atrial fibrillation: clinical significance, mechanisms, and treatments alexander burashnikov phd,...
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Atrial Fibrillation: Clinical Significance, Mechanisms,
and Treatments Alexander Burashnikov PhD, FHRS
Cardiac Research InstituteMasonic Medical Research Laboratory
Utica NY
Campaign for Quality October 17-18, 2013
Sinus node
Right atrium
AV node
Right ventricle
Left atrium
Conductionpathways
Left ventricle
Normal electrical activation
Heart and ECG
Atrial tachycardia
Sinus node
AV node
Atrial Flutter
AV node
Sinus node
Atrial fibrillation (AF or AFib)
AV node
Sinus node
AF Prevalence by Age and Sex
Go AS, et al. JAMA. 2001;285:2370-2375.
9.1
7.2
5.0
3.4
1.71.0
0.40.1
11.1
10.3
7.3
5.0
3.0
1.7
0.90.2
0
2
4
6
8
10
12
<55 55-59 60-64 65-69 70-74 75-79 80-84 >85
Pre
vala
nce,
%
Men Women
Atrial Fibrillation: Prevalence
• Currently: 2.3 - 3.0 millions people have AF in the USA
• In 2050: 7 – 15 millions people will have AF in the USA
Atrial Fibrillation: Hospitalization
Atrial Fibrillation: Mortality
Atrial Fibrillation: Cost
Atrial Fibrillation vs. Ventricular Fibrillation
Atrial fibrillation can last for yearsGenerally mild immediate consequences
Ventricular fibrillation lasts for seconds or minutes in vivo.Kills within minutes.
Atrial fibrillation can cause serious complications in a long ran: • stroke • tachycardia-mediated cardiomyopathy
Stroke
• 15-20% of all stroke in the United State is due to atrial fibrillation.
AF: tachycardia-mediated cardiomyopathy
• 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
Atrial fibrillation: Risk factors
Risk of atrial fibrillation.
Benjamin et al . JAMA 1994
MI indicates myocardial infarction; HTN, hypertension; HF, heart failure; VHD, valvular heart disease; DM, diabetes mellitus; and LVH, ECG left ventricular hypertrophy.
Symptoms and Documentation of atrial fibrillation
15-30% of patients with AF are asymptomatic. Stroke is often the initial presenting sign of AF
• Shortness of breath • Palpitations• Chest pain• Fatigue• Reduced exercise
capacity• Dizziness,
lightheadedness
Cardiac Action Potential
Sinus node automaticity
Mechanisms of cardiac arrhythmias
Impulse formation:
Mechanisms of cardiac arrhythmias
Conduction disturbances:reentry
Atrial fibrillation: Initiation and maintenance
ECG
Action potential
Trigger (or extra-beat)
Substrate(remodeling)
Mechanisms of maintenance of atrial fibrillation
Nattel J Cardiovascular Research 54 (2002) 347-360
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
Atrial fibrillation: Spatial and temporal electrical heterogeneity
AF begets AF: Atrial electrical and structural remodeling
Wijffels et al Circulation 1995
Ito1
IKurIKur
IKr
INa
ICa
IKs
IK-ACh, IK-ATPIK-ACh, IK-ATP
IK1
Ito1
IKurIKur
IKr
INa
ICa
IKs
IK-ACh, IK-ATPIK-ACh, IK-ATP
IK1
Constitutively Constitutively Active (CA)Active (CA)
ICa
Ito
IK1
IK-ACh (CA)
IKur
Atrial electrical remodeling (commonly due to AF)
Atrial structural remodeling
Can be due to:•Rapid activation rate (AF)•Hypertension•Coronary artery disease•Heart failure •Age
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.
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
Treatment of Atrial fibrillation
Rhythm control: Restoration and maintenance of sinus
rhythm.
• Pharmacological • Catheter ablation• Surgery• Electrical cardioversion
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
“Pill-in-the-Pocket” approach for termination of paroxysmal AF
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
Rhythm control: catheter ablation
Left Atrial Catheter AblationPulmonary veins
RF = radiofrequency.
Oral H, et al. Circulation. 2003;108:2355-2360.Saad EB, et al. Circulation. 2003;108:3102-3107.
Rhythm control: Electrical cardioversion
Rate control
Pharmacological: Depression of excitablilty of atrioventricular node (making ventricular rate < 80-110 beats/min)
Surgery (Maze procedure):
Beta-blockers,calcium-channel blockers, digoxin
Rate control
Risk of stroke in patients with atrial fibrillation
Score ≥ 2. Long term anti-coagulation is recommended
Anticoagulation
Hart et al Ann Intern Med, 1999
Anticoagulation reduces stroke occurrence in patients with atrial fibrillation
Old and new anticoagulants “Old”
•Aspirin (often used with clopidogrel) •Warfarin
New:
•Dabigatran•Rivaroxaban•Apixaban
Kirchhof P et al. Europace 2013;europace.eut232
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2013. For permissions please email: [email protected].
Treatment of Atrial fibrillation
Current approach to stepwise decision making in patients with AF.
Kirchhof P et al. Europace 2013;europace.eut232
Kirchhof P et al. Europace 2013;europace.eut232
Eur Heart J, 2013
Current investigational pharmacological strategies for AF treatment
Atrial specific or selective therapytargets:IKur
IK-ACh
CA IK-ACh
INa (+IKr ?)
“Upstream” therapy Targets: Structural remodelingInflammationOxidative stressHypertrophy,Stretch,etc.
Gap junction therapy targets:Cx40Cx43
Normalization of intracellular calcium homeostasis
Improvement of “old” agents: Amiodarone derivatives: Dronedarone Celivarone ATI-2042
Thank you
About 40% patients in whom AF first time detected will not develop AF within next 5 years.
Treatment of Atrial fibrillation
Fuster et al Circ 2011
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.
Rhythm control: pharmacological approach