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Atrial Fibrillation: Past, Present and Future

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1 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

2 Avicenna, Persian physician, philosopher & poet 980-1037 AD
M. Shenasa 2010

3 M. Shenasa 2010

4 Lecture Highlights New and Atrial specific Antiarrhythmics
Epidemiology Mechanisms Heart Failure and AF Asymptomatic AF Stroke and AF Inflammation and AF AF and Remodeling AF and Fibrosis New and Atrial specific Antiarrhythmics Upstream Therapies in AF AF and Ablation Future Directions M. Shenasa 2010

5 AF Past, Present, Future 2008-2009 2008: 2,469 2009: 2,528
M. Shenasa 2010

6 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

7 Hospitalization for Arrhythmias USA
Unspecified 18% JACC 1992;19(3);41A M. Shenasa 2010

8 Presence of Heart Disease in Consecutive Outpatients with Atrial Fibrillation
Lone AF N=100 (35%) Prystowsky et al, Circulation 1996(Suppl 8) 94:I:191 M. Shenasa 2010

9 M. Shenasa 2010 Wellens, H

10 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

11 AF HTN Pulmonary Disease VHD Genetics OSA Atrial Fibrosis Others DM
LA size VHD Genetics OSA Atrial Fibrosis AF Others DM CAD Hyperthyroidism Drug Induced Channelopathies CHF Cardiomyopathy & LVH HTN M. Shenasa 2010

12 Mechanisms of Atrial Fibrillation
M. Shenasa 2010 ESC: Textbook of Cardiovascular Medicine 2006

13 Heart Failure and AF M. Shenasa 2010
Mechanisms involved in the interaction of AF and CHF. (From Maisel WH, Stevenson LW. Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy. Am J Cardiol 2003;91(6A):2D–8D; with permission.) M. Shenasa 2010 Cardiology Clinics 2009; 27:79-93 (

14 Heart Failure and AF M. Shenasa 2010

15 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:

16 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: M. Shenasa 2010

17 AF and CHF M. Shenasa 2010 Mechanisms by Which CHF Leads to AF
Burstein, B. et al. J Am Coll Cardiol 2008;51:

18 Asymptomatic AF M. Shenasa 2010

19 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

20 M. Shenasa 2010

21 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 19/68 (30%) permanent AF 9/35 (25%) permanent AF in F/U M. Shenasa 2010

22 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

23 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

24 ? Inflammation and AF Inflammation Atrial Fibrillation Fibrosis
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: Normalization of inflammation markers after AF ablation and cardioversion suggests inflammation is the effect rather than the cause. M. Shenasa 2010

25 Histology of atrial biopsy from a patient with up to 20 episodes of PAF per day
M. Shenasa 2010 Frustaci, A. et al. Circulation 1997;96:

26 Oxidative stress, inflammation and AF
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 NFκB Oxidative Stress Inflammation Recruiting inflammatory cells: Macrophages, PMNs Watanabe T, Heart Vessels 2005 Watanabe E, Int J Cardiol Conway DS, Am J Cardiol 2004 Roldan V, Am J Cardiol 2005 Frustaci A, Circulation 1997 Aviles RJ, Circulation 2003 Spodick DH. JAMA 1976 Morgera T, Am Heart J 1992 Psychari SN, Am J Cardiol 2005 Chung MK, Circulation 2001 Courtesy of A. Sovari

27 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

28 After age 65, 5% per year develop atrial myocardium fibrosis
AF and Atrial Fibrosis ? AF Fibrosis After age 65, 5% per year develop atrial myocardium fibrosis M. Shenasa 2010

29 AF and Atrial Fibrosis Cardiac Electrophysiology: From cell to bedside; Munoz, Zlochiver and Jalife 2009 pp 215 M. Shenasa 2010

30 How fibrosis may cause arrhythmia
Decreased conduction velocity  Reentry Fibrosis: fibroblast /myofibroblast proliferation + increased collagen deposition Reduced sink to source  facilitating EAD/DAD propagation * F-M coupling  facilitating EAD/DAD formation *Miragoli M, Circ Res, 2007

31 AF and Atrial Fibrosis

32 Myocardial Fibrosis is the culprit!
Pulmonary Disease LA size VDH OSA Genetics DM AF Others Cardiomyopathy & LVH CAD Hyperthyroidism Drug Induced Channelopathies CHF HTN Myocardial Fibrosis is the culprit! Shenasa 2010

33 Each pathological process may play the central role only in a specific subpopulation with AF
Fibrosis Angiotensin II Gap Junctional Impairment Genetic Abnormalities Autonomic Dysfunction Clinical Associations of AF Age Hypertension Diabetes Family history Obesity Males AS/prior MI Surgery Hyperthyroidism LV dysfunction Valvular disease Inflammation Oxidative Stress Abnormal Ca2+ Handling Cardiac Alternans AF Courtesy of A. Sovari

34 Disappointment or a lesson in chess?
The main result: AF recurred in 51.4% in valsartan group, 52.1% in placebo group

35 AF and Remodeling M. Shenasa 2010

36 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: M. Shenasa 2010

37 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. M. Shenasa 2010

38 M. Shenasa 2010

39 New Antiarrhythmics for AF
M. Shenasa 2010

40 ATHENA: Primary Outcome
Time to first cardiovascular hospitalization or death 50 HR=.76 P<.001 40 30 Cumulative Incidence (%) Placebo 20 Dronedarone 10 6 12 18 24 30 Patients at risk Placebo Dronedarone Months Mean follow-up 21  5 months. Hohnloser. Presented at Heart Rhythm Society 2008; May 2008; San Francisco, CA (A). M. Shenasa 2010

41 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

42 Atrial Specific Antiarrhythmic Therapy
Lancet 2006;367:262-72 M. Shenasa 2010

43 Glycogen accumulation
Atrial Fibrillation Causes Histologic Remodeling of Atria as Early as 4 Months Myolysis Enlarged atrial cells Severe myolysis Glycogen accumulation Reduction in connexin 40 expression Sinus rhythm Atrial fibrillation Connexin 40 Ausma J et al. Circulation. 1997;96: Van der Velden HMW et al. J Cardiovasc Electrophysiol. 1998;9:

44 The Action Potential and Key Ion Currents
Atrial-selective pharmacologic approaches represent promising novel therapeutic options for the treatment of AF Besides limited clinical efficacy (cardioversion success and sinus-rhythm maintenance), side effects like ventricular proarrhythmia and negative inotropy are important limitations to present class I and III drug therapy Shown on this schematic are the differences in key ion currents between atrial (blue) and ventricular (red) action potentials (APs). Atrial APs have smaller AP amplitude and less negative resting membrane potential. Currents (green) identified above the line illustrating the APs are present in both regions. Atrially expressed ionic currents are illustrated below the AP schematic (blue) 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: Ehrlich JR, Biliczki P, Hohnloser SH, Nattel S. Atrial-selective approaches for the treatment of atrial fibrillation. J Am Coll Cardiol. 2008;51: 44

45 Pharmacotherapy for atrial arrhythmias: Present and future
Michael J. Mazzini MD et al Heart Rhythm 2008;5:S26-S31 M. Shenasa 2010

46 Statins Decrease in Atrial Fibrillation Anti-inflammatory properties
Anti-oxidant effect Plaque stabilization Statins Regulation of nitric-oxide-dependent endothelial function Atrial remodeling attenuation Renin angiotensin system downregulation Autonomic nervous system regulation Decrease in Atrial Fibrillation M. Shenasa 2010

47 Summary of Basic EP Effects of Fish Oil
EPA prolongs the QTc in the Langendorff rabbit model Fish oils block L-type calcium channels EPA and DHA suppress Na channels in cardiomyocytes and DHA slows Na channel dependent longitudinal conduction in the perfused heart model DHA and EPA raise the threshold to elicit an extrasystole In humans, fish oils slow heart rate, increase the PR and decrease the likelihood of a prolonged QTc Dhein, et. al. Arch Phamacol 2005;371: Xiao, et. al. Proc Natl Acad Sci 1997;94: London B, et al Circ 2007:116;e320-e335, Omega-3 Fatty Acids and Cardiac Arrhythmias M. Shenasa 2010

48 Ablation of AF Current Controversies
Definition Cure? Procedural endpoints Anticoagulation and Anti arrhythmic therapy post ablation Outcomes Follow ups Guidelines Cost M. Shenasa 2010

49 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; ) M. Shenasa 2010

50 M. Shenasa 2010

51 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:

52 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

53 Catheter-Based Management of AF
Valderrabano, M JMDHC 2;2007:24-29 M. Shenasa 2010

54 AF and Ablation M. Shenasa 2010 Courtesy of U.Penn

55 Catheter ablation of atrial fibrillation Heart Center Leipzig 1998 – 2008
1999 Courtesy of G. Hindricks M. Shenasa 2010

56 Plumonary vein Ablation in Atrial Fibrillation
AF and Ablation Plumonary vein Ablation in Atrial Fibrillation Hype or Hope? Hein Wellens Circ:2000;102: Circumferential Radiofrequency Ablation of Pulmonary Vein Ostia A New Anatomic Approach for Curing Atrial Fibrillation Carlo Pappone Circ:2000;102: Controversies In Cardiovascular Medicine Should atrial fibrillation ablation be considered first-line therapy fow some patients? (Circulation 2005; 112:1231)

57 Criteria for patient selection
Patients’ expectations: symptom relief, freedom from anticoagulation, freedom from antiarrhythmic therapy, resolution of tachycardia-induced myopathy Failure of prior antiarrhythmic therapy or prior procedures Pattern of atrial fibrillation: paroxysmal vs. chronic Presence of structural heart disease: left atrial size, left ventricular dysfunction, hypertrophic cardiomyopathy Duration of atrial fibrillation Valderrabano, M JMDHC 2;2007:24-29 M. Shenasa 2010

58 Cardiovascular Imaging in the Management of AF
M. Shenasa 2010 Valderrabano, M JMDHC 2;2007:24-29

59 ( Catheter Ablation versus Anti-Arrhythmias Drugs for Afib)
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

60 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

61

62 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

63 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

64 ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation.
HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: Recommendation for Personnel, Policy, Procedures and Follow-up Fuster, V: Circulation, Aug 2006; 114: e257 - e354. Calkins H, et al Heart Rhythm 2007;4: M. Shenasa 2010

65 The Watchman device (A, inset) is designed to occlude the left atrial appendage at its ostium. In a patient treated with this device, two-dimensional (B) and three-dimensional (C) CT images of the left atrium were obtained 1 year after implantation. Note the location of the Watchman device and the absence of contrast in the left atrial appendage, indicating its successful exclusion from the systemic circulation. (Part A Courtesy of Atritech, Plymouth, Minnesota; with permission.) M. Shenasa 2010 Cardiology Clinics 2009; 27:

66 Management Decision in AF
Antiarrhythmic Ablation Rate Control Anticoagulation M. Shenasa 2010

67 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

68 Thank you M. Shenasa 2010

69 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

70 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

71 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:

72 M. Shenasa 2010

73 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:

74 Summary and conclusion? ACEIn and ARB should treat AF
Ang-II Inflammation, ROS Fibrosis Cx43 remodeling Courtesy of A. Sovari

75 Best therapy is the one that is not needed

76 Ideal antiarrhythmic drug
Completely safe Completely effective Fun and easy to take Makes you live longer Cheaper than aspirin Immortilide for arrhythmias Take one per life time M. Shenasa 2010

77 AF and Atrial Fibrosis M. Shenasa 2010
Raman, S. V. J Am Coll Cardiol 2010;55:91-96

78 Angiotensin II-dependent cellular signalling via type 1 and type 2 receptors.
Angiotensin II-dependent cellular signalling via type 1 and type 2 receptors. Increased activation of AT-1 receptors can lead to cellular hypertrophy, apoptosis, and interstitial fibrosis. Most of these cellular effects are inhibited by activation of AT-2 receptors. Activation of AT-1 receptors increases phosphorylation of L-type calcium currents, and thereby, calcium influx is enhanced, whereas potassium currents are reduced. Of note, angiotensin II receptor blocker (ARB) have been shown to block directly Kv4.3 (Ito) and hKv1.5 channels (IKur). ANG II, angiotensin II; AT-1/AT-2, angiotensin II type 1 receptor, angiotensin II type 2 receptor; G, G protein; DAG, diacylglycerol; Erk1/2, extracellular-signal regulated kinase; Grb2, growth factor receptor-binding protein; JNK, c-jun terminal kinase; JNKK, JNK kinase; MAPK, mitogen-activated protein kinase; MEK, Erk-activating kinase; MEKK1, MEK kinase; PKC, protein kinase C; PLC, phospholipase C; Shc, sequence homology of collagen; Sos, ‘son of sevenless’; Src, sarcoma gene product (Rous sarcoma virus). Goette A , Lendeckel U Europace 2008;10: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author For permissions please

79 Gap Junctions M. Shenasa 2010
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

80 Novel anti-arrhythmics for AF
M. Shenasa 2010

81 Non-antiarrhythmic agents with antiarrhythmic properties
Therapeutic class Possible target Angiotensin-converting enzyme inhibitors, angiotensin II-receptor blockers Hypertension, heart failure, direct antithrombotic and antiarrhythmic effects? Aldosterone antagonists 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 Euro Heart J (2007) 9 (Supp G), G17-G25 M. Shenasa 2010

82 Concepts to Consider Selective ion channel blocker
Multi-channel blockade (like amiodarone) Atrial channel selective (usually “relative”) Substrate based Gap junction conduction Fibrosis Inflammation

83 New AAD Development: Possible Mechanisms
Beta-blockers with class I or III effects Amiodarone congeners Atrial-selective antiarrhythmic drugs IKur and IKACh blocker Atrioselective Na channel blocker 5-HT4–receptor antagonist Stretch Activated channel blockers ACE-I/ARB NCX (Na/Ca exchanger) inhibitor Anti-inflammatories (statins) Gap junction conduction facilitation

84 Beatch GN et al. Circulation. 2003;108:IV-85.
Vernakalant (RSD1235) Unique ion channel–blocking profile Frequency- and voltage-dependent INa block Early activating K+ channel block Blocks IKACh Rate-enhanced activity on conduction Atrial-selective APD/ERP prolongation Activity confirmed in several species No adverse hemodynamic effects Novel aminocyclohexyl ether drug Beatch GN et al. Circulation. 2003;108:IV-85.

85 AF and Atrial Fibrosis M. Shenasa 2010
Representative hematoxylin and eosin sections. In control LA (A), LAA (B), RA (C), and RAA (D), occasional inflammatory cells were present within the interstitium, while extensive interstitial inflammatory cells were noted in hypertensive LA (E), LAA (F), RA (G), and RAA (H). Magnification ×350. M. Shenasa 2010 Source: Heart Rhythm 2010; 7: (DOI: /j.hrthm )

86

87 David J. Wilber MD et al JAMA 2010;303(4)333-340
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)

88 Patient Flow Diagram

89 Kaplan-Meier Curves of Time to Protocol-Defined Treatment Failure, Recurrence of Symptomatic Atrial Arrhythmia, and Recurrence of Any Atrial Arrhythmia by Treatment Group

90 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 follow-up period.

91 AF and Atrial Fibrosis/Remodeling

92 Micro Circuit Re-Entry Secondary to Conduction Velocity Heterogeneity
Roberts, J. D. et al. J Am Coll Cardiol 2010;55: Copyright ©2010 American College of Cardiology Foundation. Restrictions may apply.

93 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

94 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.

95 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

96 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

97 Can Sinus Rhythm Improve Survival?
Effects of Maintaining NSR After AF Ablation on Survival Nademanee, K. et al. J Am Coll Cardiol 2008;51:

98 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, anti-fibrosis Development of atrial selective channel blockers Upstream therapies i.e. ARB, ACE, Omega-3, and statins Patient Outcome and follow up

99 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

100 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

101 Multimodality imaging plays an important role in the evaluation of atrial fibrillation patients, and in the management of atrial fibrillation. Multimodality imaging plays an important role in the evaluation of atrial fibrillation patients, and in the management of atrial fibrillation. Various modalities are available for screening for underlying heart disease causing atrial fibrillation. For left atrial size assessment, various methods are available; three-dimensional imaging techniques provide the most accurate estimation. In particular, in the non- pharmacological treatment of atrial fibrillation, imaging plays an important role in patient selection and guidance of the procedure. See text for explanation. Tops L F et al. Eur Heart J 2010;31:

102 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

103 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

104

105 Wellens, H

106 General Mechanisms of AF
1.) Multiple rapidly discharging foci 2.) Focal sources with fibrillatory conduction 3.) Multiple re-entrant circuit

107 AF and Atrial Fibrosis/Remodeling

108 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

109 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

110 The Future of Atrial Fibrillation Ablation 1/2
Optical Mapping Bioluminescence Diffused Optical Spectroscopy Magnetic Resonance Imaging Magnetic Resonance Spectroscopy (only noninvasive) Diffusion Tensor Imaging Fiber Tracking Multimodality Mapping and Ablation

111 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)

112 Nattel S; Nature Vol 415, 2002

113 The History of Atrial Fibrillation: The Last 100 Years
ERIC N. PRYSTOWSKY, M.D. J Cardiovasc Electrophysiol, Vol. 19, pp , June 2008.

114

115 A Volunteer Sitting with His Arms in Saline-Filled Tubs with Wires Connected to Einthoven's Electrocardiograph. From Einthoven.4 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:

116 Pulsus Inaequalis et Irregularis
From Einthoven.4 Fye W. N Engl J Med 2006;355: Definition of AF: At present any arrhythmia that has the ECG criteria of AF and lasts 30 seconds or longer is considered AF

117 AF Heart Failure and AF Heart failure Heterogeneous conduction
Loss of atrial contraction AF Increased fibrosis Rapid Ventricular rate -energy depletion Remodeling Ischemia Abnormal Ca⁺ handling Triggered activity Heart failure Altered atrial refractoriness R-R variability Volume + pressure overload

118 Camm, J

119 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:

120 Stroke and AF Heart Disease and Stroke: 2010
National Health and Nutrition Examination Survey : 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:

121 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

122 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:

123 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:

124 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

125

126 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:

127 AF and Atrial Fibrosis/Remodeling

128 Kirchhof, P. et al. Eur Heart J 2009 30:2969-2980; doi:10
Kirchhof, P. et al. Eur Heart J : ; doi: /eurheartj/ehp235

129 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.

130 AF and Atrial Fibrosis Burstein, B. et al. J Am Coll Cardiol 2008;51:

131 AF and Atrial Fibrosis Burstein, B. et al. J Am Coll Cardiol 2008;51:

132 Effect of Ion Channels on Atrial APD
Roberts, J. D. et al. J Am Coll Cardiol 2010;55:

133 Two Different sources of ectopy
AF and Ablation Two Different sources of ectopy Haïssaguerre, M Circ.2000;101:

134 The role of imaging in AF ablation 1/3
EHJ 2010;31:

135 The role of imaging in AF ablation 2/3
EHJ 2010;31:

136 The role of imaging in AF ablation 3/3
EHJ 2010;31:

137 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.

138 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

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140 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

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142 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:

143 Atrial Fibrillation: Past, Present and Future II

144 Roberts, J. D. et al. J Am Coll Cardiol 2010;55:705-712

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146 M. Shenasa 2010

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148

149 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

150 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

151 Heart Failure and AF M. Shenasa 2010
Electrical, contractile, and structural remodeling in atrial fibrillation. (From Allessie M, Ausma J, Schotten U. Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res 2002;54(2):230–46; with permission). M. Shenasa 2010 Cardiology Clinics 2009; 27:79-93

152 Active Currents In Atria and Ventricle
0 mV 50 mV 200 ms currents channel proteins currents Kv4.3+Kv1.4 KChIP2 Ito Ito Kv1.5 (Kv3.1) Not expressed IKur IKr (H)ERG+miRP1 IKr IKs KvLQT1+minK IKs Ik1 Kir 2.1 (Kir2.x) Ik1 GIRK4 IKAch Not expressed IK(ATP) Kir6.2+SUR2A IK(ATP)

153 Cumulative incidence of primary and secondary outcomes in treatment of Dronedarone with Placebo
M. Shenasa 2010 NEJM 2009;360:

154 M. Shenasa 2010

155 History of Atrial Fibrillation Scientific Era
William Stokes (1854) Wenckebach (1904) Mackenzie (1907) Sir Thomas Lewis ( ) described details of AF and reentry Gordon Moe (1959) described the computer model of multi-wavelet of reentry; Am Heart J 1946:67: Lown and colleagues (1962) first cardioversion for AF M. Shenasa 2010

156 Anti Arrhythmic Drug Therapy in AF
LVH CHF CAD None Amiodarone Dofetilide Sotalol Dronedarone Dofetilide Amiodarone Flecanide Propafonone Dronedarone Sotalol Dofetilide Amiodarone Flecanide Propafonone Catheter Ablation Catheter Ablation Catheter Ablation


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