Atrial Fibrillation: Clinical Significance, Mechanisms, and Treatments Alexander Burashnikov PhD, FHRS Cardiac Research Institute Masonic Medical Research.

Atrial Fibrillation: Clinical Significance, Mechanisms,

and Treatments Alexander Burashnikov PhD, FHRS

Cardiac Research InstituteMasonic Medical Research Laboratory

Utica NY

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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.

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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: journals.permissions@oup.com.

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