Cardiac Arrhythmias

Physiology Gone Bad

Arrhythmias

Bradycardia Tachycardia 1st degree AV block 2nd degree AV block 3rd degree AV block

Premature Ventricular Complex (PVC) Atrial Fibrillation Ventricular Tachycardia Ventricular Fibrillation

Alterations in Normal Rhythm

Bradycardia
conventional: < 60 beats/min More useful: < 50 beats/min

Tachycardia
conventional > 100 beats/min More useful: > 90 beats/min

1st Degree A-V Block

Not really block Just P-R interval longer than normal (> 0.2 sec) Treatment: none

2nd Degree AV Block

Some action potentials fail to get through the A-V node Normal Sinus Rhythm

2nd degree A-V block

Treatment: none or ventricular pacing

3rd Degree A-V Block

No action potentials from the SA node/atria get through the A-V node Normal Sinus Rhythm

3rd degree A-V block

Treatment: ventricular pacing

Normal Sinus Rhythm and Premature Venticular Complex

Transient reduction in arterial pressure

Normal AP Conduction in Ventricles

AP Conduction of PVC

Initiation site

Atrial Fibrillation

Only modest reduction of arterial pressure

Atrial Fibrillation Treatment

Try to restore normal rhythm (cardioversion)

vagatonic maneuvers (carotid massage, Valsalva maneuver, gagging) adenosine

If persistent rhythm:
control ventricular rate (verapamil) anticoagulant therapy

Ventricular Tachycardia
Large, sustained reduction of arterial pressure

Treatment:

Lidocaine Electrical Cardioversion

Ventricular Fibrillation

Chaotic ventricular electrical activity which causes the heart to lose the ability to function as a pump.

Treatment: defibrillation

Defibrillation

Arrhythmia Mechanisms

Arrhythmias are Rare

64,000,000,000,000 heart beats in U.S./year 0.1% incidence of sudden cardiac death Severe pathologies leading to fatalities are rare So a consistent arrhythmia may require several independent, simultaneous, pathological conditions

Pathological Conditions
Ischemia Intracellular Ca2+ overload Stress: adrenergic stimulation Genetic defects- especially in ion channels Anatomic defects Drug effects

Arrhythmia Mechanisms
Single cell mechanisms Multi-cell mechanisms

Note: Most arrhythmias originate as inappropriate electrical activity in ventricular and Purkinje cells.

Single Cell Mechanisms

Delayed After Depolarization (DAD) Early After Depolarization (EAD)

Early Afterdepolarization (EAD)

0

Requires trigger More likely with long action potentials

slower heart rate (why?) low extracellular K+ (?) Drugs

Action potential

-50

antiarrhythmic drugs antihistamines others K channels Na channels

Congenital long QT

200 msec

A Multi-Cell Mechanism

Consequences of Ischemia: Purkinje Fibers and Ventricular Muscle

Depolarization Inactivation of Na (not Ca) channels Ca channel-based action potential Slower conduction velocity

0 0

-50

-50 200 msec

200 msec

Normal Action Potential Conduction

Action potential
0

Purkinje fibers
20 msec
-50

Conduction times (1 mm/msec): A-C A-B C-B 10 msec 10 msec 10 msec

A
200 msec

Ventricular Muscle

Ischemia and Reentry Arrhythmia

Healthy Action Potential
0

Conduction Times
250 msec
-50

Conduction times (1 mm/msec): 10 msec 10 msec 20 msec

A-C C-B Total A

200 msec

(0.04 mm/msec): A-B 250 msec B C 10 mm

Genetic Ion Channel Defects

Long QT Syndrome

From: Ion Channels and Disease F.M. Ashcroft. Academic Press 2000

LQT Genetics
Type Gene
LQT1 LQT2 LQT3 LQT4 KCNH2 (hERG) SCN5A unknown

Chromosome Comment
Trigger: Stress Trigger: Startle (e.g. sudden noise) Trigger: Sleep Variants found in one large family with long QT. Precise location of gene is unknown. Associated with Jervell and LangeNielsen syndrome (congenital deafness) Triggers: drugs, exercise Associated with Andersen syndrome 7 3 4

KCNQ1 (KvLQT1) 11

LQT5 LQT6 LQT7

KCNE1 (minK) KCNE2 (mirp1) KCNJ2 (Kir 2.1)

21 21 17

After: http://www.qtsyndrome.ch/bio.html by Raymond L. Woosley Dept. Pharmacology, Georgetown University

Summary
Normal cardiac function relies on channels and anatomy Arrhythmias involve ion channels in a pathological setting Most antiarrhythmic drugs involve ion channels

Antiarrhythmic Drugs

Class I: Local anesthetic action, reducing Na channel current

Lidocaine, Quinidine Propranalol

Class II: b-Adrenergic antagonists

Class III: action potential prolongation

Amiodarone
Verapamil

Class IV - Ca channel antagonists