1. Atrial Fibrillation: Clinical Significance, Mechanisms, and Treatments
Alexander Burashnikov PhD, FHRS
Cardiac Research Institute
Masonic Medical Research Laboratory
Utica NY
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October 17-18, 2013

2. Heart and ECG Normal electrical activation Left atrium Sinus node
Right
atrium
AV node
ventricle
Left atrium
Conduction
pathways
Left
Figure 1
The impulse then travels to the ventricles through conduction pathways made of specialized muscle fibers. The pathways divide into a network of smaller fibers which distribute the impulse throughout both ventricles. The impulse stimulates the ventricles, causing them to contract and pump blood. At rest, the sinus node normally initiates 60 to 80 beats a minute. With activity or excitement, the body requires greater blood circulation. A healthy sinus node responds to these changes in the body by increasing the heart rate accordingly.

3. Atrial tachycardia
Sinus node
AV node

4. Atrial Flutter
Sinus node
AV node

5. Atrial fibrillation (AF or AFib)
Sinus node
AV node

6. AF Prevalence by Age and Sex
Atrial Fibrillation: Prevalence
Currently: millions people have AF in the USA
In 2050: 7 – 15 millions people will have AF in the USA
AF Prevalence by Age and Sex
Age, y
Prevalence of AF in a population of 1.89 million members of a large health maintenance organization in California. The error bars represent 95% confidence intervals. The numbers represent the number of men and women with AF in each age category.
Go AS, et al. JAMA. 2001;285:

7. Atrial Fibrillation: Hospitalization

8. Atrial Fibrillation: Mortality

9. Atrial Fibrillation: Cost

10. Atrial Fibrillation vs. Ventricular Fibrillation
Ventricular fibrillation lasts for seconds or minutes in vivo.
Kills within minutes.
Atrial fibrillation can last for years Generally mild immediate consequences
Atrial fibrillation can cause serious complications in a long ran:
stroke
tachycardia-mediated cardiomyopathy

11. Stroke
15-20% of all stroke in the United State is due to atrial fibrillation.

12. AF: tachycardia-mediated cardiomyopathy

13. Atrial fibrillation: Risk factors
Older than 60 years of age
Diabetes
High blood pressure
Coronary artery disease
Prior heart attacks
Congestive heart failure
Structural heart disease (valve problems or congenital defects)
Prior open-heart surgery
Untreated atrial flutter (another type of abnormal heart rhythm)
Thyroid disease
Chronic lung disease
Sleep apnea
Excessive alcohol or stimulant use

14. Risk of atrial fibrillation.
The population-attributable risk of atrial fibrillation in men and women determined from a community-based longitudinal study.36 For both men and women, a substantial portion of atrial fibrillation risk remains unexplained. MI indicates myocardial infarction; HTN, hypertension; HF, heart failure; VHD, valvular heart disease; DM, diabetes mellitus; and LVH, ECG left ventricular hypertrophy.
MI indicates myocardial infarction; HTN, hypertension; HF, heart failure; VHD, valvular heart disease; DM, diabetes mellitus; and LVH, ECG left ventricular hypertrophy.
Benjamin et al . JAMA 1994

15. Symptoms and Documentation of atrial fibrillation
Shortness of breath
Palpitations
Chest pain
Fatigue
Reduced exercise capacity
Dizziness, lightheadedness
15-30% of patients with AF are asymptomatic.
Stroke is often the initial presenting sign of AF

16. Cardiac Action Potential

17. Sinus node automaticity

18. Mechanisms of cardiac arrhythmias
Impulse formation:

19. Mechanisms of cardiac arrhythmias
Conduction disturbances:
reentry

20. Initiation and maintenance
Atrial fibrillation:
Initiation and maintenance
Trigger
(or extra-beat)
Substrate
(remodeling)
ECG
Action potential

21. Mechanisms of maintenance of atrial fibrillation
Nattel J Cardiovascular Research 54 (2002)

22. Masonic Medical Research Laboratory, Utica, NY
Gordon Moe, 1958, 1962, 1964
Masonic Medical Research Laboratory, Utica, NY
The multiple Wavelet Hypothesis has been the dominating theory of cardiac fibrillation for several decades

23. Atrial fibrillation: Spatial and temporal electrical heterogeneity

24. AF begets AF: Atrial electrical and structural remodeling
Wijffels et al Circulation 1995

25. Constitutively Active (CA)
Atrial electrical remodeling
(commonly due to AF)
Normal
Atria
Remodeled
Atria
Ito1
ICa
Ito1
IKur
IKur
Ito
IKur
ICa
ICa
IK1
IKr
IKr
IK-ACh (CA)
IKs
IKs
IK1
IK1
INa
INa
IK-ACh, IK-ATP
IK-ACh, IK-ATP
Constitutively Active (CA)

26. Atrial structural remodeling
Can be due to:
Rapid activation rate (AF)
Hypertension
Coronary artery disease
Heart failure
Age

28. Atrial fibrillation classification:
Paroxysmal AF – self-terminating (< 7 days)
Persistent AF – (> 7 days). Can be terminated
(drugs, ablation or electrical cardioversion)
Permanent AF – completely refractory to revision to sinus rhythm
AF often progresses from short, rare episodes, to longer and more frequent attacks.

29. Treatment of Atrial fibrillation
Rhythm or Rate control?
Rhythm control:
maintenance of sinus rhythm
Rate control:
control ventricular rate without making any specific attempts to suppress or prevent AF
Anticoagulation (to prevent stroke):
Commonly in both

30. Rhythm control: Restoration and maintenance of sinus rhythm.
Pharmacological
Catheter ablation
Surgery
Electrical cardioversion

31. Rhythm control: pharmacological
Sodium channel blockers (propafenone, flecainide, etc):
Potassium channel blockers (sotalol, dofetilide, ibutilide, etc):
Multiple channel blockers (amiodarone, ranolazine, etc)
Drugs prolong repolarization and depress excitability. AF
Termination of AF

32. “Pill-in-the-Pocket” approach for termination of paroxysmal AF

33. Antiarrhythmic Drug Proarrhythmia: an Extension of Pharmacologic Effects
Class IC toxicity: Atrial flutter with 1:1 AV conduction
Class IA/III toxicity: Torsades de pointes

34. Rhythm control: catheter ablation

35. Left Atrial Catheter Ablation Pulmonary veins
RF = radiofrequency.
Oral H, et al. Circulation. 2003;108:
Saad EB, et al. Circulation. 2003;108:

36. Rhythm control: Electrical cardioversion

37. Rate control Surgery (Maze procedure): Pharmacological:
Depression of excitablilty of atrioventricular node (making ventricular rate < beats/min)
Surgery (Maze procedure):
Beta-blockers,
calcium-channel blockers, digoxin

38. Rate control

39. Anticoagulation Risk of stroke in patients with atrial fibrillation
Score ≥ 2. Long term anti-coagulation is recommended

40. Anticoagulation reduces stroke occurrence in patients with atrial fibrillation
Hart et al Ann Intern Med, 1999

41. Old and new anticoagulants
Aspirin (often used with clopidogrel)
Warfarin
New:
Dabigatran
Rivaroxaban
Apixaban

42. Several large clinical trials (i. e
Several large clinical trials (i.e., AFFIRM, RACE, PIAF, HOT CAFÉ, STAF, AF-CHF) have demonstrated that the rhythm control with anti-arrhythmic drugs is not superior to the rate control in terms of morbidity and mortality
Adverse effects of drugs may balance or even exceed the beneficial effects.
Several post-hoc or sub-study analyses of the large clinical trials (such as the DIAMOND, AFFIRM, CHF-STAF trials), directly comparing “sinus rhythm” vs. “AF” regardless of the initial rate or rhythm control assignment, indicate that AF patients maintained in sinus rhythm (with or without drugs) have better survival rate and better quality of life than those in whom AF persists

43. Treatment of Atrial fibrillation
Different types of information, gained from clinical assessment (upper left, turquoise), ECG (upper right, red), blood-based biomarkers (lower right, purple), and imaging (lower left, green) which may be useful to personalize AF management. The black boxes in the middle portion of the diagram illustrate different management domains which may be informed by different measures.
Kirchhof P et al. Europace 2013;europace.eut232
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author For permissions please

44. Current approach to stepwise decision making in patients with AF.
Kirchhof P et al. Europace 2013;europace.eut232

45. Kirchhof P et al. Europace 2013;europace.eut232

46. Eur Heart J, 2013

47. Current investigational pharmacological strategies for AF treatment
Atrial specific or selective therapy
targets:
IKur
IK-ACh
CA IK-ACh
INa (+IKr ?)
“Upstream” therapy Targets:
Structural remodeling
Inflammation
Oxidative stress
Hypertrophy,
Stretch,
etc.
Gap junction therapy targets:
Cx40
Cx43
Normalization of intracellular calcium homeostasis
Improvement of “old” agents:
Amiodarone derivatives:
Dronedarone
Celivarone
ATI-2042
Thank you

48. Treatment of Atrial fibrillation
Fuster et al Circ 2011
About 40% patients in whom AF first time detected
will not develop AF within next 5 years.

49. Pro-arrhythmias in ventricles!
At slow heart rates and pauses, specific IKr blockers predominantly prolong ventricular vs. atrial APD/ERP and induce EAD and TdP in ventricles not in atria.

50. Rhythm control: pharmacological approach