Tutorial On Electrophysiology of The Heart) Sam Dudley, Brown University

Tutorial on Electrophysiology of
the Heart
Sam Dudley, MD, PhD

Chief of Cardiology, The Miriam and Rhode Island Hospitals
Director, Lifespan Cardiovascular Institute
Ruth and Paul Levinger Professor of Cardiology
The Warren Alpert Medical School of Brown University
DISCLOSURE
• Hold patents on blood test for arrhythmic risk,
hLuc7A/RBM25 as antiarrhythmic targets,
NAD+ and mitochondrial anti-oxidants for
treatment of arrhythmia
• Off label uses of NAD+ and mitoTEMPO
• Owner of 3PrimeDx
Objectives
 Review normal cardiac cellular excitation
 Review generation and spread of electrical

activity in the heart
 Understand three major mechanisms of

arrhythmogensis:
Automaticity
Triggered Activity
Reentry
 Review treatments
Review of Cellular
Electrophysiology
Molecular and cellular
correlates of the
electrocardiogram
(ECG)
Major Ion Channel Players
• All three major

components (inward
Na+ and Ca2+ and
outward K+) are
voltage gated
• Four domains
• Each domain has 6
membrane spanning
segments
Antiarrhythmic drugs:
State-dependent block of ion channels
drug
Closed Open Increased affinity of channel
Na+
blockers for open and inactivated
states
Depol.
Relevant for antiarrhythmic effects

of Class I drugs
repolarization depolarization
Inactivated
Class I drug
RMP ≈ K+ Equilibrium potential
Myocytes- - +
+
- +
K+ (150) K+ (4 mM)
←  Na+ (145 mM)

Nernst equation: -90 mV
Na+ (20)
Ca2+ (0.001) ← Ca2+ (2 mM)

EK = -61 log[K+]i/[K+]o = -96 mV
Cl- (20 ) ← Cl- (140 mM)
Ca
2K
3Na
3Na Ca
RMP is determined primarily by 3 factors:

1) the concentration of ions on the inside and outside of the cell
2) the activity of electrogenic pumps (e.g., Na+/K+-ATPase and
Ca2+ transport pumps)
3) the permeability of the cell membrane to K+
Changing the membrane potential
Nernst Goldman Hodgkin Katz

[ S ]i RT PK [ K ]o + PNa [ Na ]o
Eeq = −61 log Em = ln 10
[ S ]o F PK [ K ]i + PNa [ Na ]i
Gap Junction: Cardiac Cell Coupling
• Gap Junction Channels are made of Connexons

• Each channel is made of two connexons, one in the plasma membrane of each of
the cells linked
• Each connexon is made of up to 6 connexin subunits
• The most abundant is Cx43, other (Cx 37, Cx 40, Cx 45) are only in small amounts
Severrs et al. Cardiovascular Research 62 (2004) 368

Concept of Refractoriness
Conduction System Properties
Conduction Velocity in Cardiac Tissue
• Velocity of spread of activation along
tissue dependent on
– Action potential upstroke speed (i.e.,
amount of depolarizing current)
– Coupling of cells (gap junction function)
• Slow Conduction
– Blocking sodium channels in working
myocardium
– Blocking calcium channels in nodal tissue
– Affecting gap junction function
Differences Between Normal Physiology of
Nodal and Working Myocardial Tissue
• Nodal tissue
– Action potential dependent primarily on Ca2+
ions (because RMP is -60mV → little Na+ current)
– AP has slow upstroke, therefore conduction
velocity is slow
– As rate of stimulation is increased,
conduction velocity slows, refractory period
increases
– Behavior influenced profoundly by
autonomic tone
Cellular Electrophysiology
Automaticity
The property of cardiac cells to depolarize spontaneously
Normally only cells of the SA node, the AV node, and His-
Purkinje system possess automaticity.
SA Node
(Ca2+)
Purkinje
Fiber
(Na+)
Autonomic effects on automaticity
ICa
P
IKs K+
Mechanisms of Arrhythmia
Mechanisms of bradyarrhythmia
Failure of impulse Failure of impulse

formation (e.g. propagation (e.g.
sinus bradycardia) Mobitz II
atrioventricular
nodal block)
Mechanisms of tachyarrhythmia
Automaticity Triggered activity Reentry

• Early
• normal (e.g. afterdepolarizations • favored by slow
sinus associated with action conduction (low
potential prolongation
tachycardia) (torsades de pointes) dV/dt or Vmax)
• abnormal (e.g. • Delayed • favored by
reperfusion afterdepolarizations cellular
associated with Ca2+
arrhythmias) overload and
heterogeneity
depolarization (e.g.
digoxin)
Tachycardia
Enhanced Normal Automaticity
Basal condition
Increased slope of phase 4 depolarization

Characteristics of Arrhythmias Mediated by
Automaticity
• Morphology of the initiating P or QRS is the

same as subsequent complexes
• Exhibit progressive “warm-up” (acceleration

in rate)
• Automatic tachycardias cannot be initiated

by programmed electrical stimulation (PES)
or pacing.
Triggered activity
Early afterdepolarizations
• Seen with bradycardia and prolonged action
potentials
• Thought to be secondary to L-type Ca2+
channel recovery
Delayed afterdepolarizations
• Seen with tachycardia and cell Ca2+ overload
• Thought to be secondary to a Ca2+–
dependent transient inward current or
sodium calcium exchange
Long QT Syndrome
Normally the QT interval is

< ½ RR interval.
QT interval = 540 msec

Cause of Torsades: EADs
Nattel and Carlsson Nature Reviews

Drug Discovery 5, 1034–1049
Reentrant Tachycardia
~ 95% of clinical arrhythmias
Absolute requirement:
Unidirectional conduction block
Favoring conditions:
Slow conduction such as occurs with fibrosis
Anisotropy of conduction or other electrophysiological

properties such as ≥2 pathways for impulse
conduction that can be joined proximally and distally
Unidirectional block and reentry
Rotors: a new concept in reentry
Specific examples of
arrhythmia
ATRIAL FIBRILLATION AND
FLUTTER
Atrial fibrillation versus atrial flutter
Atrial Fibrillation Atrial Flutter

Atrial fibrillation risks and characteristics
• Atrial fibrillation
– Age
– HTN
– DM
– FH
– Obesity
– Males
– Atherosclerosis/prior MI
– Surgery
– Hyperthyroidism
– LV dysfunction
– Valvular disease
Complications of atrial fibrillation
Tachycardia
• SOB
• Lightheadedness
• Edema
• ↓Exercise tolerance
• Myopathy
Stroke
Thrombus formation and stroke risk
in atrial fibrillation
Atrial Fibrillation: Mechanisms
Ventricular Tachycardia and
Fibrillation
Ventricular fibrillation versus
tachycardia
Ventricular Fibrillation Ventricular Tachycardia
Sudden Death
Defining the Problem of Sudden
Cardiac Death (SCD)
Etiologies of Sudden Death
• An estimated 13 million people

had CHD in the U.S. in 2002. 1 5% Other*
• Sudden death was the first
manifestation of coronary heart
disease in 50% of men and 63%
of women. 1
• Approximately 50% of CHD
deaths are sudden2 15% 80%
Coronary
• Incidence of SCD in the US is 1- Cardiomyopathy
2/10002 Heart Disease
• CHD accounts for at least 80%
of sudden cardiac deaths in
Western cultures.3
1 American Heart Association. Heart Disease Adapted from Heikki et al. N Engl J Med, Vol. 345,
and Stroke Statistics—2003 Update. Dallas, No. 20, 2001.
Tex.: American Heart Association; 2002.
* ion-channel abnormalities, valvular or congenital
2 ACC/AHA/ESC 2006 Guidelines. JACC 48: heart disease, other causes
1064, 2006
3 Myerberg RJ. Heart Disease, A Textbook of
Cardiovascular Medicine. 6th ed. P. 895.
Treatments of Arrhythmia
Pacemaker Indications
 Sinus node dysfunction
 Sinus bradycardia with symptoms
 Symptomatic chronotropic
incompetence
 Sinus node dysfunction and
syncope
 HR < 40 while awake
 AV block
 Complete AV block
 High degree AV block
 Symptomatic AV block
 Mobitz II
 Exercise induced 2nd or 3rd degree
AV block
 Bifascicular block and syncope
 Iatragenic
 Neurocardiogenic syncope
 Long QT
 Heart failure and resynchronization
Vaughan Williams classification
Class I – Na+
blockers
• Class Ia – blocks
Na+ and K+ channels
• Class Ib – blocks Class IV – Ca2+
Na+ channels with channel
rapid kinetics blockers.
• Class Ic – blocks Class II - β Class III – blocks
Dihydropyridines
Na+ channels with blockers K+ channels
slow kinetics are not effective
antiarrhythmic
drugs
Getting Rid of Reentry
K+ channel block
Prolong the refractory period
Na+ channel block
• The critical wavelength

is APD x CV = the
minimum path length
Critically slow conduction
required for reentry
Proarrhythmia
• Class I proarrhythmia may be drug induced

Brugada syndrome
• Class III proarrhythmia is related to QT
prolongation
Finding (Mapping) and ablating
arrhythmias
Surgery for arrhythmias
Implanted cardiac defibrillators (ICDs)
SOCS-HEFT results: ROC curve for
prediction of sudden death
Variants
EF
Raising sodium current to treat
arrhythmias
Summary
• Ion channels and ion movement across a membrane underlie
cardiac electrophysiology
• Conduction moves from the high right atrium to the ventricles
• There are five mechanisms of arrhythmia
– Failed automaticity
– Failed conduction
– Enhanced or abnormal automaticity
– Triggered activity
– Reentry
• Treatments
– Pacemaker
– Blocking ion channels – all drugs have proarrhythmia
– Ablation
– ICDs
– Raising ion channels

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Tutorial on Electrophysiology of

Sam Dudley, MD, PhD

 Review generation and spread of electrical

 Understand three major mechanisms of

• All three major

Relevant for antiarrhythmic effects

←  Na+ (145 mM)

Ca2+ (0.001) ← Ca2+ (2 mM)

RMP is determined primarily by 3 factors:

Nernst Goldman Hodgkin Katz

• Gap Junction Channels are made of Connexons

Severrs et al. Cardiovascular Research 62 (2004) 368

Failure of impulse Failure of impulse

Automaticity Triggered activity Reentry

Increased slope of phase 4 depolarization

• Morphology of the initiating P or QRS is the

• Exhibit progressive “warm-up” (acceleration

• Automatic tachycardias cannot be initiated

Normally the QT interval is

QT interval = 540 msec

Nattel and Carlsson Nature Reviews

Anisotropy of conduction or other electrophysiological

Atrial Fibrillation Atrial Flutter

• An estimated 13 million people

Prolong the refractory period

Na+ channel block

• The critical wavelength

• Class I proarrhythmia may be drug induced

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