The upward slope of phase 0, referred to as Vmax
, is related to the conduction
velocity. The steeper the slope, the more rapid the rate of depolarization. Another
is the point at which depolarization occurs. The less negative the
threshold potential, the slower Vmax will be, and hence conduction velocity is
slowed. Drugs can affect Vmax and conduction velocity by blocking the fast sodium
channels or by making the resting membrane potential less negative (e.g., class I
The action potential duration (APD) is the length of time from phase 0 to the end of
phase 3. The effective refractory period is the length of time that the cell is refractory
and will not propagate another impulse. Both of these measurements can be obtained
from intracardiac recordings of the action potential. Class Ia and III agents prolong
the refractoriness of the heart.
NORMAL CARDIAC ELECTROPHYSIOLOGY
Automaticity is the ability of cells (often called pacemaker cells) to depolarize
spontaneously. These cells are located in the SA and AV nodes and the His-Purkinje
system. The SA node is normally the dominant pacemaker because it reaches the
threshold faster than other nodes in a normal heart, resulting in 60 to 100
2 The innate AV node and Purkinje rate of depolarization
is 40 to 60 and 40 depolarizations per minute, respectively. In the healthy heart, the
AV node and Purkinje fibers are prevented (overridden) from spontaneous
depolarization by the more frequent impulses from the SA node.
An impulse normally originates in the SA node and travels down specialized
intranodal pathways to activate atrial muscle and the AV node. The AV node holds
the impulse briefly before releasing it to the bundle of His. It then travels to the right
and left bundle branches and out to the ventricular myocardium via the Purkinje
fibers. The ECG tracing consists of a series of complexes that correspond to
electrical activity in a specific location or anatomic site. By convention, these
electrical deflections have been labeled the P wave, QRS complex, and T wave. The
P wave represents depolarization of the atria, whereas the QRS complex reflects
ventricular depolarization. The T wave reflects repolarization of the ventricles. To
evaluate the intact conduction system, conduction intervals at different sites can be
obtained. The normal intervals as measured by ECG or intracardiac electrodes are
shown in Table 15-1. Drugs and ischemia can alter the conduction and hence the
ECG intervals. The effects of antiarrhythmic agents on the ECG are described in
Normal Electrocardiographic Intervals
Interval Normal Indices (ms) Electrical Activity
PR 120–200 Atrial depolarization
QRS <140 Ventricular depolarization
a <400 Ventricular repolarization
Abnormal impulse formation can arise from abnormal automaticity or triggered
activity originating from the SA node (e.g., sinus bradycardia) or other sites (e.g.,
junctional or idioventricular tachycardia). Causes of abnormal automaticity include
hypoxia, ischemia, or excess catecholamine activity.
Triggered activity occurs when there is an attempted depolarization before or after
the cell is fully repolarized, but not by a pacemaker cell. These after-depolarizations
may occur in phase 2 or 3 (early) or phase 4 (delayed) of the action potential. Early
after-depolarizations (EAD) arise from a reduced level of membrane potential and
may require a bradycardic state. Torsades de pointes (TdP), a form of polymorphic
overload of intracellular free calcium.
The most common abnormal conduction leading to arrhythmogenesis is reentry. A
reentrant circuit is formed as normal conduction occurs down a pathway that
bifurcates into two pathways (e.g., AV node or left and right bundle branches). The
impulse travels along one pathway (Fig. 15-2), but encounters unidirectional
antegrade block in the other pathway (see Fig. 15-2). The impulse that passed through
the unblocked pathway propagates in a retrograde manner (i.e., moves backward)
through the previously blocked pathway. This abnormal impulse can travel down the
first pathway again when it is not refractory. Supraventricular and monomorphic VT
are both examples of reentrant arrhythmias.
Pharmacologic Properties of Antiarrhythmic Agents
Type PR Interval QRS Interval QT Interval
aConduction increases at low dosages and decreases at higher dosages.
bOn atrial and atrioventricular nodal tissue.
cMay cause PR prolongation independent of class III antiarrhythmic activity.
Another form of abnormal impulse conduction occurs when the normal conducting
pathway is blocked and the impulse is forced to travel through nonpathway tissues to
cause depolarization. Common examples are left and right bundle branch blocks in
the ventricles. A block in one path necessitates retrograde conduction through the
opposite bundle to stimulate both ventricles. Nonpathway tissue conducts the
electrical impulse more slowly than conduction tissues do.
through the pulmonary vein and a route for it to stimulate the atria as well.
All arrhythmias originating above the bundle of His are referred to as
supraventricular arrhythmias. These may include sinus bradycardia, sinus
tachycardia, paroxysmal supraventricular tachycardia, atrial flutter, atrial fibrillation
(AF), Wolff–Parkinson–White (WPW) syndrome, and premature atrial contractions
(PACs). All of these arrhythmias are characterized by normal QRS complexes (i.e.,
normal ventricular depolarization) unless there is a bundle branch block. Not all of
these rhythm changes are necessarily a sign of pathology. For example, athletes with
a well-conditioned heart and large stroke volume commonly have slow heart rates
(sinus bradycardia). Vigorous exercise is accompanied by transient sinus
Arrhythmias originating below the bundle of His are referred to as ventricular
arrhythmias. These include premature ventricular contractions (PVCs), VT, and
ventricular fibrillation (VF). Conduction blocks often are categorized separately
based on their level or location, which can be a supraventricular site (e.g., first-,
second-, or third-degree AV block, see Case 15-6, Question 2) or in the ventricle
(e.g., right or left bundle branch block). An alternative method of classifying
arrhythmias is based on the rate: bradyarrhythmia (<60 beats/minute) or
tachyarrhythmia (>100 beats/minute). There is a website with useful rhythm
evaluation tutorials at http://www.blaufuss.org.
On the basis of their electrophysiologic (EP) and pharmacologic effects, there are
four Vaughn-Williams antiarrhythmic drug classes. Class I drugs, sodium-channel
blockers, are subdivided further depending on the duration of blockade (class Ia:
intermediate; Ib: fast; and Ic: long). Class II drugs are β-adrenergic blockers, class III
drugs are potassium-channel blockers, and class IV drugs are calcium-channel
blockers. The classification, pharmacokinetics, and adverse effects of these agents
Class Ia and class III antiarrhythmic agents increase repolarization time, the QTc
interval, and the risk of TdP. Class II and IV antiarrhythmic agents may decrease
heart rate (cause bradycardia), decrease ventricular contractility (decrease stroke
volume), and prolong the PR interval (cause second- or third-degree AV block).
Class Ib antiarrhythmic agents work only in ventricular tissue, so they cannot be used
in AF or atrial flutter. Class Ic antiarrhythmic agents are useful, but should never be
used after an MI or with systolic heart failure or severe left ventricular hypertrophy
(classified as structural heart diseases) because increased mortality can result. These
drugs are discussed in greater detail later.
Vaughn-Williams Classification of Antiarrhythmic Agents
Drug and Classification Pharmacokinetics Indications Side Effects
Class Ia (can cause torsades de pointes similar to class III agents)
t1/2 = 6.2 ± 1.8 hours (affected
CYP2D6 inhibitor, Pglycoprotein inhibitor
Procainamide t1/2 = 3 ± 0.6 hours; Vd = 1.9 ±
0.3 L/kg; liver metabolism 40%;
t1/2 = 6 ± 1 hours; Vd = 0.59 ±
(cannot be used to treat atrial arrhythmias)
Lidocaine t1/2 = 1.8 ± 0.4 hours; Vd = 1.1
Mexiletine t1/2 = 10.4 ± 2.8 hours; Vd =
Class Ic (cannot be used in patients with structural heart disease)
Flecainide t1/2 = 12–27 hours; CYP2D6
substrate, 75%; renal clearance,
25%; Cp = 0.4–1 mcg/mL vision, metallic
Propafenone t1/2 = 2 hours (extensive
metabolizer); Vd = 2.5–4 L/kg,
CYP2D6 substrate/inhibitor, Pglycoprotein inhibitor
Class III (can cause torsade de pointes similar to class Ia agents, amiodarone, and dronedarone and
Amiodarone t1/2 = 40–60 days; Vd = 60–
liver metabolism, 100%; oral F
inhibitor, P-glycoprotein inhibitor
c t1/2 = 10–20 hours; Vd = 1.2–
2.4 L/kg; renal clearance, 100%
Dofetilide t1/2 = 7.5–10 hours; Vd = 3
Ibutilide t1/2 = 6 (2–12) hours; Vd = 11
Dronedarone t1/2 = 13–19 hours; Vd = 20
aNAPA is 100% renally eliminated and possesses class III antiarrhythmic activity.
bPhenytoin is classified as a class Ib antiarrhythmic.
cPossesses both class II and III antiarrhythmic activity.
, steady-state plasma concentration; CR, controlled release; CTS, cation tubular secretion;
, volume of distribution; VF, ventricular fibrillation; VT, ventricular tachycardia;
WPW, Wolff–Parkinson–White syndrome.
waves, normal width of the QRS complexes, and ventricular rate of 140 beats/minute.
The specific arrhythmias include (a) those primarily atrial in origin, such as AF,
atrial flutter, paroxysmal sinus tachycardia, ectopic atrial tachycardia, and multifocal
atrial tachycardia; and (b) AV nodal reentrant tachycardia (AVNRT) and AV
reentrant tachycardia (AVRT) involving accessory pathways within the atria or
ventricle. AVNRT and AVRT often self-terminate and are paroxysmal (episodic) in
nature; thus, they are commonly referred to as paroxysmal supraventricular
tachycardias (PSVT). The most common supraventricular arrhythmias are AF, atrial
Atrial Fibrillation and Atrial Flutter
AF is usually initiated when a depolarization stimulus arising from an ectopic focus
or reentrant circuit impacts the atria while the tissue is in the vulnerable period. The
vulnerable period in the atria and ventricles occurs during the first half of the QRS
complex; this period is vulnerable because the net charge is near normal but the ion
concentrations of sodium, calcium, and potassium inside and outside the cells are
radically different. Stimulation during the vulnerable period causes multiple ectopic
foci to arise and attempt to pace the atria with no single pacemaker in control,
eliminating discernable P waves on the ECG (Fig. 15-3) and eliciting a rapid,
ineffective writhing of the atrial muscle with a classic “irregularly irregular”
ventricular rate. In contrast, atrial flutter (Fig. 15-4) is characterized by typical
sawtooth atrial waves, at a rate of 280 to 320 beats/minute, and a variable
ventricular rate, depending on the nature of the AV block present (e.g., 2, 3, or 4
atrial beats for each ventricular beat or 2:1, 3:1, or 4:1 block). In most cases, the
ventricular rate is approximately 150 beats/minute. Episodes of atrial flutter can
progress to AF if the ectopic atrial depolarization stimulus impacts the surrounding
atrial tissue in the vulnerable period. When patients initially experience AF, the
episodes are usually short lived, and spontaneous conversion occurs. The pattern of
erratic initiation and termination of AF is termed paroxysmal atrial fibrillation
(PAF), and if enough AF events occur in close proximity to each other, the duration
of subsequent AF events increases in length and the event degenerates into persistent
AF. In persistent AF, the AF episode will continue until the heart is electrically or
chemically converted out of the rhythm. With time, persistent AF degenerates into
permanent AF, in which normal sinus rhythm cannot be achieved and sustained. An
example of PAF is presented in the following section.
CLINICAL MANIFESTATION AND UNDERLYING CAUSES
and temperature of 98.2°F. His body mass index is 32 kg/m
. What factors in J.K.’s past medical history
predispose him to development of AF? What is his 10-year risk of developing AF?
AF is commonly associated with, or a manifestation of, other diseases or disorders
3,3a When treatable underlying causes are present, they should be
corrected because this may resolve the AF. A risk prediction tool highlights common
factors associated with the development of AF, particularly older age, male gender,
hypertension, heart failure, obesity, and valvular disease.
patients who do not have underlying heart disease, AF is called “lone” AF and
usually has a more benign course.
J.K. has several risk factors for the development of AF within the next 10 years,
including the presence of treated hypertension, heart failure, his age, and his sex. A
detailed scoring system is described in the referenced manuscript but is beyond the
scope of this chapter. Using his risk factors, his 10-year risk of developing AF would
Consequences of Atrial Fibrillation
CASE 15-1, QUESTION 2: Two years later, J.K. presents with complaints of dyspnea on exertion (DOE)
but these were not associated with DOE. On physical examination, he is found to have rales. Cardiac
The most common complaint in patients with AF, as with J.K., is palpitations (the
sensation of the heart beating rapidly or unusually in the chest). This is a result of the
rapid ventricular rate, which typically ranges from 100 to 160 beats/minute. The R–R
interval (time from the R wave in one QRS complex to the R wave in the next
complex) is irregularly irregular (random irregularity). During AF, the atrial kick or
the atria’s contribution to stroke volume is lost. Because the atrial kick may account
for 20% to 30% of the total stroke volume, this, coupled with rapid ventricular rates
and irregular R–R interval spacing during AF, can cause symptoms of inadequate
blood flow such as light-headedness, dizziness, or reduced exercise tolerance.
However, some patients are asymptomatic except for the palpitations. Depending on
the underlying ventricular function, signs of HF, such as DOE and peripheral edema,
may develop, as experienced by J.K. Conversely, underlying HF may precipitate AF.
Causes of Atrial Fibrillation and Flutter
Alcohol Nonrheumatic Heart Disease
Atrialseptal defect Pericarditis
Cardiomyopathy Pulmonary embolism
Cerebrovascular accident Sick sinus syndrome
Chronic obstructive pulmonary disease Stimulants
Ischemic heart disease Wolff–Parkinson–White syndrome
Patients with AF are at risk for thrombotic stroke (see Stroke Prevention section
6 With the chaotic movement of the atria, normal blood flow is disrupted, and
atrial mural thrombi (usually in a pouch called the left atrial appendage) may form.
The risk of stroke increases after restoration of normal sinus rhythm, which allows
more efficient cardiac contractility and expulsion of the thrombus. Patients with
nonvalvular AF have a fivefold increase in the risk of stroke; this risk increases as
patients have an increased number of associated risk factors. Other concurrent
diseases that may increase the risk of stroke are HF, cardiomyopathy, thyrotoxicosis,
congenital heart disease, and valvular heart disease. Because of the high risk of
stroke and significant impact of stroke on patient outcomes, pharmacologic stroke
prophylaxis is often indicated. Selection of an appropriate antithrombotic regimen for
the patient with AF must be based on assessment of the underlying stroke and
bleeding risk. Risk stratification in AF is performed with the use of the CHA2DS2
VASc scoring system. A CHA 2DS2
-VASc score is calculated by assigning one point
each for the presence of congestive heart failure, hypertension, diabetes, vascular
disease, age of 65 to 74 years, or female gender and two points for age of 75 years or
greater or a history of stroke. Points are totaled, and the subsequent score correlates
greater or a history of stroke. Points are totaled, and the subsequent score correlates
TREATMENT OF ATRIAL FIBRILLATION
CASE 15-1, QUESTION 3: What are the therapeutic goals and general approaches used to treat AF in
The two primary goals of treatment are to control the ventricular response rate and
to reduce the risk of stroke. In some cases, a third therapeutic goal may be conversion
CASE 15-1, QUESTION 4: J.K. is given a 1-mg loading dose of digoxin, followed by a 0.25-mg every day
maintenance dose. What is the purpose of administering digoxin? What are the relative advantages and
disadvantages of digoxin compared with other agents to control ventricular rate?
Agents Used for Controlling Ventricular Rate in Supraventricular Tachycardias
Digoxin 10–15 mcg/kg LBW up to
hours (e.g., 0.5 mg initially,
Esmolol 0.5 mg/kg IV for 1 minute 50–300 mcg/kg/minute
digoxin and calciumchannel blockers
Propranolol 0.5–1.0 mg IV repeated
Metoprolol 5 mg IV at 1 mg/minute PO: 25–100 mg BID Use with caution in
120–480 mg in sustainedrelease form daily
permanent and may require chronic ventricular pacing afterward.
QID, four times a day; TID, three times a day.
The first treatment goal is to slow the ventricular response rate, which allows
better ventricular filling with blood. Table 15-5 displays the agents commonly used
to control the ventricular response and, provides typical loading and maintenance
doses. Because of its direct AV node-blocking effects and vagomimetic properties,
digoxin prolongs the effective refractory period of the AV node and reduces the
number of impulses conducted through the AV node (negative dromotropy).
There are several limitations associated with digoxin use in AF. Digoxin has a
slow onset of action. After an intravenous (IV) dose, it will take more than 2 hours
for the onset of effect and 6 to 8 hours for the maximal effect, which is markedly
slower than other negative dromotropic agents.
heightened sympathetic tone (e.g., exercise or emotional stress), a common
7–11 The 2014 American Heart Association/American College of
Cardiology/Heart Rhythm Society Guidelines for the management of patients with AF
recommend that digoxin use be reserved for control of ventricular response rate in
patients with impaired left ventricular function or HF or for use as an add-on therapy
when treatment with a β-blocker or calcium-channel blocker provides inadequate
12 Patients who require rate control of AF and have a lower BP may also
benefit from rate control with digoxin. It should also be noted that digoxin serum
concentrations may be increased when combined with P-glycoprotein inhibitors such
as verapamil, propafenone, quinidine, flecainide, and amiodarone.
13–15 Normally, Pglycoprotein in the brush border membrane of intestinal enterocytes pumps digoxin
into the lumen of the gut reducing its bioavailability and pumps digoxin out of the
body via the renal tubules (see Chapter 14, Heart Failure, for discussion of digoxin
and digoxin drug interactions).
dosing be changed if J.K. had renal dysfunction?
J.K.’s renal function is normal. If he had significant renal dysfunction, both the
loading and the maintenance doses of digoxin would need to be altered. A loading
dose is used to achieve a therapeutic level and volume of distribution of digoxin is
reduced in patients with renal dysfunction. The digoxin maintenance dose is highly
dependent on renal clearance, because digoxin is eliminated 50% to 75% unchanged
in the urine (see Chapter 14, Heart Failure, for further discussion of digoxin dosing in
patients with normal and impaired renal function). Although the usual digoxin target
range is generally 0.5 to 1.0 ng/mL in the management of patients with heart failure,
higher serum concentrations may be necessary when using digoxin as a rate control
CASE 15-1, QUESTION 6: What other drugs can be used for ventricular rate control, and what are their
relative advantages and disadvantages compared with digoxin?
β-Adrenergic blocking agents are another class of negative dromotropic agents
used in AF. Propranolol, metoprolol, and esmolol are available for IV
administration. Each agent rapidly controls the ventricular rate both at rest and during
exercise. β-Blockers are the first choice in high catecholamine states such as
thyrotoxicosis and postcardiac surgery. However, given their negative inotropic
effects, β-blockers should be used cautiously to acutely control the ventricular
response in patients with decompensated HF. Even though β-blockers are used to
treat systolic HF (e.g., bisoprolol, carvedilol, and metoprolol), they need to be
started at low doses and titrated slowly for several weeks to therapeutic doses
Chapter 14, Heart Failure). When trying to achieve rapid rate control, more
aggressive dosing may be needed. β-Blockers should also be avoided in patients
with asthma because of their β2
-blocking properties, and blood glucose levels should
be monitored more closely in patients with diabetes mellitus because the signs and
symptoms of hypoglycemia (except sweating) can be masked.
Nondihydropyridine calcium-channel blockers are also effective in slowing
ventricular rate at rest and during exercise. Both verapamil and diltiazem can be
administered IV for a rapid (4–5 minutes) reduction in heart rate.
Nondihydropyridine calcium-channel blockers should not be used in patients
presenting with decompensated HF.
7 They work through their effect on slow calcium
channels within the AV node. Although the duration of action produced by bolus
dosing is short, both agents can be administered either as a continuous drip or orally.
Given the ability of calcium-channel blockers to cause arteriolar dilation, a transient
decrease in BP may be seen. IV calcium pretreatment can be used to attenuate the BP
decrease among patients with hypotension, near-hypotensive BP, or left ventricular
dysfunction. Calcium pretreatment does not appear to diminish the negative
dromotropic effects of nondihydropyridine calcium-channel blockers.
is contraindicated in patients with an ejection fraction less than 35% and diltiazem
should be used with caution in HF with a reduced EF. Verapamil increases the
concentrations of other cardiovascular drugs such as digoxin, dofetilide, simvastatin,
21 Verapamil and diltiazem are good alternatives to β-blockers in
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