Diagnostic Cardiac Catheterization and Coronary Angiography

1863CHAPTER 242

cardiac chambers. The severity of the shunt is determined by the ratio of

pulmonary blood flow (Qp

) to the systemic blood flow (Qs

), or Qp

/Qs

 =

([systemic arterial oxygen content − mixed venous oxygen content]/

pulmonary vein oxygen content − pulmonary artery oxygen content).

For an atrial septal defect, a shunt ratio of 1.5 is considered significant

and factored with other clinical variables to determine the need for

intervention. When a congenital ventricular septal defect is present, a

shunt ratio of ≥2.0 with evidence of left ventricular volume overload is

a strong indication for surgical correction.

■ VENTRICULOGRAPHY

AND AORTOGRAPHY

Ventriculography to assess left ventricular function may be performed during cardiac catheterization. A pigtail

catheter is advanced retrograde across

the aortic valve into the left ventricle,

and 30–45 mL of contrast is powerinjected to visualize the left ventricular

chamber during the cardiac cycle. The

ventriculogram is usually performed

in the right anterior oblique projection

to examine wall motion and mitral

valve function. Normal wall motion

is observed as symmetric contraction

of all segments; hypokinetic segments

have decreased contraction, akinetic

segments do not contract, and dyskinetic segments appear to bulge paradoxically during systole (Fig. 242-3).

Ventriculography may also reveal a

left ventricular aneurysm, pseudoaneurysm, or diverticulum and can be

used to assess mitral valve prolapse

and the severity of mitral regurgitation.

The degree of mitral regurgitation is

estimated by comparing the density

of contrast opacification of the left

atrium with that of the left ventricle.

Minimal contrast reflux into the left

atrium is considered 1+ mitral regurgitation, while contrast density in the

left atrium that is greater than that in

the left ventricle with reflux of contrast into the pulmonary veins within

three beats defines 4+ mitral regurgitation. When it takes more than 3

beats but fully fills the atrium, it is 3+. Both 3+ and 4+ are considered

severe regurgitation. Ventriculography performed in the left anterior

oblique projection can be used to identify a ventricular septal defect.

Calculation of the ventricular volumes in systole and diastole allows

calculation of stroke volume and cardiac output.

Aortography in the cardiac catheterization laboratory visualizes

abnormalities of the ascending aorta, including aneurysmal dilation

and involvement of the great vessels, as well as dissection with compression of the true lumen by an intimal flap that separates the true

TABLE 242-3 Hemodynamic Findings in Tamponade, Constrictive Pericarditis, and Restrictive Cardiomyopathy

CARDIAC TAMPONADE

CONSTRICTIVE

PERICARDITIS

EFFUSIVE-CONSTRICTIVE

PERICARDITIS

RESTRICTIVE

CARDIOMYOPATHY

Pericardial pressure ↑ ↑ ↑ Normal

Right atrium pressure ↑ ↑ ↑ (Fails to decrease by 50% or to <10

mmHg after pericardiocentesis)

↑

Right atrium pressure

waveform

Prominent “x” descent

Diminished or absent “y”

descent

Prominent “x” descent

Prominent “y” descent

Prominent “x” descent

“y” descent less prominent than

expected

Prominent “y” descent

Right ventricle systolic

pressure

<50 mmHg <50 mmHg <50 mmHg >60 mmHg

Right ventricle end-diastolic

pressure

>1/3 right ventricular

systolic pressure

>1/3 right ventricular systolic pressure <1/3 right ventricular systolic

pressure

Equals left ventricular enddiastolic pressure within

5 mmHg

Equals left ventricular enddiastolic pressure within

5 mmHg

Equals left ventricular end-diastolic

pressure within 5 mmHg

Less than left ventricular enddiastolic pressure by ≥5 mmHg

Right ventricle pressure

waveform

Dip and plateau or “square

root” sign

Dip and plateau or “square root” sign Dip and plateau or “square

root” sign

Right ventricle–left

ventricle systolic pressure

relationship with inspiration

Discordant Discordant Discordant Concordant

DIASTOLE SYSTOLE

FIGURE 242-3 Left ventriculogram at end diastole (left) and end systole (right). In patients with normal left ventricular

function, the ventriculogram reveals symmetric contraction of all walls (top). Patients with coronary artery disease may

have wall motion abnormalities on ventriculography as seen in this 60-year-old male following a large anterior myocardial

infarction. In systole, the anterior, apical, and inferior walls are akinetic (white arrows) (bottom).

1864 PART 6 Disorders of the Cardiovascular System

and false lumina. Aortography can also be used to identify patent

saphenous vein grafts that elude selective cannulation, identify shunts

that involve the aorta such as a patent ductus arteriosus, evaluate the

takeoff or proximal anatomy of the great vessels, and provide a qualitative assessment of aortic regurgitation using a 1+−4+ scale similar to

that used for mitral regurgitation.

■ CINEFLUOROSCOPY OF PROSTHETIC

MECHANICAL VALVES

Prosthetic valve leaflet dysfunction may occur as a result of thrombus

or obstruction of leaflet excursion by pannus (Fig. 242-4). The incidence of prosthetic valve thrombosis in left-sided valves is 0.1–6.0%

per patient-year with differences in rates attributable to valve type,

position, anticoagulation status, and left ventricular function. Prosthetic valve dysfunction should be suspected in patients with subtherapeutic anticoagulation with a low mean INR, a prothrombotic

state, recent-onset heart failure, cardiogenic shock, cardiac arrest,

thromboembolic event, or, in asymptomatic patients, an increasing

gradient across the valve. Cinefluoroscopy visualizes the motion of

mechanical valve leaflets, is noninvasive, is available in most centers,

and can be performed rapidly with minimal radiation exposure. Prosthetic mechanical valves should be imaged en face and at a 90° angle

over several cardiac cycles to document opening and closing of the

valve leaflets as well as motion of the base ring. Each type of prosthetic

valve has leaflet opening and closing angles that are reported by the

manufacturer and can be used to determine if movement or closure

of the valve leaflets is restricted, suggestive of mechanical obstruction.

CORONARY ANGIOGRAPHY

Selective coronary angiography is almost always performed during

cardiac catheterization and is used to define the coronary anatomy and

determine the extent of epicardial coronary artery and coronary artery

bypass graft disease. Specially shaped coronary catheters are used to

engage the left and right coronary ostia. Hand injection of radiopaque

contrast agents creates a coronary “luminogram” that is recorded as

radiographic images (cine angiography). Because the coronary arteries are three-dimensional objects that are in motion with the cardiac

cycle, angiograms of the vessels using several different orthogonal

projections are taken to best visualize the vessels without overlap or

foreshortening.

The normal coronary anatomy is highly variable between individuals,

but, in general, there are two coronary ostia and three major coronary

vessels—the left anterior descending, the left circumflex, and the right

coronary arteries with the left anterior descending and left circumflex

arteries arising from the left main coronary artery (Fig. 242-5). When

the right coronary artery is the origin of the atrioventricular nodal

branch, the posterior descending artery, and the posterior lateral vessels, the circulation is defined as right dominant; this is found in ~85%

of individuals. When these branches arise from the left circumflex

artery, as occurs in ~5% of individuals, the circulation is defined as

left dominant. The remaining ~10% of patients have a codominant

circulation with the posterior descending vessel arising from both the

right coronary and the posterior lateral vessels from left coronary circulation. In some patients, a ramus intermedius branch arises directly

from the left main coronary artery that trifurcates into the left anterior

descending, ramus, and circumflex arteries; this finding is a normal

variant. Coronary artery anomalies occur in 1–2% of patients, with

separate ostia for the left anterior descending and left circumflex arteries being the most common (0.41%).

Coronary angiography visualizes coronary artery stenoses as luminal narrowings on the cine angiogram. The degree of narrowing

is referred to as the percent stenosis and is determined visually by

comparing the most severely diseased segment with a proximal or

distal “normal segment”; a stenosis >50% is considered significant

(Fig. 242-6). Online quantitative coronary angiography can provide

a more accurate assessment of the percent stenosis and lessen the

tendency to overestimate lesion severity visually. The presence of a

myocardial bridge, which most commonly involves the left anterior

descending artery, may be mistaken for a significant stenosis; this

occurs when a portion of the vessel dips below the epicardial surface

into the myocardium and is subject to compressive forces during ventricular systole. The key to differentiating a myocardial bridge from a

fixed stenosis is that the “stenosed” part of the vessel returns to normal

during diastole. Coronary calcification is also seen during angiography

prior to the injection of contrast agents. Collateral blood vessels may

be seen traversing from one vessel to the distal vasculature of a severely

stenosed or totally occluded vessel. Thrombolysis in myocardial infarction (TIMI) flow grade, a measure of the relative duration of time that

it takes for contrast to opacify the coronary artery fully, may provide

an additional clue to the degree of lesion severity, and the presence of

TIMI grade 1 (minimal filling) or 2 (delayed filling) suggests that a

severe coronary artery stenosis is present.

*

DIASTOLE SYSTOLE

FIGURE 242-4 Cinefluoroscopic detection of mechanical valve leaflet dysfunction.

Images of a bileaflet mechanical valve in the aortic position taken during diastole

(left) and systole (right) show that one leaflet opens normally during systole while

the other leaflet (below asterisk) remains immobile and fixed consistent with valve

leaflet thrombosis.

LAD

RCA

LCx

LAD

LM

A B C

OM

D

PDA

FIGURE 242-5 Normal coronary artery anatomy. A. Coronary angiogram showing the left circumflex (LCx) artery and its obtuse marginal (OM) branches. The left anterior

descending (LAD) artery is also seen but may be foreshortened in this view. B. The LAD and its diagonal (D) branches are best seen in cranial views. In this angiogram,

the left main (LM) coronary artery is also seen. C. The right coronary artery (RCA) gives off the posterior descending artery (PDA), so this is a right dominant circulation.

Diagnostic Cardiac Catheterization and Coronary Angiography

1865CHAPTER 242

A B C D

A

B

C

D

FIGURE 242-6 Coronary stenoses on cine angiogram and intravascular ultrasound.

Significant stenoses in the coronary artery are seen as narrowings (black arrows)

of the vessel. Intravascular ultrasound shows a normal segment of artery (A), areas

with eccentric plaque (B, C), and near total obliteration of the lumen at the site of the

significant stenosis (D). Note that the intravascular ultrasound catheter is present in

the images as a black circle.

Fibrous

A BCD E

Lipid plaque Thrombus Stent

FIGURE 242-7 Optical coherence tomography imaging. A. The optical coherence tomography (OCT) catheter (*) in the lumen of a coronary artery with limited neointima

formation. The intima is seen with high definition, but unlike intravascular ultrasound imaging, the vessel media and adventitia are not well visualized. B. A fibrous plaque

(arrow) is characterized by a bright signal. C. A large, eccentric, lipid-rich plaque obscures part of the vessel lumen. Because lipid in the plaque absorbs light, the lipid-rich

plaque appears as a dark area with irregular borders (arrow). The plaque is covered by a thin fibrous cap (arrowhead) typical of a vulnerable plaque. D. A thrombus (arrow)

adherent to a ruptured plaque that is protruding into the vessel lumen. E. A coronary stent is that is well opposed to the vessel wall. The stent struts appear as short bright

lines with dropout behind the struts (arrow).

■ INTRAVASCULAR ULTRASOUND, OPTICAL

COHERENCE TOMOGRAPHY, FRACTIONAL FLOW

RESERVE, AND CORONARY FLOW RESERVE

During coronary angiography, intermediate stenoses (40–70%), indeterminate findings, or anatomic findings that are incongruous with the

patient’s symptoms may require further interrogation. In these cases,

intravascular ultrasound (IVUS) provides a more accurate anatomic

assessment of the coronary artery and the degree of coronary atherosclerosis (Fig. 242-6). IVUS is performed using a small flexible catheter

with a 40-mHz transducer at its tip that is advanced into the coronary

artery over a guidewire. Data from IVUS studies may be used to image

atherosclerotic plaque precisely, determine luminal cross-sectional area,

and measure vessel size; it is also used during or following percutaneous

coronary intervention to assess the stenosis and determine the adequacy

of stent placement. Optical coherence tomography (OCT) is a catheterbased imaging technique that uses near-infrared light to generate

images with better spatial resolution than IVUS (12–18 microns vs 150–

200 microns); however, the depth of field is smaller. The advantage of

OCT imaging over IVUS lies in its ability to image characteristics of the

atherosclerotic plaque (lipid, fibrous cap) with high definition and to

assess coronary stent placement, apposition, and patency (Fig. 242-7).

Measurement of the fractional flow reserve provides a functional

assessment of the stenosis and is more accurate in predicting longterm clinical outcome than imaging techniques. The fractional flow

reserve is the ratio of the pressure in the coronary artery distal to the

stenosis divided by the pressure in the artery proximal to the stenosis

at maximal vasodilation. Fractional flow reserve is measured using a

coronary pressure–sensor guidewire at rest and at maximal hyperemia

following the infusion of adenosine (Fig. 242-8). A fractional flow

reserve of <0.80 indicates a hemodynamically significant stenosis that

would benefit from intervention. The instantaneous wave-free ratio,

which measures the gradient across the stenosis during the latter part

of diastole, does not require the use of adenosine and may be preferred

for some patients with asthma or documented allergy to adenosine.

An instantaneous wave-free ratio of <0.89 is considered positive for

ischemia. Resting gradients have also been shown to predict a significant stenosis. Using both pressure and velocity, an index of myocardial

resistance can also be calculated. Studies have shown this to be an

important predictor of outcome as well.

Microvascular dysfunction can be evaluated by assessing coronary

flow reserve, the ratio between coronary blood flow at maximal hyperemia and rest. Coronary flow reserve is measured using a Doppler

wire– or pressure wire–based thermodilution technique in patients

with unexplained chest pain or ischemia and no obstructive coronary

artery disease. A coronary flow reserve <2.0 is considered abnormal.

■ POSTPROCEDURE CARE

Once the procedure is completed, vascular access sheaths are removed.

If the femoral approach is used, direct manual compression or vascular

closure devices that immediately close the arteriotomy site with a staple/clip, collagen plug, or sutures are used to achieve hemostasis. These

devices decrease the length of supine bed rest (from 6 h to 2–4 h) and

improve patient satisfaction but have not been shown definitively to

be superior to manual compression with respect to access-site complications. With radial-artery access, the sheath is removed and a plastic

wristband with an air pillow is used to keep pressure on the access site

while maintaining flow through the radial artery. Bed rest is needed for

only 2 h. When cardiac catheterization is performed as an elective outpatient procedure, the patient completes postprocedure bed rest in a

monitored setting and is discharged home with instructions to liberalize fluids because contrast agents promote an osmotic diuresis, to avoid

strenuous activity, and to observe the vascular access site for signs of

complications. Overnight hospitalization may be required for high-risk

patients with significant comorbidities, patients with complications

occurring during the catheterization, or patients who have undergone

a complicated percutaneous coronary intervention. Hypotension early

after the procedure may be due to inadequate fluid replacement or

retroperitoneal bleeding from the access site. Patients who received

>2 Gy of radiation during the procedure should be examined for signs

of erythema. For patients who received higher doses (>5 Gy), clinical

follow-up within 1 month to assess for skin injury is recommended.

1866 PART 6 Disorders of the Cardiovascular System

FIGURE 242-8. Fractional flow reserve. The fractional flow reserve is measured using a coronary pressure-sensor guidewire that measures the ratio of the pressure in

the coronary artery distal to the stenosis (Pd, green) divided by the pressure in the artery proximal to the stenosis (Pa, red) at maximal hyperemia following the injection of

adenosine. A fractional flow reserve of <0.80 indicates that revascularization would be beneficial.

HISTORICAL PERSPECTIVE

Clinical cardiac electrophysiology is the subspecialty of cardiology

that focuses on the study and management of heart rhythm disorders.

The development of the modern surface electrocardiogram (ECG) by

Willem Einthoven more than 100 years ago enabled understanding

of the relationship between cardiac electrical potentials, mechanical

cardiac function, and pathophysiology of cardiac arrhythmias. In the

mid-twentieth century, the recording of cellular membrane currents

enabled the understanding that the surface ECG represents the sum

of cellular cardiac electrical activity. An understanding of cellular

Section 3 Disorders of Rhythm

Principles of Clinical

Cardiac Electrophysiology

William H. Sauer, Bruce A. Koplan, Paul C. Zei

■ FURTHER READING

Götberg M et al: The evolving future of instantaneous wave-free ratio

and fractional flow reserve. J Am Coll Cardiol 70:1379, 2017.

Moscucci M (ed): Grossman & Baim’s Cardiac Catheterization, Angiography, and Intervention, 8th ed. Philadelphia, Lippincott Williams

& Wilkins, 2014.

Naidu SS et al: Society of Cardiovascular Angiographers and Interventionalists expert consensus statement: 2016 best practices in the cardiac

catheterization laboratory. Catheter Cardiovasc Interv 88:407, 2016.

Nishimura R et al: Hemodynamics in the cardiac catheterization laboratory of the 21st century. Circulation 125:2138, 2012.

Räber L et al: Clinical use of intracoronary imaging. Part 1: guidance

and optimization of coronary interventions. An expert consensus

document of the European Association of Percutaneous Cardiovascular Interventions. Eur Heart J 39:3281, 2018.

electrophysiology also ushered in the development of antiarrhythmic

drugs utilized by cardiac electrophysiologists.

The modern era of clinical cardiac electrophysiology began with

the first recordings of human intracardiac electrograms in the 1960s.

Initially, invasive electrophysiology studies were limited as diagnostic tools. This included serial electrophysiologic testing to evaluate

arrhythmia mechanisms and evaluate arrhythmia suppression by antiarrhythmic drugs, and programmed stimulation of the heart for risk

stratification of sudden cardiac death. In the 1960s and 1970s, cardiac

surgery was the only available invasive treatment for cardiac arrhythmias. The subsequent development of radiofrequency catheter ablation

in the 1980s ushered in the era of interventional cardiac electrophysiology. In addition, with the development of implanted cardiac rhythm

management devices including pacemakers and defibrillators, clinical

cardiac electrophysiology became a distinct medical subspecialty.

CELLULAR ELECTROPHYSIOLOGY

The cardiac action potential (AP) drives the electrophysiologic behavior of all cardiac myocytes. The AP is characterized morphologically

by five distinct phases, termed phases 0–4, as shown in Fig. 243-1.

Moreover, as ventricular electrophysiologic activity accounts for the

QRS and T complexes of the surface ECG, each AP phase in ventricular

tissues corresponds to distinct phases in the surface ECG: Phase 0, the

rapid upstroke, corresponds to the QRS deflection; phases 1–2 account

for the ST segment; phase 3 accounts for the T wave; while phase 4

corresponds to the segment between the end of the T wave and the subsequent QRS deflection. In addition, the P wave corresponds to atrial

depolarization, while the PR interval corresponds to the time between

initiation of atrial depolarization to the initiation of ventricular depolarization, comprised (typically) for the most part by the conduction

time through the AV node.

AP morphologies are the result of the precise and carefully timed

sequences of opening, closing, and inactivation of an array of membrane ion channels in response to cellular membrane potential changes,

ligands that bind to the ion channel complex, or membrane stretch in

a time-dependent fashion. The open ion channel allows flux of specific

charged ions through a central pore, resulting in electrical (ionic) currents that drive the AP. The activity of different subsets of ion channels

drives the different phases of the AP. Specific ionic currents that flux

through an open channel are driven by the electrochemical gradient

243

Principles of Clinical Cardiac Electrophysiology

1867CHAPTER 243

SA node

Atrial myocardium

AV node

His

bundle

Bundle

branches

Purkinje fibers

Myocardium

P QRS T

B

Ventricular AP

Current GENE (Protein)

Depolarizing Repolarizing

I

Na

I

Ca-L

I

Na

I

Ca-L

I

NCX

I

K1

I

to

I

Kr

I

Ks

I

K1

I

to

I

Kr

I

Ks

I

Kur

SCN5A (Nav1.5)

CACNA1C (Cav1.2)

SLC8A1 (NCX1.1)

KCNJ2 (Kir2.1)

Voltage

Time

Voltage

0 1

2

3

4

Time

KCND3/KCNIP2 (Kv4.3/KChIP2)

KCNH2/KCNE2 (HERG/MiRP-1)

KCNQ1/KCNE1 (KVLQT1/minK)

KCNA5 (Kvt.5)

Atrial AP

A

FIGURE 243-1 A. Cellular atrial and ventricular action potentials. Phases 0–4 are the rapid upstroke, early repolarization, plateau, late repolarization, and diastole, respectively.

The ionic currents and their respective genes are shown above and below the action potentials. The currents that underlie the action potentials vary in atrial and ventricular

myocytes. Potassium current (IK1) is the principal current during phase 4 and determines the resting membrane potential of the myocyte. Sodium current generates the upstroke

of the action potential (phase 0); activation of Ito with inactivation of the Na current inscribes early repolarization (phase 1). The plateau (phase 2) is generated by a balance of

repolarizing potassium currents and depolarizing calcium current. Inactivation of the calcium current with persistent activation of potassium currents (predominantly IKr and IKs)

causes phase 3 repolarization. Currents that result in membrane depolarization are grouped at the top of the figure above the action potentials, while repolarizing currents are

shown below the action potentials. B. A surface ECG representation of sinus rhythm is shown with respective intracardiac action potentials that are active during each phase

of the ECG. Each cardiac conduction region’s action potential is shown in the upper portion of the panel, with colors reflected in the ECG segment shown in the lower portion of

the panel. Note that during the P wave, atrial depolarization is active. During the PR interval, the AV nodal, His, bundle branches, and Purkinje fibers are active (in sequence),

although these action potentials are not discernible on the surface ECG. During the QRS interval, ventricular action potentials are active, with the QRS morphology most reflective

of the sequence of ventricular tissue action potential activation. The ST segment is predominantly determined by the plateau phase 2 of the ventricular action potential. The

T wave is determined largely by ventricular repolarization (phase 3), while the isoelectric segment is the result of the electrically neutral phase 4 of the ventricular action

potential.

of that particular ion across the membrane, which in turn is driven by

ion pumps or transporters/exchangers, which in turn are catalyzed by

ATP (Fig. 243-2).

Ion channels are complex, multi-subunit transmembrane glycoproteins that contain a central pore that is selective for particular ionic species (selectivity); a “gating” apparatus that regulates the opening, closing,

and inactivation apparatus; and often one or more regulatory subunits.

Most channels gate in response to changes in membrane potential, a

specific ligand, or mechanical deformation. The molecular underpinnings of these specific functional properties of channels have become

well understood through decades of basic electrophysiologic study

using the tools of voltage clamp and patch clamp techniques, and more

recently, molecular, genetic, and structural/crystallographic techniques.

The structural makeup of most ion channels contains several common motifs. All channels form a central conducting pore, with ionic

selectivity determined by specific amino acids that line the central

pore. The central pore of most channels is formed by the P domain,

a series of hydrophilic amino acid residues, with one of several structural variants: four separate homologous alpha subunits, each with

homologous P domains (voltage-gated K channels); a single alpha

subunit with four internally homologous P domains (voltage-gated Na

or Ca channels); or two internally homologous P domains from two

separate subunits (most ligand-gated K channels). A series of one or

more transmembrane segments surrounds the central pore. In voltagegated channels, the fourth of six segments, the S4 segment, contains a

series of charged amino acid residues that functions as a voltage sensor,

responding to changes in membrane potential by facilitating protein

conformational changes that result in channel opening or closing (gating). In ligand-activated channels, the binding of a ligand (transmitters,

molecules, or other ions) results in channel opening or closing, while

deformations in membrane shape determine gating in stretch-activated

channels. In addition, in many ion channels, a complex of auxiliary

proteins is associated with the primary alpha subunit; most auxiliary

subunits appear to facilitate regulation of ion channel expression and

activity. A distinct type of transmembrane protein complex is the gap

junction complex. A large multimeric complex of connexin subunits

forms a large, nonselective pore that spans and thereby connects adjacent myocytes. This allows free flux of ions between adjacent myocytes,

facilitating impulse propagation across myocardial tissues.

Due to the physiologic gradient of their respective ions across the

cell membrane, Na and Ca channels account for most inward, or depolarizing, currents in cardiac myocytes, and these channels respond to

membrane depolarization with rapid opening, relatively rapid closing,

and inactivation. Na and Ca currents therefore drive phase 0 depolarization of the AP. Potassium channels, on the other hand, account for

most of the repolarizing currents seen in cardiac myocytes. Relatively

slow K channel opening, as well as Na and Ca channel closing and

inactivation, drives the plateau of phases 1–2 as well as the repolarizing

phase 3 of the AP. Mutations in K channel subtypes are causative of

many inherited channelopathies. Mutations that either inherently delay

the closing or inactivation of K channels result in prolongation of the

QT interval, leading to many forms of inherited long QT syndrome.

The morphologic and functional properties of APs vary across

different regions of the heart. These variations are the result of variations in the active ionic currents during each phase of the AP, which

in turn reflects regional variation in ion channel expression. In atrial

and ventricular myocytes, Na currents dominate the rapid upstroke

(phase 1) of the AP, while in nodal tissues, Ca currents, which activate

more slowly, dominate phase 1. Hence, for instance, drugs that bind

and block the cardiac Na channel demonstrate efficacy in treating

tachyarrhythmias arising from the atria and ventricles, whereas Ca

channel blocking agents demonstrate efficacy at nodal tissues. During

the pre-depolarizing phase 4 of the AP, ionic currents remain relatively

quiescent in atrial and ventricular myocytes as they await local depolarization that triggers the next AP. In contrast, in sinus nodal tissues,

which possess the property of automaticity, or intrinsic rhythmic

1868 PART 6 Disorders of the Cardiovascular System

Extracellular

Intracellular

Pore

segments

N

N

N N

N

S

S

P

P P P P

P

C

C

Inactivation LA

binding

C

+

+

+

+

+

+

+

+

+

+

+

+

β1

α1

α2

β

γ

δ

β2

X4

N

C

C

K channels

Na channels

Ca channels

α Subunits β Subunits

K+

FIGURE 243-2 Topology and subunit composition of the voltage-dependent ion channels.

Potassium channels are formed by the tetramerization of α or pore-forming subunits and one or

more β subunits; only single β subunits are shown for clarity. Sodium and calcium channels are

composed of α subunits with four homologous domains and one or more ancillary subunits. In all

channel types, the loop of protein between the fifth and sixth membrane-spanning repeat in each

subunit or domain forms the ion-selective pore. In the case of the sodium channel, the channel is

a target for phosphorylation, the linker between the third and fourth homologous domain is critical

to inactivation, and the sixth membrane-spanning repeat in the fourth domain is important in local

anaesthetic antiarrhythmic drug binding. The Ca channel is a multi-subunit protein complex with

the α1

 subunit containing the pore and major drug-binding domain.

depolarization, there is gradual depolarization observed during phase

4, until a threshold is reached that initiates the next AP. In these nodal

tissues, this depolarizing phase 4 current is generated by a semiselective

Na/Ca channel, termed the “funny current” or If

, which is the target for

the medication ivabradine.

NORMAL CARDIAC IMPULSE

PROPAGATION

The normal cardiac impulse initiates and travels through

specialized conduction fibers, often referred to as the

cardiac conduction system. Each impulse is initiated in

the sinoatrial (SA) node, located at the lateral junction

between the superior vena cava (SVC) and right atrium

(RA). SA nodal tissues exhibit automaticity, such that a

reliable, rhythmic impulse emanates from the SA node.

The SA node (along with the AV node) is richly innervated by autonomic fibers, allowing precise and dynamic

control of heart rate and overall function by the central

nervous system. The normal impulse then travels across

the RA then the LA across preferential conduction pathways, initiating atrial systole. Once the impulse reaches

the AV node, conduction occurs in a relatively slow time

frame through the AV nodal tissues. This conduction time

not only serves to provide physiologic AV synchrony, but

it also is reflected in the surface ECG as the PR interval,

or time between the atrial inscription and the subsequent

ventricular, or QRS, complex. In normal hearts, the AV

node serves as the only electrical connection between

atria and ventricles. Both the SA and AV nodes respond

exquisitely to autonomic input; for instance, with exercise

and increased adrenergic tone, the PR interval physiologically shortens. After the AV node, the impulse travels

through a network of specialized conduction fibers: the

bundle of His divides into a right and left bundle branch,

which transmit conduction to the right and left ventricles, respectively. The left bundle then divides further

into left anterior and left posterior fascicles. The fascicles

then further divide into Purkinje fibers. The conduction

velocity of electrical impulses is much higher in Purkinje

fibers (2–3 m/s) than in myocardial cells (0.3–0.4 m/s).

Different connexins in gap junctions of Purkinje networks

are partially responsible for more rapid conduction. This

network of conductive Purkinje fibers is located endocardially and serves to rapidly transmit depolarization

throughout the ventricles, such that myocardial depolarization, and hence mechanical contraction, occur rapidly

and in a coordinated, synchronized fashion, optimizing

mechanical contraction of the ventricles. Repolarization

of the ventricular myocardium, on the other hand, occurs

relatively slowly and progresses from the epicardial surface back toward the endocardium. Hence, the T wave

inscription in most ECG leads is concordant with the

QRS complex.

MECHANISMS OF CARDIAC

ARRHYTHMIAS

Cardiac arrhythmias are the manifestation of abnormalities in the initiation and/or propagation of the cardiac

electrical impulse. Bradyarrhythmias result most commonly from abnormalities in the specialized conduction

tissues. Abnormal function of the SA node may result in

pathologic sinus bradycardia; AV node disease may result

in conduction block; pathology in the His-Purkinje system may result in conduction block as well. Tachyarrhythmias may arise from not only nearly every location within

the conduction tissues, but also within atrial or ventricular tissues. Tachyarrhythmias are typically classified by

mechanism: enhanced automaticity refers to abnormal

spontaneous depolarization, which can occur along the

conduction system, the atria, or ventricles; triggered arrhythmias result

from abnormal afterdepolarizations that occur in either phase 2/3

(early afterdepolarizations) or phase 4 (delayed afterdepolarizations) of

the AP; reentry results from circus movement of an electrical impulse

(see Table 243-1 and Fig. 243-3).

Principles of Clinical Cardiac Electrophysiology

1869CHAPTER 243

Table 243-1 Overview of the Mechanisms of Cardiac Tachyarrhythmias

TACHYARRHYTHMIA

CATEGORY MECHANISM

PROTOTYPICAL

ARRHYTHMIAS

Abnormal

Automaticity

Enhanced (acceleration

of phase 4 repolarization)

Idiopathic VT; AT

Suppressed (absent or

decelerated phase 4

repolarization)

Sinus node dysfunction

Triggered Activity EADs TdP in long QT syndrome,

PVCs

DADs Reperfusion PVCs/VT,

AT and VT with digitalis

toxicity

Reentry 1) Anatomical or

functional confinement

of a circuit (i.e., scar,

accessory pathway);

2) unidirectional block

after a premature

impulse; 3) wave of

excitation that travels

in a single direction

returning to its point of

origin

AVNRT, AVRT, atrial flutter,

scar-related VT

while in other tissues K currents, Ca currents, or even the Na/Ca and

ATP-driven Na/K exchangers contribute.

The rate of depolarization during phase 4 drives the frequency APs,

and hence automaticity rate of these tissues. In nodal tissues, this rate of

depolarization is highly regulated by the autonomic system. Parasympathetic input results in local acetylcholine (ACh) release, which then binds

the IKACh potassium channel complex (specifically via a G protein

mediated mechanism). The opening of IKACh channels, resulting in K

efflux, hyperpolarizes these cells, resulting in slowing of phase 4 depolarization, thereby slowing the automaticity rate. Sympathetic input, via

catecholamines, activates both alpha- and beta-adrenergic receptors.

Beta-1 adrenergic stimulation results in activation of L-type Ca channels,

Ca influx, and as a result, enhanced depolarization rates during phase 4,

and increased automaticity rates. The normal range of SA automaticity

rates is between 30–220 beats/min, corresponding to the normal range

of rates during sinus rhythm. The sinus rate at any instant is therefore a

dynamic balance between sympathetic and parasympathetic input, with

the latter dominating in the restful state. The intrinsic heart rate (IHR)

is defined as the “native” automaticity rate of the SA node, absent any

autonomic input.

Abnormally enhanced automaticity may occur at any site that

exhibits automaticity, including the SA node, AV node, or His-Purkinje

system, resulting in pathologic tachycardia. In addition, in pathologic

states, other stereotyped regions in the heart may exhibit enhanced

automaticity, including the pulmonary veins, coronary sinus superior

vena cava, and ventricular outflow tracts. Injury to myocardium,

whether through ischemia or other mechanisms, may alter its cellular

membrane properties, resulting in automaticity in these tissues. For

instance, the border zones of infarcted ventricular myocardium, or rapidly reperfused ischemic myocardium, often exhibit automatic arrhythmias including PVCs or automatic idioventricular rhythms (AIVR).

Abnormal automaticity in the pulmonary veins is believed to underpin

the triggers that drive paroxysmal atrial fibrillation, while automaticity

elsewhere in the atria drives atrial tachycardias.

■ AFTERDEPOLARIZATIONS AND TRIGGERED

ARRHYTHMIAS

Afterdepolarizations and triggered arrhythmias refer to abnormal

depolarizations that occur in the late phases of the AP (afterdepolarizations) that can initiate sustained arrhythmias. Early afterdepolarizations (EADs) occur typically during phases 2–3 of the AP and may be

facilitated by intracellular Ca loading. When the QT interval prolongs,

typically in a heterogeneous fashion across the ventricles, EADs may

trigger wavefronts of abnormal depolarizations, resulting in torsades

des pointes (TdP), a nonsustained or sustained ventricular arrhythmia

that may result in cardiac arrest. Medications that prolong QT interval, as well as other QT prolonging factors including hypokalemia,

hypomagnesemia, and bradycardia, predispose the ventricles to EADs

leading to TdP. Electrical remodeling in cardiomyopathies may also

predispose to QT prolongation and risk of EADs and TdP.

Delayed afterdepolarizations (DADs) are abnormal depolarizations

occurring in phase 4 of the AP. The mechanism underlying DADs

is increased intracellular Ca, which then enhances repetitive depolarizations during the late phases of the AP. As a result, repetitive

depolarizations ensue, including the well-described phenomenon

of bidirectional ventricular tachycardia. Digitalis glycoside toxicity,

ischemia, and catecholamines are the most commonly described causes

for DADs.

■ REENTRY

Reentry refers to the circus movement of a wavefront of electrical

activation. Reentry can occur around a fixed anatomic barrier, referred

to as anatomic reentry, or around a functionally blocked or refractory

barrier or anchor, termed functional reentry. Initiation and maintenance of a reentrant arrhythmia requires (1) unidirectional block,

where the electrical wavefront can only propagate in one direction,

and (2) slow conduction, a zone within the reentrant circuit where

conduction is relatively slow, allowing the remainder of the circuit to

repolarize and recover from refractoriness (the inability to re-excite).

■ ENHANCED AUTOMATICITY

Automaticity, defined as spontaneous depolarizations occurring during phase 4 of the AP, is a normal property of several myocardial

tissues, including the SA node, AV node, and the His-Purkinje system.

The automaticity of the SA node triggers the normal cardiac impulse.

When the automaticity of a more proximal conduction system tissue

is unreliable or slow, the automaticity of a more distal aspect of the

conduction system may result in an “escape rhythm” that may maintain

cardiac output. Automaticity in these tissues results from phase 4 depolarization of cellular membranes driven by several ionic currents. In the

SA node, the nonselective Na/Ca If current drives this depolarization,

Abnormal automaticity

Reentry

Triggered activity

Early afterdepolarizations

Triggered activity

Delayed

afterdepolarizations

FIGURE 243-3 Schematic action potentials with early afterpolarizations (EADs) and

delayed afterdepolarizations (DADs).

1870 PART 6 Disorders of the Cardiovascular System

The more common form of reentry is anatomic, which requires

a defined electrical/anatomic circuit with a pathway around a fixed

barrier. A wavefront of depolarization encounters a barrier to conduction that allows propagation in only one direction (unidirectional

block), forcing activation preferentially along one limb or pathway.

Due to slow conduction, the depolarization wavefront travels through

the remaining circuit and continually encounters tissues that have

recovered from refractoriness and are hence excitable. This results in

perpetual circus movement. Moreover, if the total length of the circuit

exceeds a distance determined by the product of the conduction velocity (theta) of the tissue and the refractory period (duration) of that tissue (tr), referred to as the wavelength of tachycardia (lambda = theta ×

tr), an excitable gap, where tissue is recovered from refractory and able

to depolarize, is created, allowing reentry. Reentry is the mechanism

for several clinically important and common cardiac arrhythmias,

including atrial flutter, AV nodal reentry, AV reciprocating tachycardia

utilizing an accessory pathway, and scar-based reentrant VT.

When reentry occurs in the absence of a fixed anatomic barrier, it is

termed functional reentry. A nidus of partially refractory tissue anchors

the depolarization wavefront, resulting in a circular or rotational reentrant wavefront. In this case, the reentrant circuit or activity tends to

be less stable than that from anatomic reentry, resulting in variations in

depolarization rate and propensity to easily terminate and/or reinitiate.

There is evidence that functional reentry is the underlying mechanism

for perpetuation and maintenance of both atrial fibrillation (AF) and

ventricular fibrillation (VF). In both of these apparently chaotic and

disorganized arrhythmias, multiple wavefronts resulting from multiple

functional reentrant circuits appear to drive arrhythmia in many, if not

most, instances. Underlying pathology of the myocardium resulting in

heterogeneous electrophysiologic properties, altered activation, and

repolarization properties predispose myocardial tissues to initiation

and propagation of functional reentry-based arrhythmias.

In addition to intrinsic alterations in cellular membrane electrophysiologic properties that underpin most arrhythmias, extrinsic

factors may precipitate other architectural and tissue changes that

contribute proarrhythmia. Ischemia and infarct may create regions

of heterogeneous fibrosis, resulting in islands of scar surrounded by

injured tissue. This creates the anatomic substrate that can sustain

anatomic reentry, which underlies scar-based VT, as well as many

macro-reentrant atrial arrhythmias. Peri-infarct border zones often

contain injured myocardium as well, and the resultant alterations in

cellular membrane properties may promote enhanced automaticity

or triggered arrhythmias. Chronic ischemia also results in downregulation of connexin proteins and gap junctions, resulting in slowed

impulse propagation, which is one of the factors required for reentrant

arrhythmias. Alterations in ion channel function, either through inherited mutations or through drug effect, can promote arrhythmias. QT

prolongation can occur when the closing of potassium channels that

should hyperpolarize cells is delayed or slowed, or when the closing or

inactivation of Na channels is impaired.

■ UNDERPINNINGS OF THE TREATMENT OF

ARRHYTHMIAS

Pharmacologic therapies for arrhythmias are directed toward the

specific underlying mechanism. For enhanced automaticity-based

arrhythmia, medications that target phase 4 depolarization, including

Ca channel blockers, beta-adrenergic blockers (via indirect action on

adrenergic input), or ivabradine may be used. For triggered activitybased arrhythmia, correcting the precipitating factor is most effective.

This includes, among other therapies, removal of digitalis glycosides

from the body, removal of QT-prolonging medications, or even

increasing heart rate, thereby shortening QT interval. For reentrant

arrhythmia, medications that increase the refractory period, in particular K channel blocking agents, will hence increase the wavelength

of conduction beyond the circuit length of tachycardia, resulting in

inability to sustain reentry. Medications that slow conduction velocity,

if only partially effective, may have the paradoxical effect of shortening the wavelength of tachycardia compared to the anatomic circuit

length, resulting in a larger excitable gap. This explains much of the

proarrhythmic effect of many antiarrhythmic medications. Therefore,

for these agents, which typically include Na channel blockers, sufficient

dosing is required to slow conduction velocity to the point of extinguishing meaningful arrhythmia circuit conduction.

A major aspect of clinical cardiac electrophysiology that has

evolved over several decades is the ability to mechanically disrupt

arrhythmic substrates through catheter-based (or rarely surgical)

ablation. For automaticity-based arrhythmias, precise localization and

elimination through ablation of the site of focal automaticity is effective in eliminating arrhythmia. For anatomic reentrant circuits, identifying a critical zone of slow conduction that both sustains reentry

and is amenable to focused ablation and damaging that zone through

ablation is effective for most reentrant arrhythmias. In contrast, given

the lack of a fixed anatomic circuit, and perhaps also due to the presence of multiple, often migratory, circuits, it appears that mechanical

disruption, typically through catheter-based ablation, of identified

sites of functional reentry appears to be ineffective in eliminating

arrhythmia.

CARE OF THE ARRHYTHMIA PATIENT

■ EVALUATION AND DIAGNOSIS

The evaluation of a patient with suspected arrhythmia begins with

a directed history and physical examination, which must include an

ECG. The history and examination should focus on determining the

nature of symptoms attributable to the arrhythmia itself and clues to

potential underlying cardiac, medical, or metabolic conditions that

may predispose to specific arrhythmias, and hence direct further studies and evaluations, ultimately directing appropriate therapy, prognosis,

and counseling. Family history may also provide clues toward possible

inherited arrhythmia syndromes. Symptoms attributable to arrhythmia can vary from vague sensation of fatigue, chest pain, dyspnea, or

lightheadedness to more specific sensation of rapid, slow, or irregular

heart rate. Premature contractions, whether atrial or ventricular, may

be sensed as extra beats, or if these extrasystoles result in diminished

stroke volume for that particular beat, a sensation of a missed beat.

Second, the hemodynamic sequelae of impaired cardiac output may

result in symptoms, from presyncope to frank syncope, dyspnea, chest

discomfort, or generalized weakness. Importantly, as the cadence and

duration of arrhythmia episodes are highly variable, the temporal manifestations of arrhythmia symptoms may vary significantly. Sporadic

episodes of arrhythmia will result in intermittent symptoms, including

syncope if hemodynamic compromise is significant; protracted episodes of arrhythmia may cause persistent symptoms. In patients with

underlying compromise in cardiac function, most typically in patients

with structural heart disease, arrhythmia leading to diminished cardiac output may trigger or exacerbate symptoms associated with the

underlying condition such as angina, congestive heart failure, or

hypoxia-associated symptoms.

Inciting factors or associations may also provide clues to the diagnosis. Arrhythmias associated with activities that increase adrenergic

tone, such as exercise, stimulant intake, or emotional stress, may

suggest not only tachyarrhythmias but also automaticity-triggered

arrhythmias. However, keep in mind that exceptions will occur. Medication use may be highly suggestive of an etiology: use of Ca channel

blockers or beta blockers may suggest bradycardia exacerbated by these

medications. Medications known to potentially prolong QT interval

may suggest a malignant ventricular arrhythmia, specifically TdP.

Eliciting a thorough family history, not only for known arrhythmia

diagnoses, but of unexplained sudden death, may point toward a heritable syndrome. Demographic factors may point toward or away from

certain diagnoses. For instance, AF rarely occurs in children and young

adults, save rare familial forms, or AF associated with structural heart

disease; a strong male predominance, as well as a higher prevalence in

certain ethnic populations such as Southeast Asians, is seen in Brugada

syndrome; inappropriate sinus tachycardia is nearly exclusively a condition affecting young women; degenerative conduction system disease

leading to symptomatic bradycardia is most commonly a condition

seen in older patients.

Principles of Clinical Cardiac Electrophysiology

1871CHAPTER 243

Arrhythmias may run the gamut from benign to malignant,

life-threatening etiologies. Therefore, an important aspect of the evaluation of suspected arrhythmia is to discern patient prognosis, which

then informs treatment. Arrhythmias that result in more significant

hemodynamic compromise, and therefore more profound symptoms,

tend to correlate with more malignant disease. In turn, the higher the

suspicion for a malignant arrhythmia, the more aggressive the evaluation will likely be. Loss of consciousness, which may be the result of

cardiac arrhythmia but also other etiologies that may be more benign,

presents a particularly challenging yet common diagnostic dilemma.

Therefore, careful thought into the appropriate evaluation for a patient

with syncope is critical. In general, the presence of underlying structural abnormality of ventricular myocardium favors more malignant

arrhythmias, both due to the increased risk of lethal ventricular

arrhythmias, as well as potential inability to hemodynamically tolerate

any particular arrhythmia.

The ECG is the cornerstone and most important diagnostic test that

should be performed on every patient with suspected arrhythmia. A

12-lead resting ECG may offer clues to the diagnosis. Most simply, if

active arrhythmia is captured on the ECG, a definitive diagnosis can

be made. In addition, evidence suggesting underlying cardiac disease,

such as prior myocardial infarction, LVH and possible hypertrophic

cardiomyopathy, atrial disease, or baseline conduction system disease

may suggest a diagnosis. A subset of conditions that predispose to

arrhythmia, both inherited or acquired, may be discerned as well,

including ventricular preexcitation, prolonged or shortened QT interval, or ECG findings suggestive of specific inherited conditions such as

Brugada syndrome or right ventricular cardiomyopathy.

However, the ECG typically records only 6 s of cardiac electrical

activity, and therefore more intermittent and transient arrhythmias,

particularly those not typically associated with abnormalities on the

resting ECG, may not be seen. Many arrhythmias, including forms

of both SVT and VT, can only be diagnosed definitively if an ECG is

performed during active arrhythmia and/or symptoms from arrhythmia, or alternatively provoked in the electrophysiology laboratory.

Therefore, various forms of ambulatory monitoring may be performed

to attempt to capture ECG activity during active arrhythmia. A growing variety of monitoring options are available; the most appropriate option should be primarily guided by the cadence of suspected

arrhythmia episodes. For instance, if daily symptoms occur, a 24- or

48-hour continuous Holter monitor is appropriate. On the other hand,

a patient-activated event recorder is inappropriate in a patient with

syncope, as the arrhythmic event will likely have passed once the

patient reawakens.

Attempts at provoking arrhythmia may be warranted in the appropriate circumstances. An ECG-monitored treadmill test may elicit

exercise-induced arrhythmias, or if LQT is suspected, QT interval that

fails to shorten appropriately with increased heart rate may be helpful.

Pharmacologic provocation may be indicated for certain suspected

diagnoses, such as Brugada syndrome. Judicious and appropriate use

of carotid sinus massage or other means to enhance vagal tone may be

helpful to diagnose carotid hypersensitivity or overall vagally mediated

syncope.

Tilt table testing (TTT) involves having a patient strapped to a

tiltable table. While monitoring HR and BP, the patient is quickly

moved from a supine to upright position. In patients with suspected autonomic dysfunction-mediated syncope or presyncope,

this provocation may elicit a paradoxical vagal response, resulting in

bradycardia and/or sinus pauses as well as hypotension, and perhaps

frank syncope. However, given significant lack of both sensitivity and

specificity, the current role of TTT is unclear, and TTT has widely

fallen out of favor.

Invasive electrophysiologic testing is the nearest to a gold-standard

diagnostic modality for many arrhythmias. Catheter-based recordings of intracardiac electrograms, with or without provocative pacing

or pharmacologic maneuvers, may elicit the clinical arrhythmia. This

will in turn help to define the mechanism of arrhythmia. However,

one must keep in mind that for certain arrhythmia mechanisms,

such as automaticity-driven tachycardia, EP study may fail to elicit

arrhythmia due to the often transient and multifactorial nature of

initiation of these arrhythmias. The nature of arrhythmia elicited will

in turn aid in determination of the patient’s prognosis. In a typical

EP study, catheters are placed within the heart, typically via femoral

venous access. Baseline conduction properties are measured. Provocative maneuvers including electrical pacing maneuvers, programmed

stimulation, and pharmacologic provocation are performed. In the

modern era, the vast majority of invasive EP studies are performed in

conjunction with planned catheter ablation, although programmed

ventricular stimulation for risk stratification of sudden death may

still be utilized occasionally. EP study during catheter ablation is

performed both to confirm diagnosis and localize appropriate ablation target(s) but also to evaluate the efficacy of ablation performed

during the procedure.

Depending on the suspected arrhythmia diagnosis, further testing

may be indicated. If structural heart disease is suspected, echocardiography is most often the best next test, as it can assess for underlying

structural disease, evaluate LV function, and assess atrial dimensions

and mitral valve function if AF is suspected, both of which are fair

prognostic indicators. In patients in whom underlying coronary artery

disease is suspected, an evaluation for coronary ischemia is indicated.

Further evaluation for underlying structural heart disease will be

directed based on the differential diagnosis. Cardiac CT provides broad

diagnostic utility, depending on the scanning protocol, including evaluation for ischemia, ventricular scar, anatomic evidence of CAD, congenital anomalies, and left atrial anatomy. Cardiac MRI provides significant

resolution of soft-tissue characteristics and may be used to assess

for ischemia, infarct, myopathy, or infiltrative disease. Cardiac PET can

also discern underlying ischemia, as well as metabolic/inflammatory/

infiltrative conditions.

TREATMENT

Cardiac Arrhythmias

ANTIARRHYTHMIC DRUG THERAPY

The effects of pharmacologic agents on cardiac electrophysiologic properties are often complex and, in many instances, remain

incompletely understood. The complexity is the result of complex

pharmacodynamics and pharmacokinetics, in particular significant

cross-reactivity of certain drugs across different targets as well

as variable effects on drug targets across drugs within the same

category. There are regional differences in drug effect within the

myocardium, and interpatient variations in drug metabolism play

important roles. This has in part led to many instances of harm that

have come from the adverse effects of many agents used over the

years. In fact, many antiarrhythmic agents currently in use carry

significant risks of side effects, some of which may be significant

and even lethal. Therefore, judicious use of antiarrhythmic medications by those with appropriate knowledge base and experience is

warranted. The practical result of the narrow therapeutic index of

this class of medications has rendered their use more and more as

ancillary options (Table 243-2).

The traditional nomenclature of antiarrhythmic drugs (AADs)

is known as the Vaughan Williams classification schema. In this

schema, there are four classes (I–IV; Table 243-2). Class I AADs

primarily target the Na channel, Class II agents target the betaadrenergic receptor, Class III agents target potassium channels,

and Class IV agents target Ca channels. Class I agents are further

subdivided into three subclasses based on the kinetics of drug to

Na channel interactions. Class IA agents, including procainamide

and quinidine, possess intermediate binding kinetics and potency.

Class IB agents, including lidocaine and mexiletine, possess rapid

binding kinetics and relatively low potency. Class IC agents (flecainide, propafenone) possess slow kinetics and high potency.

Class II agents consist entirely of beta adrenergic blocking agents.

Class III agents (sotalol, dofetilide, ibutilide) specifically target

the HERG potassium channel and risk prolongation of the QT

interval through effects on the K channel (HERG) that in large

1872 PART 6 Disorders of the Cardiovascular System

part determine phases 2/3 of the AP, and hence ventricular repolarization. Class IV agents are cardioselective Ca channel blockers

including verapamil and diltiazem. This classification has significant limitations, however. Many AADs interact with multiple ion

channels, and as a result many exhibit behavior consistent with

multiple classes. Amiodarone, in particular, exhibits properties of

all AAD classes.

CATHETER ABLATION

The rationale that underlies catheter ablation for cardiac arrhythmia

is that an anatomic substrate can be identified and localized, and

mechanical disruption of that substrate will eliminate the cardiac

arrhythmia. For automaticity-driven arrhythmias, a focal source of

automaticity is identified, localized, and ablated. For anatomic reentrant arrhythmias, a critical zone of slow conduction that sustains

arrhythmia and can be reasonably targeted is ablated. Moreover,

the ablation target must be in a location deemed at acceptable risk

of not damaging critical structures such as the native conduction

system, coronary arteries, or epicardial structures including the

esophagus and phrenic nerve. Advances in electroanatomical mapping, a technology that uses alterations in electrical impedance and

a magnetic field as measured by an intracardiac mapping catheter,

have allowed for real-time reconstruction of cardiac chambers and

identification of arrhythmogenic tissue to be targeted for ablation

while safely avoiding nontargeted critical structures. Intracardiac

Table 243-2 Antiarrhythmic Drug Actions

DRUG

CLASS ACTIONS

I II III IV OTHER ACTIONS/COMMON SIDE EFFECTS

Quinidine ++ ++ Anticholinergic

Flecainide +++ + Can promote reentrant arrhythmias

(AFL, VT)

Propafenone ++ + Mild beta-blocker effect

Amiodarone ++ ++ +++ + Multiorgan toxicity with long-term use

Sotalol ++ +++ Prominent beta-blocker effect

Dofetilide +++ Prolongation of QT at slower heart rates

Dronedarone + + + + Mild effect

Ibutilide +++ Used only for acute cardioversion

Ranolazine ++ ++ Late sodium channel blockade

Lidocaine ++ Used for reperfusion arrhythmias

echocardiography has also been used to enhance the safety of invasive electrophysiologic procedures with real-time visualization of

cardiac structures (Fig. 243-4).

In the 1950s–1960s, as the underlying anatomic substrates for

arrhythmias became better understood, open surgical disruption of

arrhythmia circuits was the only available interventional and curative therapy for many arrhythmias. Surgical ligation of accessory

pathways or resection of ischemic VT substrates was performed at

specialized surgical centers. The first attempts at clinical catheter

ablation utilized direct current (DC) energy. This resulted in a

jarring pulse of electrical energy that would indeed ablate cardiac

tissue, but with a difficult-to-control scope, often leading to significant complications. Radiofrequency (RF) energy was adapted

to catheter-based cardiac ablation in the 1980s. Radiofrequency

alternating electrical current (300–550 kHz) delivered through a

catheter tip results in local tissue heating and permanent injury.

This type of ablation is similar to the technology used in electrosurgical techniques using a Bovie electrocautery device. For more than

35 years, RF delivery via catheters has been iteratively optimized

such that it has become the most common and mainstay energy

source for catheter ablation. Catheter ablation is indicated for a wide

variety of clinical arrhythmias, including SVT, accessory pathways,

atrial flutter, atrial fibrillation, PVCs, and VT. Alternative ablative

energy sources have been explored over the years, including light

spectrum (laser), microwave, ultrasound, and more recently pulsed

field electroporation, which injures targeted myocardium through

high energy, ultra-short pulses of electrical current that disrupts the

lipid cell membrane, resulting in permanent cell death. Recently,

the well-established ablative technique of stereotactic (focused and

directed) external beam ionizing radiation has been applied to the

heart to treat various arrhythmias, including VT and AF. This particular treatment modality holds promise given its ability to target

regions of the heart that may be inaccessible to catheters, as well as

the completely noninvasive, and thereby theoretically lower risk,

nature of the procedure.

The most widely applied non-RF ablative energy source today is

cryothermy, where an ablative catheter tip is cooled to a temperature range (typically below –40°C) that results in permanent tissue

death. Cryothermy is most widely applied to ablation of paroxysmal

atrial ablation, via an expandable balloon introduced sequentially

into each pulmonary vein and cooled to produce a circumferential

ablative lesion at the ostium/antrum of each pulmonary vein (see

Fig. 243-4B).

A B

FIGURE 243-4 Catheter ablation of cardiac arrhythmias. A. A schematic of the catheter system and generator in a patient undergoing radiofrequency catheter ablation

(RFCA); the circuit involves the catheter in the heart and a dispersive patch placed on the body surface (usually the back). The inset shows a diagram of the heart with a

series of intracardiac catheters placed via the IVC, typically through femoral venous access. Catheters are located at the high right atrium, His bundle location, RV apex, and

through a transseptal puncture within the left atrium. B. Images from an electroanatomic mapping system are shown during mapping and ablation of typical cavo-tricuspid

isthmus-dependent atrial flutter. This system allows three-dimensional real-time localization and annotation of catheter position and cardiac anatomy to guide mapping and

ablation. In this instance, two projections of the map are shown at the top of the RA, an RAO, and LAO caudal view. Annotations of ablation lesion delivery are shown as

red dots. In the left lower aspect of this panel, a simultaneous image from intracardiac echocardiography (ICE) is shown of the RA, with the ablation catheter in view in all

three images. In the lower right aspect of this panel, surface ECG and intracardiac electrograms acquired in real-time are shown.

The Bradyarrhythmias: Disorders of the Sinoatrial Node

1873CHAPTER 244

IMPLANTED ELECTRICAL DEVICE THERAPY

Implanted cardiac rhythm management devices are commonly

utilized to manage arrhythmia. The first definitive pacemaker was

implanted in 1958 and this technology has evolved to be the mainstay in the management of bradyarrhythmias. Sinus node dysfunction or AV conduction disease, particularly with symptoms, are the

primary indications for most implanted pacemakers. Pacemakers

are typically implanted percutaneously, with conductive/sensing

wires, or leads, inserted through the upper extremity venous system into the right atrial and/or ventricular myocardium, with

the lead tip secured to the myocardium mechanically. The leads

are connected to a pulse generator that is placed typically in the

prepectoral space, which contains electronic circuitry and a battery,

allowing sensing and/or delivery of pacing stimuli to maintain

adequate heart rate. More recently, a completely leadless pacemaker

inserted through a large femoral venous sheath directly into the RV

endocardium has become available. Although these devices possess

more limited pacing options, they likely reduce the risks associated

with transvenous lead systems, including infection or lead fracture

requiring extraction.

Implanted cardioverter-defibrillators (ICDs) are placed in a similar fashion to pacemakers. However, ICDs have the ability to sense

abnormal ventricular arrhythmias and deliver either antitachycardia pacing or defibrillation to prevent sudden death. In patients

who experience a potentially lethal VA, ICD therapy may be lifesaving. Indications for ICD therapy are considered for either primary

prevention of sudden cardiac death (SCD) due to arrhythmia in

an at-risk patient, or as secondary prevention in a patient who has

survived an SCD event. More recently, a completely subcutaneous

ICD system has become available, avoiding intravenous leads that

increase risk for systemic infection, and potentially the procedure

to extract a potentially fibrosed lead in cases of lead malfunction or

endovascular infection.

Acknowledgment

David Spragg and Gordon Tomaselli contributed to this chapter in the

20th edition and some material from that chapter has been retained here.

■ FURTHER READING

Callans DJ: Josephson’s Clinical Cardiac Electrophysiology: Techniques

and Interpretations, 6th ed. Philadelphia, Wolters Kluwer, 2020.

Ellenbogen K et al (eds): Clinical Cardiac Pacing, Defibrillation, and

Resynchronization Therapy, 5th ed. Philadelphia, Elsevier, 2016.

Jalife J, Stevenson W (eds): Zipes and Jalife’s Cardiac Electrophysiology:

From Cell to Bedside, 8th ed. Philadelphia, Elsevier, 2021.

The sinoatrial (SA) node serves as the natural pacemaker of the heart

and has variable rates in response to parasympathetic and sympathetic

stimulation. If the sinus node is dysfunctional or suppressed a subsidiary pacemaker in the atrioventricular node or specialized conduction

system will take over leading to a slower junctional or ventricular

rhythm. Symptoms of sinus node dysfunction can vary but typically

present as fatigue, exercise intolerance, or dyspnea. The diagnostic

evaluation includes an investigation into reversible causes of sinus

bradycardia, confirmation of sinus node dysfunction with outpatient

244 The Bradyarrhythmias:

Disorders of the

Sinoatrial Node

William H. Sauer, Bruce A. Koplan

telemetry monitoring or exercise testing, and possibly cardiac imaging

if structural heart disease is suspected. Once irreversible sinus node

dysfunction is confirmed, permanent pacemaker implantation is the

only reliable therapy for symptomatic bradycardia.

■ STRUCTURE AND PHYSIOLOGY OF THE SA NODE

The SA node region is rather complex in structure. Clusters of myocytes

with pacemaker activity are surrounded by fibroblasts, endothelial cells,

and transitional cells. These clusters of small fusiform cells in the sulcus

terminalis on the epicardial surface of the heart at the right atrial–superior vena caval junction envelop the SA nodal artery. The SA node is

structurally heterogeneous, but the central prototypic nodal cells have

fewer distinct myofibrils than does the surrounding atrial myocardium,

no intercalated disks visible on light microscopy, a poorly developed

sarcoplasmic reticulum, and no T tubules. Cells in the peripheral

regions of the SA node are transitional in both structure and function.

The SA nodal artery arises from the right coronary artery in 55–60%

and the left circumflex artery in 40–45% of persons. This feature along

with a protective extracellular matrix of connective tissue insulates the

SA node from the hyperpolarizing influence of the larger atrium. In

addition, the alignment of this complex matrix is associated with nearly

unidirectional electrical propagation to the atrium (Fig. 244-1).

Pacemaker cells spontaneously depolarize in a continuous manner

setting the natural rate of depolarization and myocardial contraction.

Action potential depolarization in the SA node is normally at a resting

rate of 60–100 beats/min. The autonomic nervous system exhibits

control over the sinus node, with a preponderance of parasympathetic innervation at baseline. Removal of parasympathetic tone or

an increase in sympathetic innervation leads to an increase in rate of

depolarization. In denervated hearts, the rate of electrical depolarization (intrinsic heart rate) is approximately 100 beats/min, reflecting the

rate of automaticity of the sinus node uninhibited by parasympathetic

tone. The complement of ionic currents present in nodal cells results

in a less negative resting membrane potential compared with atrial or

ventricular myocytes. Electrical diastole in nodal cells is characterized

by slow diastolic depolarization (phase 4), which generates an action

potential as the membrane voltage reaches threshold. The action

potential upstrokes (phase 0) are slow compared with atrial or ventricular myocytes, being mediated by calcium rather than sodium current.

Cells with properties of SA nodal tissue are electrically connected to

the remainder of the myocardium by cells with an electrophysiologic

phenotype between that of nodal cells and that of atrial or ventricular

myocytes. Cells in the SA node exhibit the most rapid phase 4 depolarization and thus are the dominant pacemakers in a normal heart.

Myocytes within the SA node complex include specialized cells

surrounded by fibrous tissue. Unlike atrial and ventricular cells, sinus

node pacemaker cells have no true resting potential, but instead depolarize automatically and repetitively after the end of an action potential,

and the depolarizing current in the SA node myocytes results primarily

from slow calcium currents instead of fast sodium channels, which are

absent in SA node cells. Spontaneous phase 4 depolarization results

from a combination of slow inward depolarizing sodium currents

(if

, “funny currents”), along with T-type and L-type calcium channels.

The upstroke of depolarization in SA node myocytes is slower and

lower in amplitude than in ventricular myocytes.

In patients <85 years of age, the resting heart rate is strongly influenced by parasympathetic tone at baseline. Absence or elimination of

autonomic influence on the SA node leads to an intrinsic heart rate that

is normally 100–110 beats/min. The myocytes within the SA node that

initiate pacing change with different rates. A superior shift occurs at

higher heart rates and an inferior shift at lower heart rates, which may

lead to a slightly different P wave inscribed on ECGs recorded during

different rates of sinus rhythm.

In addition, a progressive decline in maximum heart rate occurs

with age, although the resting heart rate normally remains unchanged.

Intrinsic heart rate declines 5–6 beats/min for each decade of age.

However, the constancy of resting heart rate is associated with a gradual decrease in parasympathetic tone and a transition to predominant

sympathetic tone by the ninth decade.