana M Al-Khatib MD
MHS5, Paul L Hess MD5, Paulus Kirchhof MD8, 9, 10, Joseph De Bono DPhil7, Gregory Y H Lip
MD6, Amitava Banerjee DPhil6, Jeremy Ruskin MD11, Dan Blendea MD11, A John Camm MD2*
Heart Institute, Montreal, QC, Canada; 2Division of Clinical Sciences, Cardiovascular
Science, St George’s University of London, London, UK; 3Cardiología Department, Hospital
Universitario de Getafe, Madrid, Spain; 4Zena and Michael A. Wiener Cardiovascular Institute,
Mount Sinai School of Medicine, New York, USA (affiliation at the time of initial manuscript
development); 5Department of Medicine, Cardiology Division, Duke University Medical Center,
Durham, NC, USA; 6University of Birmingham Centre for Cardiovascular Sciences, City Hospital,
Birmingham, UK; 7University Hospitals Birmingham NHS Trust, Birmingham, UK; 8University of
Birmingham Centre for Cardiovascular Sciences, University of Birmingham and Sandwell and
West Birmingham NHS Trust, Birmingham, UK; 9Department of Cardiology and Angiology,
Hospital of the University of Münster, Münster, Germany; 10German Atrial Fibrillation Competence
NETwork (AFNET), Münster, Germany 11Department of Medicine, Massachusetts General
Hospital, Boston, MA, USA
• AF is a progressive disease that evolves from
paroxysmal through persistent to “permanent” forms.
• Some data suggest that persistent AF is present
in 40% of cases at diagnosis.1
• Earlier diagnosis and treatment may limit progression.
• Personalized treatment may improve outcomes
through analysis of each individual’s pathophysiology,
risk factors, and genetic predisposition.
1. Panizo JG et al. Conference of the World Society of Arrythmias 2011;34:1307-61
Registry Data
• Studies have been undertaken to evaluate the clinical progression
of AF.
• The prevalence of progression varies with patient population
and duration of follow-up, but is as high as 77% over 14 years.1
• The overall progression rate is ~5% per annum (excluding younger
patients without CV disease).1
• Older patients and those with underlying heart disease have faster
progression rates.
• Risk of AF is exacerbated by obesity, diabetes, and lack of exercise,
however, extreme training can predispose other healthy individuals
to AF.2
1. Kato T et al. Circulation Journal 2004;68:568-572.
2. Kirchhof P et al. Thrombosis and Haemostasis 2011;106:1012-1019.
Abbreviation: CV, cardiovascular
Registry Studies
No. of
Osaka, 1997
61 ±12
Durham, 2000
60 ±13
67 (55–78)
Progression of AF
Predictors of progression
Sustained AF
≥6 months: 11.5
Left atrial size, abnormal
P-signal-averaged ECG
Abe Y et al. Circulation
8 at 1 year
18 at 4 years
Age, AF at presentation
Al-Khatib SM et al. American Heart
Journal 2000;140:142-145
HATCH score
Barrett TW et al. American Journal
of Emergency Medicine
Overall: age, development of
heart failure and hypertension
Paroxysmal: age, development of
heart failure and hypertension
Potpara TS et al. CHEST
study, 2012
43.2 ± 9.9
Overall:33.5 Paroxysmal
AF: 19.1
10-year cumulative rate
of progression: 26.1
CARAF, 2005
8.6 at 1 year 24.7 at 5
years Any recurrent AF:
63.2 at 5 years
Age, cardiomyopathy, mitral
regurgitation, left atrial
Kerr CR et al. American Heart
Journal 2005;149:489-496
Danish Study,
Underlying heart disease,
Petersen P and J Godtfredsen.
Stroke 1986;17:622-626
Heart Survey,
64 ± 13
(Permanent: 8
Other: 7)
Age, heart failure, hypertension,
stroke/TIA, COPD
De Vos CB et al. Am Heart J. 2012
Age, heart failure, hypertension,
COPD, number of electrical
cardioversions, dilated
cardiomyopathy, prosthetic valve
Fauchier L et al. Circulation
Tours, 2010
71 ± 13
Abbreviations: AF, atrial fibrillation; CARAF, Canadian Registry of Atrial Fibrillation; COPD, chronic
obstructive pulmonary disease; ECG, electrocardiogram; TIA, transient ischemic attack.
Registry Studies
No. of
58.3 ± 11.8
Progression of AF
Predictors of progression
57 at 10 years
77 at 15 years
Age, myocardial infarction, valvular
heart disease, left atrial enlargement
Kato T et al. Circ J 2004;68:
Tokyo, 2004
County, 1987
Recurrent paroxysmal: 58
Kopecky S et al. N Engl J Med
County, 2007
44.2 ±11.7
31 (30-year
Age, QRS abnormalities
Jahangir A et al. Circulation
66 ± 11.9
31 Rhythm vs rate
control: 13 vs 54
Age, AF ≥3 months, persistent vs
paroxysmal AF, rhythm control,
sinus rhythm, heart failure
Camm AJ et al. J Am Coll Cardiol
65.1 ±12
Heart failure, hypertension,
rate control
De Vos CB et al. Am Heart J
63 ± 11
Recurrent paroxysmal:
55.6 Sustained: 4.7%
Rostagno C et al. Am J Cardiol
Tokyo, 1995
62.4 ± 11
(70.1 ± 8.2
Tokyo, 1981
Sustained AF ≥6 months:
Rheumatic valvular disease;
frequency of paroxysms
Takahashi N et al. Jpn Heart J
70 ±14
11 at 1 year
17 at 2.7 years
Valvular heart disease, moderate to
high alcohol intake
Ruigomez A et al. BMC
Cardiovasc Disord 2005;5:20.
Age, heart failure, CTR ≥50%,
Sustained AF ≥6 months:
diabetes, LA ≥38 mm, LVEF ≤0.76, f
waves in V1 ≥2 mm
Sakamoto H et al. Jpn Heart J
Abbreviations: AF, atrial fibrillation; RECORD-AF, REgistry on Cardiac rhythm disORDers assessing control
of Atrial Fibrillation.
Basic Mechanisms of AF-related Remodelling
‘AF begets AF’
AF induces mechanisms for self-perpetuation.
The arrhythmia induces structural, electrical, and autonomic remodelling
upon pre-existing abnormalities to increase susceptibility to recurrent
and more persistent AF.
Clinical observations
Prevalence of AF is higher in older age groups.
There is an age-dependent loss of cardiomyocytes in the heart.
Basic Mechanisms Contributing to AF
Conditions that improve AF: atrial structural, electrical, and autonomic abnormalities
and/or remodelling that lead to re-entry or triggered activity.
Slow conduction
velocities and short
refractory periods allow
the establishment and
stabilization of re-entrant
Delayed afterdepolarizations emerge
from abnormal Ca2+
release from the
sarcoplasmic reticulum
during diastole, acting as
triggers for re-entry or,
when sustained, as a
focal source for AF.
Mechanistic Details of AF Remodelling
Within hours of AF-onset, the refractory period during
AF heterogeneously shortens in response to electrical
and autonomic remodelling.
Tachycardia-induced Ca2+ accumulation activates
α1-subunit mRNA down-regulation.
PKC isoform-switch activates the ion channel (see right)
leading to decreased atrial conduction velocity by
impairing cellular coupling.
The importance of Ca2+-handling is increasingly recognized:
Rapid atrial activation rates stimulate CaMKII.
This phosphorylates the Ca2+-release channel (Ryr2), increasing its Ca2+- sensitivity
and facilitating diastolic Ca2+-leakage events.
Ca2+- leak events cause delayed afterdepolarizations that induce atrial premature beats
and/or tachycardias.
Intracellular calcium oscillations might also induce atrial repolarization heterogeneity,
favoring re-entry.
Abbreviations: PKC, protein-kinase C; CaMKII, Ca2+-/calmodulin-dependent kinase-II; Ryr2, type 2 ryanodine
Figure taken from Xander HT et al. Circulation Research.2004; 94: e61-e70
Mechanistic Details of AF Remodelling (cont…)
Autonomic tone-remodelling also contributes to the AF-induced
arrhythmia substrate.
Short periods of atrial tachycardia (3 hours) increase discharge-rates in the intracardiac
ganglionated plexi.
Ablation of the intracardiac autonomic ganglia blunts tachycardia-induced refractoriness
shortening and AF-susceptibility, demonstrating a role for autonomic tone in AF-induced
Spatially-heterogeneous sympathetic hyper-innervation results from longer-lasting AF.
Arrhythmogenic structural remodelling develops after longer-term AF-induced
remodelling, and uncontrolled ventricular rates accelerate structural remodelling by
inducing myocardial dysfunction.
Cardiomyocyte-fibroblast interactions consequent to sustained atrial
tachycardia also promote fibrosis.
Cardiac fibrosis, a hallmark of the structural AF substrate, could be responsible for the
atrial endo-epicardial electrical dissociation that underlies complex intra-atrial re-entry.
Mechanistic Details of AF Remodelling (cont…)
Electrical remodelling and AF-inducibility develop rate-dependently
in dogs, and are almost negligible at rates ≤200 beats/minute.1
Atrial ectopic activity and AF often coexist, and patients with frequent
atrial tachyarrhythmias, even of relatively short duration, are at increased
risk of AF.
The association between AF and atrial tachyarrhythmias could be due
to common underlying conditions, to atrial tachycardias acting as a
repetitive trigger for AF, or to the induction of AF-promoting remodelling
by tachycardias.
These explanations are by no means mutually exclusive and might all
apply, to some extent, in many cases.
Shiroshita-Takeshita A et al. Cardiovasc Res 2009;81:90-97
Relationship Between Basic Mechanisms
and Clinical Forms
AF occurrence requires the
presence of both triggers and
substrate for the arrhythmia.
Changes in substrate are
believed to contribute to AF
Progression rate is affected
by the frequency, duration,
and time between
paroxysmal AF episodes.
AF episodes become more
persistent when the substrate
is highly developed.
Figure modified from Cosio FG et al. Europace 2008;10:21-27.
Relationship Between Basic Mechanisms
and Clinical Forms (cont…)
• Ongoing triggers may also contribute to the maintenance of
sustained AF.
– Some patients do not progress to “permanent” forms,
presumably because of limited development of the primary
condition, resistance to AF-induced remodelling, or
genetically-determined patient-specific protective factors.
– Patients without structural remodelling progress more
gradually than those with heart disease.
• Prospective studies with careful clinical, biomarker, genetic, and
atrial-imaging assessment are needed to better understand the
basic determinants of AF-progression.
Anti-remodelling Therapy
Classic AADs aim to prevent AF recurrences, however, there are no firm data to
substantiate positive results the efficacy.
Anti-modelling success has been with amiodarone – the current forerunner in treatment
for long-term SR maintenance.
Targeting primary disease
and AF-induced remodelling
may increase therapeutic
Anti-remodelling therapy is
directed at potentially
preventable causes of AFpromoted remodelling (see
right, represented by the red
Abbreviations: AAD, anti-arrhythmic drug; SR, sinus rhythm
Anti-remodelling Therapy (cont…)
Relieving hemodynamic overload may prevent AF recurrence:
Mitral commissurotomy may alter atrial electrophysiology and help restore SR by
electrical cardioversion.
Reversal of experimental left atrium volume overload reverts electrophysiological
remodelling, even when hypertrophy persists.
Treatment of left ventricular dysfunction by cardiac resynchronization therapy may
decrease the incidence of AF.
These observations suggest that treatment of the underlying condition,
rather than pharmacological targets alone, may be an important
component of any anti-remodelling approach.
The benefits of preventing remodelling with RAAS-inhibitors are wellestablished in experimental models, however, RAAS blockers have not
prevented AF in large, randomized prospective trials.
Inability to reverse advanced substrate or insufficient duration of therapy
may explain negative outcomes.
Abbreviation: RAAS, renin-angiotensin-aldosterone system
Anti-remodelling Therapy (cont…)
Recently-developed MRI-imaging techniques may provide new insights
by directly assessing effects of RAAS-blockers and other antiremodelling therapies on myocardial fibrosis.
MicroRNAs are evolving as important regulators of pathology. Atrialselective inhibition of microRNA-21 prevented AF by suppressing fibrosis
in a rat model, microRNA-26 restoration reversed K+-current upregulation
and AF-promotion in a mouse-model, and microRNA-29 restoration may
reverse AF-promoting profibrotic changes.
MicroRNA-modulation may provide new therapeutic strategies for
remodelling-prevention. Heat-shock protein-inducers, in development to
prevent remodeling, antioxidant-agents, and compounds targeting Ca2+handling, are attractive new therapeutic modalities.
Anti-remodelling Therapy (cont…)
Autonomic modulation via sub-threshold, low-level vagal stimulators
blunts autonomic remodelling and prevents AF-inducibility in animal
Vagus nerve stimulators are widely used, with few side-effects, to treat
refractory epilepsy, and their benefits in heart failure are under study, but
their potential role in AF-prevention has not been elucidated. Intracardiac
ganglion ablation might contribute to the success of AF ablation by
suppressing autonomic remodelling.
Renal denervation may also prevent AF-progression; whether this effect
is mediated by autonomic changes or suppression of hypertensioninduced remodelling remains to be established.
Further studies are needed to identify effective approaches to preventing
AF-progression and enable individualized therapy based on patientspecific pathophysiological processes.
Completed Rhythm Control Trials: Evidence I
Maintaining SR from the onset is one approach to preventing AF progression. Several trials
have investigated positive outcomes using this method and all but one have shown little
improvement with rhythm control compared to rate control:
Study name
AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) study
Trend towards increased mortality
with rhythm control
RACE (RAte Control vs. Electrical cardioversion)
No survival benefit when using
rhythm control strategies
PIAF (Pharmacological Intervention in Atrial Fibrillation)
No survival benefit when using
rhythm control strategies
STAF (Score for the Targeting of Atrial Fibrillation)
No survival benefit when using
rhythm control strategies
HOT CAFE (HOw to Treat Chronic Atrial Fibrillation)
No survival benefit when using
rhythm control strategies
Significant reduction in CV events
associated with rhythm rather than
rate control
Completed Rhythm Control Trials: Problems
Low rate of restoration and maintenance of SR.
Patients at last stage of the disease process.
The STAF, PIAF, and RACE trials patients had persistent AF.
PIAF median duration was 103-118 days prior to entry.
STAF recruited patients with higher risk of AF recurrence.
Two thirds of AF-CHF study patients had persistent AF. 46% had AF
for ≥6 months and all had structural disease.
AFFIRN recruited persistent and paroxymal AF, 65% had more than one
AF episode and most had structural cardiac abnormalities, including
dilated left atria 65% at the time of recruitment.
J-RHYTHM is the only trial to demonstrate an advantage of rhythm
control over rate control and was restricted to patients with paroxysmal
AF with a low underlying disease burden.
Completed Rhythm Control Trials: Evidence II
The balanced risks and benefits of rhythm control in AF may depend not only on the
agents used, but on the stage of the disease process at which treatment is initiated, as
demonstrated by these studies with patients at different stages of disease progression:
Patient recruitment
• High incidence of cardiac structural
abnormalities (60%)
• Eligible participants had SR within 6 months
of study entry (25% were in AF at
• Patients had permanent AF
(6-months’ continuous AF, 60% had
continuous AF ≥2 years)
Dronedarone group
Significant reduction in CV deaths
Increased mortality
CV hospitalization
Reduction in CV hospitalization
Increase in CV hospitalization in the
dronedarone-treated group
ATHENA, A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone
400 mg bid for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with
Atrial fibrillation/atrial flutter
PALLAS (Permanent Atrial fibriLLAtion outcome Study using dronedarone on top of standard Therapy)
Development in Trials of Aggressive Early
Rhythm Control
A greater understanding of the remodelling induced by AF has led to the
development of new treatment strategies to actively maintain sinus rhythm
early in the course of AF:
Better classification of AF might lead to more effectively directed therapy.
Current classification systems have major limitations.
Etiologically-based classifications have been suggested and are in active development.
Evaluation of atrial structural remodelling should include assessment of left
atrial function, biomarkers, and/or late enhancement MRI.
Individualized use of novel antiarrhythmic drugs, early catheter ablation, and ‘upstream’
therapy to prevent the development of the AF substrate.
Re-assessment of these markers after SR recovery for remodelling and re-classification of
AF would be advantageous.
Catheter ablation offers a greater chance of achieving and maintaining SR,
but this requires further evaluation.
Ongoing Trials of Aggressive Early Rhythm
These studies investigate whether early and active rhythm control of AF with
a strategy involving catheter ablation can break the cycle of progression of AF
and improve outcomes compared to standard therapies.
CABANA (NCT00911508)
EAST (NCT01288352)
Main aim
Compares ablation versus antiarrhythmic
Evaluates rhythm control with ablation and
antiarrhythmic drugs against guidelinemandated initial rate control
Aged ≥65 yrs, or aged <65 yrs with one or
more of the following risk factors for stroke:
Hypertension, Diabetes, Congestive heart
failure, Prior stroke or TIA
Recent onset AF and aged >75 yrs or prior
stroke, or two AF risk factors
Mortality, disabling stroke, serious bleeding,
cardiac arrest, CV hospitalization, cost
effectiveness, quality of life
CV death, stroke, CV hospitalization, time to
recurrent AF, quality of life, cognitive function
Estimated study
completion date
September 2015
July 2018
CABANA, Catheter ABlation vs ANti-Arrhythmic drug therapy for atrial fibrillation
EAST, Early treatment of Atrial fibrillation for Stroke prevention Trial
AF in the Acute Setting
AF is associated with considerable morbidity and mortality.
Patients who develop post-operative AF after cardiac surgery have a 3-fold higher
risk of stroke and a 2-fold higher risk of in-hospital and 6-month mortality compared
with those without AF.1
Risks of stroke and mortality are increased when AF complicates myocardial
infarction and sepsis.2
Rates of stroke, but not death, are elevated among patients who develop AF after
trans-catheter aortic valve replacement for severe aortic stenosis.3
The pathophysiology of transient AF varies with the type of clinical event.
Inflammation has been linked to AF during sepsis.4
Transient AF complicating acute clinical conditions may be a sentinel event,
identifying patients at risk for developing subsequent AF and its complications.
Risk factors for the development of AF in the acute setting are similar to those for
developing paroxysmal, persistent, or “permanent” AF unassociated with acute
Echahidi N et al. J Am Coll Cardiol 2008;51:793-801
Walkey AJ et al. JAMA 2011;306:2248-2254
3 Amat-Santos IJ et al. J Am Coll Cardiol 2012;59:178-188
4 Meierhenrich R et al. Crit Care 2010;14:R108
AF in the Acute Setting
Patients with acute clinical events may be at
high risk of developing longer-term AF.
More intensive monitoring to detect subclinical
AF is therefore needed, as suggested by this
Arrhythmias can be detected by simple pulsecheck or ECG rhythm-recording, or via a variety
of advanced types of monitoring equipment.
Post-MI arrhythmias were detected using implantable loop recorders in the
New-onset AF was detected using implantable devices in the ASSERT and was
found to identify increased stroke risk.
These studies await confirmation before the clinical relevance of intensive ECG
monitoring can be established. Other ongoing studies are CRYSTAL-AF
(NCT00924638) and REVEAL-AF (NCT01727297).
CARISMA, Cardiac Arrhythmias and RIsk Stratification after acute MyocArdial infarction,
ASSERT, ASymptomatic atrial fibrillation and Stroke Evaluation in pacemaker patients and the atrial
fibrillation Reduction atrial pacing Trial
Both primary disease and AF-induced structural, electrical, and autonomic
remodelling contribute to AF progression.
Earlier intervention may interrupt this progression, improving outcomes
and reducing morbidity and mortality.
Available drug therapies have not yet been shown to prevent progression,
either because they are ineffective or because we are giving them too late
or to the wrong patients.
Ongoing basic research has identified some potentially interesting novel
drug-development targets.
The failure of rhythm-control therapy to improve outcomes in most
previous large clinical trials may have been due to testing too late
in the natural history of the disease, and the results of ongoing studies
involving earlier and more active intervention are anticipated with interest.
Conclusions (cont…)
Despite abundant evidence regarding both the increasing prevalence
of AF and the associated risk of thromboembolism, many individuals with
AF worldwide remain undiagnosed or undertreated, including many at
high risk for stroke.
Existing practice guidelines for management of patients with AF provide
valuable clinical pathways for the treatment of newly discovered AF.
Integrated care pathways would aid medical providers in the earlier
identification of patients with AF, rapid assessment of thromboembolism
risk and appropriate selection of anticoagulant therapy.
Radical improvement of AF management will result if ongoing and future
research demonstrates that such approaches facilitate earlier and
possibly more effective interventions to restore and/or maintain SR.

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