Transcript Avicenna, Persian physician, philosopher & poet 980

Atrial Fibrillation:
Past, Present and Future
Mohammad Shenasa MD, FACC
O’Connor Hospital, San Jose, CA
5th Congress of Cardiologists and
Angiologists of Bosnia and Herzegovina
Bosnia
May 2010
M. Shenasa 2010
Avicenna, Persian physician, philosopher & poet
980-1037 AD
M. Shenasa 2010
M. Shenasa 2010
Lecture Highlights
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Epidemiology
Mechanisms
Heart Failure and AF
Asymptomatic AF
Stroke and AF
Inflammation and AF
AF and Remodeling
AF and Fibrosis
M. Shenasa 2010
• New and Atrial
specific
Antiarrhythmics
• Upstream Therapies
in AF
• AF and Ablation
• Future Directions
AF
Past, Present, Future
2008-2009
2008: 2,469
2009: 2,528
M. Shenasa 2010
Atrial Fibrillation: Medicare Data
• AFib is a highly prevalent disease and associated with
significant cardiovascular morbidity and morality
• AFib costs Medicare more than $15.7 billion annually
due to costly complications
• Screening and diagnosis of AFib is limited in Medicare
population
• Estimated by 2050, 15 million Americans will suffer
from AF and its adverse consequences
• Conclusion
– A need exists for Medicare to find ways to reduce overall
costs and improve the quality of care for AFib patients
M. Shenasa 2010
Hospitalization for Arrhythmias USA
Unspecified
18%
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JACC 1992;19(3);41A
Presence of Heart Disease in Consecutive
Outpatients with Atrial Fibrillation
Lone AF
N=100 (35%)
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Prystowsky et al, Circulation 1996(Suppl 8) 94:I:191
M. Shenasa 2010
Wellens, H
Identifying Patients at Risk for AF
Well-known predictors for AF:
Newer risk factors:
Age
Diastolic dysfunction
Hypertension
Obesity
Valve disease
(Extreme) exercise
Myocardial infarction
Sleep apnea syndrome
Diabetes
Inflammation
Heart Failure
Metabolic Syndrome
Biomarkers:
Gene Mutations:
ANP
KCNQ1
C-reactive protein
KCNE2
Interleukin-6
KCNE5
Angiotension II
GJA5
Markers for fibrosis
SCN5A
SCN1B/2B
M. Shenasa 2010
Pulmonary Disease
LA size
VHD
Genetics
OSA
Atrial Fibrosis
Others
DM
AF
CAD
Hyperthyroidism
Drug Induced
Channelopathies
CHF
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Cardiomyopathy
& LVH
HTN
Mechanisms of Atrial Fibrillation
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ESC: Textbook of Cardiovascular Medicine 2006
Heart Failure and AF
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Cardiology Clinics 2009; 27:79-93 (
Heart Failure and AF
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Heart Failure and AF
Rate vs. Rhythm control
Rhythm Control versus Rate Control for AF & HF.
Conclusion
In patients with AF and CHF, a routine strategy of rhythm control does not reduce the
rate of death from cardiovascular causes, as compared with a rate-control strategy.
M. Shenasa 2010
NEJM 2008;358:2667-77
Heart Failure and AF
Maintenance of Sinus Rhythm and Survival in Patients With CHF and AF
Conclusion:
A rhythm-control strategy or the
presence of sinus rhythm are not
associated with better outcomes in
patients with AF and CHF.
Talajic, M. et al. JACC 2010;55:1796-1802
M. Shenasa 2010
AF and CHF
Mechanisms by Which CHF Leads to AF
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Burstein, B. et al. J Am Coll Cardiol 2008;51:802-809
Asymptomatic AF
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Stroke and AF
Heart Disease and Stroke
• Stroke affects about 795,000 individuals annually in the
US only.
• 1 every 40 seconds.
• Third leading cause of death
• Number 1 cause of disability
• 87% are ischemic stroke i.e. embolic
• 13% are hemorrhagic stroke
• 1 in 15 people develop brain aneurysm in their life
• Ruptured aneurysm are 30,000 cases of hemorrhagic
stroke.
• Silent stroke cognitive decline, dementia and
Alzheimer's are associated with AF
M. Shenasa 2010
M. Shenasa 2010
Silent Atrial Fibrillation
195 Patients
86(44%)
CHB
No Hx of AF
109 (55%)
Hx of AF in SR at the
time of impact
35 (40%)
Silent AF
Duration <1 min to 2
weeks
68 (62%)
Silent AF
9/35 (25%)
permanent AF in F/U
M. Shenasa 2010
19/68 (30%)
permanent AF
Inflammation and AF
Markers for inflammation
1.) High Sensitivity C-reactive protein (hs-CRP)
2.) Interleukin (IL)-6
3.) White cell count
4.) Tumor necrosis factor alpha (TNFα)
Others Cause of inflammation
• Oxidative Stress
• Endothelial dysfunction
• Coexisting co-morbid risk factors & others
M. Shenasa 2010
Inflammation and AF
Hypothesis:
• Ang-II may play a key role in
pathogenesis of AF only in a subset of
patients
• ACEIn and ARB may prevent and treat
AF in those patients with elevated
serum ACE and Ang-II activity.
Courtesy of A. Sovari
Inflammation and AF
Inflammation
Fibrosis
?
Atrial Fibrillation
Intracardiac and extracardiac markers of inflammation during atrial fibrillation.
Markers of inflammation before and after curative ablation of atrial flutter.
Marcus G.M., et al Heart Rhythm 2008;5:215-221
Normalization of inflammation markers after AF
ablation and cardioversion suggests inflammation
is the effect rather than the cause.
M. Shenasa 2010
Histology of atrial biopsy from a patient with up to 20 episodes of
PAF per day
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Frustaci, A. et al. Circulation 1997;96:1180-1184
Oxidative stress, inflammation and AF
AF
NFκB
Oxidative
Stress
Inflammation
Recruiting
inflammatory
cells:
Macrophages
, PMNs
•Aviles RJ, Circulation 2003
•Spodick DH. JAMA 1976
•Morgera T, Am Heart J 1992
•Psychari SN, Am J Cardiol 2005
•Chung MK, Circulation 2001
AF is higher in
inflammatory states such as
post operative state
Inflammatory cytokines
and markers are associated
with AF (TNF-α, IL-6,
CRP)
Atrial tissue in AF has
inflammatory infiltrates
Inflammatory markers
(e.g. CRP) predicts AF
relapse after cardioversion
•Watanabe T, Heart Vessels 2005
•Watanabe E, Int J Cardiol 2005.
•Conway DS, Am J Cardiol 2004
•Roldan V, Am J Cardiol 2005
•Frustaci A, Circulation 1997
Courtesy of A. Sovari
Inflammation and AF
• AF is clearly associated with increased level of inflammatory
markers.
• Atrial biopsies with in patients with AF have also confirmed
the presence of inflammation
• There is also evidence supporting a link between
inflammation and AF, and some of the drug therapies, such as
the ACE-inhibitors, ARBs, Steroids, fish oils, and vitamin C,
that might be efficacious in the prevention of AF by
modulating inflammatory pathways.
• However, randomized trial and longitudinal studies are
needed to confirm the direct relationship between AF and
inflammation
M. Shenasa 2010
AF and Atrial Fibrosis
AF
?
Fibrosis
After age 65, 5% per year develop
atrial myocardium fibrosis
M. Shenasa 2010
AF and Atrial Fibrosis
M. Shenasa 2010
Cardiac Electrophysiology: From cell to bedside;
Munoz, Zlochiver and Jalife 2009 pp 215
How fibrosis may cause arrhythmia
Decreased conduction velocity 
Reentry
Fibrosis: fibroblast
/myofibroblast
proliferation + increased
collagen deposition
Reduced sink to source  facilitating
EAD/DAD propagation
*
*Miragoli M, Circ Res, 2007
F-M coupling  facilitating EAD/DAD
formation
AF and Atrial Fibrosis
Pulmonary Disease
LA size
VDH
OSA
Genetics
DM
Others
Cardiomyopathy
& LVH
AF
CAD
Hyperthyroidism
Drug
Induced
Channelopathies
CHF
HTN
Myocardial Fibrosis is the culprit!
Shenasa 2010
Each pathological process may play the central role only in a
specific subpopulation with AF
Fibrosis
Gap
Junctional
Impairment
Clinical Associations of AF
Angiotensin II
Genetic
Abnormalities
–Age
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–
–
–
–
Hypertension
Diabetes
Family history
Obesity
Males
AS/prior MI
–Surgery
– Hyperthyroidism
– LV dysfunction
– Valvular disease
Inflammation
Autonomic
Dysfunction
Oxidative
Stress
Abnormal
Ca2+ Handling
Cardiac
Alternans
AF
Courtesy of A. Sovari
Disappointment or a lesson in chess?
The main result:
AF recurred in 51.4% in
valsartan group, 52.1% in
placebo group
AF and Remodeling
M. Shenasa 2010
Atrial remodeling in AF
Electrical remodeling
• Atrial remodeling refers to the changes in
atrial properties and function that promote
AF. Rapid atrial activation provokes both a
shortening of the atrial action potential and
refractory period, as well as an impaired rate
adaption with reduced wave length, thereby
enhancing the risk for functional reentry.
Europace 2009;11:860-885
M. Shenasa 2010
Atrial remodeling in AF
Structural remodeling
• LA dilatation and increasing atrial fibrosis.
Increased atrial pressure and volume related
to structural heart disease. HTN or aging will
cause ultra structural changes in the heart and
leads to activation of fibroblasts, enhanced
collagen depositions and fibrosis, which in
term result in electrical remodeling.
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M. Shenasa 2010
New Antiarrhythmics for AF
M. Shenasa 2010
ATHENA: Primary Outcome
Cumulative Incidence (%)
Time to first cardiovascular hospitalization or death
HR=.76
P<.001
50
40
30
Placebo
20
Dronedarone
10
0
0
Patients at risk
Placebo
Dronedarone
2327
2301
6
1858
1963
12
18
24
30
Months
1625
1072
1776
1177
385
403
3
2
Mean follow-up 21  5 months.
Hohnloser. Presented at Heart Rhythm Society 2008; May 2008; San Francisco,
CA (A).
M. Shenasa 2010
Ideal characteristics of a new antiarrhythmic drug
Slows heart rate to normal sinus rhythm
Reduces ventricular rate during AF recurrence
Prolongs APD and QT/QTc, increasing atrial effective refractory
period without risk of inducing TdP
Reduces intrinsic and drug-induced heterogeneity of
myocardial refractoriness
Displays no proarrhythmic effect
Exhibits anti-torsadogenic activity
Displays a positive inotropic effect, with increase in the left
ventricular ejection fraction if impaired
Has a favorable or neutral impact on survival
Is effective and safe in atrial as well as ventricular
tachyarrhythmia's
Exhibits long-term effectiveness without major adverse effects
or organ toxicity
Is not incompatible with other frequently used essential
cardioactive drugs
M. Shenasa 2010
Euro Heart J (2007) 9 (Supp G), G17-G25
Atrial Specific Antiarrhythmic Therapy
Lancet 2006;367:262-72
M. Shenasa 2010
The Action Potential and Key Ion
Currents
APs = action potentials; IKACh = acetylcholine-regulated potassium current; IKur = ultrarapid delayed-rectifier potassium current; INa = sodium current.
Ehrlich JR, et al. J Am Coll Cardiol. 2008;51:787-792.
Pharmacotherapy for atrial
arrhythmias: Present and future
M. Shenasa 2010
Michael J. Mazzini MD et al
Heart Rhythm 2008;5:S26-S31
Anti-inflammatory
properties
Anti-oxidant
effect
Plaque
stabilization
Atrial remodeling
attenuation
Statins
Autonomic
nervous system
regulation
Renin angiotensin system
downregulation
Decrease in Atrial Fibrillation
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Regulation of
nitric-oxide-dependent
endothelial function
Ablation of AF
Current Controversies
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Definition
Cure?
Procedural endpoints
Anticoagulation and Anti arrhythmic therapy post
ablation
Outcomes
Follow ups
Guidelines
Cost
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AF and Ablation
Spontaneous initiation of
atrial fibrillation by ectopic
beats originating in the
pulmonary veins.
Haïssaguerre M et al, (N Engl J Med 1998;339;659-66.)
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M. Shenasa 2010
Pattern of Myocardium on Left Atrium and Pulmonary Veins (PV) and Representative
Electroanatomical Map of Left Atrium in Patient Receiving Successful Ablative Therapy
M. Shenasa 2010
Marine, J. E. JAMA 2007;298:2768-2778.
Questions?
• Why do some patients have numerous paraxsysmol AF
without ever developing persistent forms, while other
progress to sustained forms of AF within a short time?
• If muscle sleeves are present in the pulmonary veins in
everyone, why do some develop AF and other do not?
• Does a “natural” functional electrical block between
pulmonary veins and the left atrial myocardium exist, and
would this protect against AF?
• Why does “focal” AF develop at age 30 in one patient and age
70 in another?
• Why do periods of frequent AF paroxysms alternate in
unpredictable patterns with periods of sinus rhythm in most
patients?
M. Shenasa 2010
Catheter-Based Management of AF
M. Shenasa 2010
Valderrabano, M JMDHC 2;2007:24-29
AF and Ablation
M. Shenasa 2010
Courtesy of U.Penn
Catheter ablation of atrial fibrillation
Heart Center Leipzig 1998 – 2008
1000
[n]
750
500
250
0
1998
M. Shenasa 2010
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Courtesy of G. Hindricks
AF and Ablation
Plumonary vein Ablation in Atrial Fibrillation
Hype or Hope?
Hein Wellens
Circ:2000;102:2562-2564
 Circumferential Radiofrequency Ablation of Pulmonary Vein Ostia
 A New Anatomic Approach for Curing Atrial Fibrillation Carlo Pappone
Circ:2000;102:2619-2628
 Controversies In Cardiovascular Medicine
 Should atrial fibrillation ablation be considered first-line therapy fow
some patients?
(Circulation 2005; 112:1231)
Criteria for patient selection
1. Patients’ expectations: symptom relief, freedom from
anticoagulation, freedom from antiarrhythmic
therapy, resolution of tachycardia-induced myopathy
2. Failure of prior antiarrhythmic therapy or prior
procedures
3. Pattern of atrial fibrillation: paroxysmal vs. chronic
4. Presence of structural heart disease: left atrial size,
left ventricular dysfunction, hypertrophic
cardiomyopathy
5. Duration of atrial fibrillation
M. Shenasa 2010
Valderrabano, M JMDHC 2;2007:24-29
Cardiovascular Imaging in the Management of AF
M. Shenasa 2010
Valderrabano, M JMDHC 2;2007:24-29
Future Trials in AFib
CABANA
( Catheter Ablation versus Anti-Arrhythmias Drugs
for Afib)
NIH sponsored
Multicenter /Randomized
Comparing catheter ablation with rhythm control
therapy
Endpoints: Afib recurrences and Mortality
outcomes
M. Shenasa 2010
Catheter Ablation versus Antiarrhythmic
Drug Therapy for Atrial Fibrillation
(CABANA)
• Randomized trial comparing ablation to best drug therapy
(rate or rhythm control)
• 1⁰ endpoint: mortality (powered for 30% mortality reduction
assuming 12% 3-year mortality in drug group)
• 2 ⁰ endpoint: QOL, AF recurrence, composite MAE
• Enrollment criteria: age ≥ 65 years, or <65 years with ≥ 1 risk
factor for stroke
• Ablation technique to include PVI ± additional procedures
(lines, CFAE, focal triggers)
• Planned 3,000 patients, 120 enrolling centers
• Pilot phase completed 2008, full study started fall 2009
M. Shenasa 2010
Future Development in AF Ablation
•
•
•
•
•
•
Mapping and Imaging
Remote Catheter Navigation
Molecular Imaging
Genetic Engineering
Stem Cell Therapy
Energy Source
– Laser, Radiation, Ultrasound
• Eventually noninvasive mapping and ablation
M. Shenasa 2010
Genetics of AF
• Familial AF: KCNQ1 gene
– Familial auricular fibrillation reported by Wolff, L,
1943
• Nonfamilial AF: KCNE1
• Genes of potassium: KCNE1
• Genes of sodium channel subunits: SCN5A
• Genes of sarcoplasmic reticulum calcium ATPase: SERCA2
• Renin-angiotensin system: RAS
• Genes related to inflammation
M. Shenasa 2010
JACC 2008;52:241-50
• ACC/AHA/ESC 2006 Guidelines for the
Management of Patients With Atrial
Fibrillation.
Fuster, V: Circulation, Aug 2006; 114: e257 - e354.
• HRS/EHRA/ECAS Expert Consensus Statement
on Catheter and Surgical Ablation of Atrial
Fibrillation: Recommendation for Personnel,
Policy, Procedures and Follow-up
Calkins H, et al Heart Rhythm 2007;4:816-861
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M. Shenasa 2010
Cardiology Clinics 2009; 27:201-216
Management Decision in AF
Anticoagulation
M. Shenasa 2010
Conclusion
• All Atrial Fibrillation patients are not the same.
• Atrial Fibrillation is not a disease. It is a
symptom like fever, syncope and etc.
• Atrial Fibrillation should be treated based on
etiologies rather than mechanisms.
• Prevention should be the first line of therapy.
Most importantly focusing on fibrosis and
inflammation.
M. Shenasa 2010
Thank you
M. Shenasa 2010
Stroke and AF
Heart Disease and Stroke
• Stroke affects about 795,000 individuals annually in the
US only.
• 1 every 40 seconds.
• Third leading cause of death
• Number 1 cause of disability
• 87% are ischemic stroke i.e. embolic
• 13% are hemorrhagic stroke
• 1 in 15 people develop brain aneurysm in their life
• Ruptured aneurysm are 30,000 cases of hemorrhagic
stroke.
• Silent stroke cognitive decline, dementia and
Alzheimer's are associated with AF
M. Shenasa 2010
Wish list for the next mapping system
• Enough reality of correct anatomical
representation
• Ability to incorporate ablation catheter into
anatomy
• Real-time
• Lesion quantification
• Reduce radiation exposure
• Increase success rate
• Ultimate imaging is Visual imaging
• Technology begets technology like an arm race
M. Shenasa 2010
Antiarrhythmics After Ablation of
Atrial Fibrillation (5A Study)
AAD treatment during the first 6 weeks after AF ablation is well tolerated and
reduces the incidence of clinically significant atrial arrhythmias and need for
cardioversion/hospitalization for arrhythmia management.
M. Shenasa 2010
Circulation. 2009;120:1036-1040
M. Shenasa 2010
Challenges and Opportunities in Atrial
Fibrillation
Projected number of persons with AF in the United States between 2000 and 2050, assuming no further
increase in age-adjusted AF incidence (solid curve) and assuming a continued increase in incidence
rate as evident in 1980 to 2000 (dotted curve)
M. Shenasa 2010
Miyasaka, Y. et al. Circulation 2006;114:119-125
Summary and conclusion?
ACEIn and ARB should treat AF
AF
Ang-II
Inflammation
, ROS
Fibrosis
Cx43
remodeling
Courtesy of A. Sovari
Best therapy is the one that is
not needed
Ideal antiarrhythmic drug
Immortilide
for arrhythmias
Take one per life time
M. Shenasa 2010
•
•
•
•
•
Completely safe
Completely effective
Fun and easy to take
Makes you live longer
Cheaper than aspirin
AF and Atrial Fibrosis
M. Shenasa 2010
Raman, S. V. J Am Coll Cardiol 2010;55:91-96
Angiotensin II-dependent cellular signalling via type 1 and type 2 receptors.
Goette A , Lendeckel U Europace 2008;10:238-241
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author
2008. For permissions please email: [email protected]
Gap Junctions
Gap junctions are intercellular channels some 1.5–2 nm in diameter.
These permit the free passage between the cells of ions and small molecules (up to a
molecular weight of about 1000 daltons).
They are constructed from 4 (sometimes 6) copies of one of a family of a
transmembrane proteins called connexins.
Because ions can flow through them, gap junctions permit changes in membrane
potential to pass from cell to cell
M. Shenasa 2010
Novel anti-arrhythmics for AF
M. Shenasa 2010
Non-antiarrhythmic agents with
antiarrhythmic properties
Therapeutic class
Angiotensin-converting enzyme
inhibitors, angiotensin II-receptor
blockers
Aldosterone antagonists
Possible target
Statins
Coronary artery disease, systemic
atherosclerosis, direct anti-inflammatory,
and antioxidant effects
Corticosteroids
Anti-inflammatory effects, direct
antiarrhythmic effects
Omega-3 PUFA (fish oil)
Lipid-lowering effects, direct antiarrhythmic
effects
Slow sodium-channel blockers
Modification of atrial metabolism, direct
antiarrhythmic effect
M. Shenasa 2010
Hypertension, heart failure, direct
antithrombotic and antiarrhythmic effects?
Hypertension, heart failure, direct
antithrombotic and antiarrhythmic effects?
Euro Heart J (2007) 9 (Supp G), G17-G25
Concepts to Consider
•
•
•
•
Selective ion channel blocker
Multi-channel blockade (like amiodarone)
Atrial channel selective (usually “relative”)
Substrate based
– Gap junction conduction
– Fibrosis
– Inflammation
AF and Atrial Fibrosis
M. Shenasa 2010
Source: Heart Rhythm 2010; 7:396-404 (DOI:10.1016/j.hrthm.2009.11.031 )
Comparison of Antiarrhythmic Drug Therapy and
Radiofrequency Catheter Ablation in Patients With
Paroxysmal Atrial Fibrillation A Randomized Controlled
Trial
David J. Wilber MD et al
JAMA 2010;303(4)333-340
Patient Flow Diagram
Kaplan-Meier Curves of Time to Protocol-Defined Treatment Failure, Recurrence of Symptomatic
Atrial Arrhythmia, and Recurrence of Any Atrial Arrhythmia by Treatment Group
Conclusion
• Among patients with paroxysmal AF who had
not responded to at least 1 antiarrhythmic
drug, the use of catheter ablation compared
with ADT resulted in a longer time to
treatment failure during the 9-month followup period.
AF and Atrial Fibrosis/Remodeling
Micro Circuit Re-Entry Secondary to Conduction Velocity Heterogeneity
Roberts, J. D. et al. J Am Coll Cardiol 2010;55:705-712
Copyright ©2010 American College of Cardiology Foundation. Restrictions may apply.
Future Trials in AFib
CABANA
( Catheter Ablation versus Anti-Arrhythmias Drugs
for Afib)
NIH sponsored
Multicenter /Randomized
Comparing catheter ablation with rhythm control
therapy
Endpoints: Afib recurrences and Mortality
outcomes
What to do with silent Afib
( Asymptomatic)
The true prevalence of Asymptomatic “Silent” Atrial Fibrillation
by its nature is unknown.
The interest in Silent Afib is emerging from symptomatic patients
who are now closely followed after device implantations or
ablative procedures.
It is estimated that the asymptomatic Afib are at least 6 folds
greater than the symptomatic rate.
Cessation of anticoagulation in patients presumed to be in sinus
rhythm associated with increased risk of stroke and death in the
AFFIRM Trial.
Rhythm or Rate Control in Atrial
Fibrillation
•
•
•
•
•
Evidence base
5 prospective, controlled, randomized trials comparing 2
different strategies
PIAF: Pharmacological Interventions in Atrial Fibrillation
STAF: Strategies in Atrial Fibrillation ( pilot)
AFFIRM: Atrial Fibrillation Follow-up Investigation of Rhythm
Management
RACE: Rate Control versus Electrical Cardioversion of Atrial
Fibrillation
SAFE-T: Sotalol and Amiodarone for Effectiveness Trial
AFFIRM Trial
• Atrial Fibrillation Follow-up Investigation of Rhythm
Management (AFFIRM)
• Sponsored by National Heart, Lung, and Blood Institute of the
National Institutes of Health
• Randomized evaluation of treatment of AF by 1 of 2 strategies
(rate control versus rhythm control and anticoagulation)
• Total of 4,160 patients followed for an average of 2.6 years
Can Sinus Rhythm Improve Survival?
Effects of Maintaining NSR After AF Ablation on Survival
Nademanee, K. et al. J Am Coll Cardiol 2008;51:843-849
Future Directions
•
•
•
•
•
Inflammation and AF
Fibrosis and AF
Genetics of AF
Role of Stem Cell in AF
Targeted therapy for AF i.e. anti-inflammatory, antifibrosis
• Development of atrial selective channel blockers
• Upstream therapies i.e. ARB, ACE, Omega-3, and
statins
• Patient Outcome and follow up
Future Directions
Upstream Therapies
Non-antiarrhythmic
Omega-3 Fatty Acids and Cardiac Arrhythmias:
Prior Studies and Recommendations for
Future Research. A report from the National
Heart, Lung, and Blood Institute and Office of
Dietary Supplements Omega-3 Fatty Acids and
Their role in Cardiac Arrhythmogenesis
Workshop
Circulation 2007;116:e320-e335
Role of Inflammation in Initiation
Perpetuation of Atrial Fibrillation
1.) Increased CRP levels
2.) Hypercoagulapathy
3.) HMG-CoA
4.) Statins
5.) Fish oil , Omega-3 and Vitamin C
6.) ACE and ARB
7.) Glucocorticoids
8.) Aldosterone blocking agents
Issac TT et al., JACC 2007;50:2021-8
Multimodality imaging plays an important role in the evaluation of atrial
fibrillation patients, and in the management of atrial fibrillation.
Tops L F et al. Eur Heart J 2010;31:542-551
Unanswered Questions in AF Ablation
• Catheter ablation of paraxsysmol AF has the best outcome
compared to permanent AF ablation: 80% (success rate 1
year) vs. 50%, particularly in a low risk population
• Image guidance
• Balloon Cryoablation
• Balloon-Based High-Intensity Focused Ultrasound ablation
• Safety of AF Ablation
• Continuation of anti-coagulation
• Follow up and success rate, problem of silent recurrences
Future Development in Afib Ablation
•
•
•
•
•
•
Mapping and Imaging
Remote Catheter Navigation
Molecular Imaging
Genetic Engineering
Stem Cell Therapy
Energy Source
– Laser, Radiation, Ultrasound
• Eventually noninvasive mapping and ablation
Wellens, H
General Mechanisms of AF
1.) Multiple rapidly discharging foci
2.) Focal sources with fibrillatory conduction
3.) Multiple re-entrant circuit
AF and Atrial Fibrosis/Remodeling
The Future cardiac mapping/imaging would offer
multi-modality virtual imaging including:
1.) Nuclear Perfusion and Functional Scans
2.) Rotational Angiography
3.) Structural, Functional, Coronary and Perfusion
Magnetic Resonance Imaging
4.) Ultra Fast Computerized Tomography
5.) Neurocardiac Imaging
6.) 3-4 Dimensional Echocardiography
7.) 3-D Biosense Electromagnetic Mapping
8.) Intracardiac/Intravascular Ultrasound
9.) Optical Coherence Tomography
Cardiac Mapping and EP in 2010
1.) In vivo optical mapping
2.) Cardiac MR Spectroscopy
3.) Laser Optical Spectroscopy
4.) Near Infrared Spectroscopy
5.) Molecular Imaging
6.) Fluorescence Imaging
7.) Genetic Engineering and Drug Delivery
8.) Biological Pacemakers
9.) Stem Cell Imaging
The Future of Atrial Fibrillation
Ablation 1/2
1.
2.
3.
4.
5.
Optical Mapping
Bioluminescence
Diffused Optical Spectroscopy
Magnetic Resonance Imaging
Magnetic Resonance Spectroscopy (only
noninvasive)
6. Diffusion Tensor Imaging
7. Fiber Tracking
8. Multimodality Mapping and Ablation
The Future of Atrial Fibrillation
Ablation 2/2
9. Image Integration and Fusion
10. CT Integration with Electroanatomical Mapping
11. CT with rotational angiography
12. PET/CT integration
13. Intracardiac Echo
14. Electro anatomical Mapping
15. High intensity ultrasound mapping
16. One-Stop Shop (integration of all multimodality
techniques)
Nattel S; Nature Vol 415, 2002
The History of Atrial Fibrillation:
The Last 100 Years
ERIC N. PRYSTOWSKY, M.D.
J Cardiovasc Electrophysiol, Vol. 19,
pp. 575-582, June 2008.
A Volunteer Sitting with His Arms in Saline-Filled Tubs with Wires Connected to Einthoven's Electrocardiograph
Fye W. N Engl J Med 2006;355:1412-1414
Pulsus Inaequalis et Irregularis
Fye W. N Engl J Med 2006;355:1412-1414
Definition of AF:
At present any arrhythmia that has the ECG criteria of
AF and lasts 30 seconds or longer is considered AF
Heart Failure and AF
Heterogeneous
conduction
Increased
fibrosis
Loss of atrial
contraction
AF
Triggered
activity
Altered atrial
refractoriness
Volume +
pressure overload
Heart
failure
Rapid
Ventricular rate
-energy depletion
-Remodeling
-Ischemia
-Abnormal Ca⁺
handling
R-R variability
Camm, J
Stroke and AF
Heart Disease and Stroke: 2010
• Each year:
– 795,000 new or recurrent stroke
– 610,000 first attacks
– 185,000 recurrent attacks
Circ 2010:121:9480954
Stroke and AF
Heart Disease and Stroke: 2010
• National Health and Nutrition Examination
Survey
– 2003-2006: 33.6% of US adults ≥ 20 years of age
have hypertension
– 74,500,000 US adults with hypertension
• Hypertensive adults:
– 78% are aware of condition
– 68% using antihypertensive medications
– 44% treated had their hypertension controlled
Circ 2010:121:9480954
Stroke and AF
Heart Disease and Stroke: 2010
• Total serum cholesterol levels ≥ 240 mg/dL
• 2006:
• 17,200,000 diagnosed with diabetes , 7.7% of
the adult population
• 6,100,000 undiagnosed diabetes
• Paraxsysmol AF carries the same risk stroke as
persistent or permanent AF
Stroke and AF
Heart Disease and Stroke: 2010
• Prevalence of overweight and obesity in the
US adults (≥20 years of age) is 144,100,000
• 66.3% in 2006
• 32.9% of US adults are obese
• Children ages 2-19
• 31.9% overweight and obese (23,500,000
children)
• 16.3% are obese (12,000,000)
Circ 2010:121:9480954
Stroke and AF
Heart Disease and Stroke: 2010
• Current usage of cardiovascular surgical and invasive
procedures
• Operations and procedures increased
• 33% from 5,444,000 to 7,235,000 annually
• Total direct and indirect cost of CVD and stroke in the US for
2010 is estimated to be $503.2 billion
– Cancer and benign neoplasms $228 billion
– $93 billion in direct costs
– 19billion in morbidity indirect
– $116 billion in mortality indirect
Circ 2010:121:9480954
Stroke and AF
Heart Disease and Stroke
• Stroke affects about 795,000 individuals annually in the
US only.
• 1 every 40 seconds.
• Third leading cause of death
• Number 1 cause of disability
• 87% are ischemic stroke i.e. embolic
• 13% are hemorrhagic stroke
• 1 in 15 people develop brain aneurysm in their life
• Ruptured aneurysm are 30,000 cases of hemorrhagic
stroke.
• Silent stroke cognitive decline, dementia and
Alzheimer's are associated with AF
Role of inflammation and oxidative stress in AF
• Concentrations of inflammatory biomarkers
were significantly increased in patients with
AF and supports a strong association between
AF and inflammation. Elevated inflammatory
markers in patients with lone AF suggest that
inflammation is associated with AF
independent of comorbidities such as heart
failure.
Heart Rhythm 2010;7:438-444
AF and Atrial Fibrosis/Remodeling
Kirchhof, P. et al. Eur Heart J 2009 30:2969-2980; doi:10.1093/eurheartj/ehp235
Silent Cerebral Infarction in Patients
with Nonrheumatic Atrial Fibrillation
• Silent cerebral infarction is frequently seen in
asymptomatic patients with AF.
• Silent AF carries the same risk of stroke as
symptomatic AF.
AF and Atrial Fibrosis
Burstein, B. et al. J Am Coll Cardiol 2008;51:802-809
AF and Atrial Fibrosis
Burstein, B. et al. J Am Coll Cardiol 2008;51:802-809
Effect of Ion Channels on Atrial APD
Roberts, J. D. et al. J Am Coll Cardiol 2010;55:705-712
AF and Ablation
Two Different sources of ectopy
Haïssaguerre, M Circ.2000;101:1409-1417
The role of imaging in AF ablation 1/3
EHJ 2010;31:542-551
The role of imaging in AF ablation 2/3
EHJ 2010;31:542-551
The role of imaging in AF ablation 3/3
EHJ 2010;31:542-551
In whom and when can antiarrhythmic
drug therapy be discontinued?
• Antiarrhythmic drug discontinuation may be
reasonable in patients in whom concomitant
conditions have been successfully treated or
in whom prominent triggers have been
eliminated.
• The problem remains with silent AF.
Inflammation and AF
Markers for inflammation
1.) High Sensitivity C-reactive protein (hs-CRP)
2.) Interleukin (IL)-6
3.) White cell count
4.) Tumor necrosis factor alpha (TNFα)
Others Cause of inflammation
• Oxidative Stress
• Endothelial dysfunction
• Coexisting co-morbid risk factors & others
Heart Failure and AF
• High atrial rates particularly in
the presence of HF enhances
Ca²+ influx which in term
enhances in activation voltage
dependent L-type Ca²+
channels
Stroke and AF
Heart Disease and Stroke: 2010
• 2010: estimated 785,000 Americans will have a new
coronary attack
• 470,000 will have a recurrent attack
• 195,000 silent first myocardial infarctions/year
• 25 seconds: American will have a coronary event
• 1 minute: someone will die
• Third cause of death
• First cause of disability
• Silent stroke will cause silent AF
Circ 2010:121:9480954
Atrial Fibrillation:
Past, Present and Future II
Roberts, J. D. et al. J Am Coll Cardiol 2010;55:705-712
M. Shenasa 2010
Milestones in the management of
Atrial Fibrillation
• Awareness of prognostic implications of AF
• Prevention of thromboembolic strokes
• Comparison of rate versus rhythm control
strategies
• Catheter ablation to cure AF
• New antiarrhythmic agents
• Improving outcomes in AF
M. Shenasa 2010
Milestones in the management of AF
• AF begets AF ( M. Allessi)
• Moe GK: Atrial Fibrillation as a self-sustaining
arrhythmia independent of focal discharge. Am Heart
J 1959;58:59-70
• Atrial remodeling
• Left atrial isolation and Maze procedure (Cox)
• Guiraudon corridor procedure (1985)
• Tachycardia induced cardiomyopathy
• AF ablation (M. Haissaguerre, NEJM 1998)
• Role of Atrial fibrosis
• Development of Atrial selective anti-arrhythmics
• Percutaneous atrial appendage closure (Watchmen
device)
M. Shenasa 2010
Heart Failure and AF
M. Shenasa 2010
Cardiology Clinics 2009; 27:79-93
Cumulative incidence of primary and secondary
outcomes in treatment of Dronedarone with Placebo
M. Shenasa 2010
NEJM 2009;360:668-78.
M. Shenasa 2010
History of Atrial Fibrillation
Scientific Era
•
•
•
•
William Stokes (1854)
Wenckebach (1904)
Mackenzie (1907)
Sir Thomas Lewis (1909-1910) described details
of AF and reentry
• Gordon Moe (1959) described the computer
model of multi-wavelet of reentry; Am Heart J
1946:67:200-20.
• Lown and colleagues (1962) first cardioversion for
AF
M. Shenasa 2010
Anti Arrhythmic Drug Therapy in AF
LVH
Flecanide
Propafonone
CHF
Amiodarone
Dofetilide
Catheter
Ablation
CAD
Sotalol
Dronedarone
Dofetilide
Amiodarone
None
Flecanide
Propafonone
Dronedarone
Sotalol
Dofetilide
Amiodarone
Catheter
Ablation
Catheter
Ablation