Any change in cardiac rhythm from the normal sinus rhythm is defined as an arrhythmia. Although some arrhythmias are pathological and even life-threatening, others are normal and appropriately adaptive, including sinus tachycardia and sinus arrhythmia.
Sinus tachycardia is a heart rate faster than normal, driven by the sinus node. This arrhythmia is seen in frightened or startled individuals or during normal exercise. Rarely, sinus tachycardia can be pathological—for example, in patients with acute hyperthyroidism (see pp. 1011–1013).
Sinus arrhythmia is the name given to a normal phenomenon: a subtle change in heart rate that occurs with each respiratory cycle. Inspiration accelerates the heart rate (see pp. 547–548); expiration slows it. Deepening of the respirations exaggerates these cyclic changes. The magnitude of the effect can vary significantly among individuals. The heart rate is still under the control of the SA node, but cyclic variations in sympathetic and parasympathetic tone modulate the SA node's pacemaker rate. The loss of sinus arrhythmia can be a sign of autonomic system dysfunction, as may be seen in patients with diabetes.
Although the list of pathological arrhythmias is long, two basic problems are responsible for nearly all arrhythmias: altered conduction and altered automaticity (Box 21-3).
An acute myocardial infarction, or heart attack, begins with the occlusion of a coronary artery. The region of myocardium subserved by that coronary artery is deprived of oxygen and will die unless blood flow resumes shortly. During the initial stages, the myocardial cells are electrically active but their function is impaired, which produces characteristic changes in the ECG. Complete but transient blockade of blood flow to the myocardium—even though it does not lead to cell death—may result in a pattern of ECG changes similar to that seen during the acute phase of myocardial infarction. Because blood flow is regional, the areas of infarction are also regional. Thus, the physician can best observe the changes in electrical activity by examining the specific ECG leads that provide the best view of the involved region of myocardium.
The first electrical change associated with an acute myocardial infarction is peaking of the T waves, followed soon after by T-wave inversion. These T-wave changes are not specific for infarction and are reversible if blood flow is restored.
The next change, and one that is more characteristic of an acute myocardial infarction, is elevation of the ST segment. This change occurs because the myocytes closest to the epicardium become depolarized by the cellular anoxic injury, but they are still electrically coupled. Returning to the two-cell model (Fig. 21-13A), consider the cell on the left (cell A) to be normal and the cell on the right (cell B) to be damaged. Figure 21-13B shows the extracellular current, which is proportional to the differences in the action potentials of the two cells shown in Figure 21-13A. Because cell B has a more positive resting potential than cell A but the same plateau during the action potential, the difference in voltage between cell A and cell B is depressed everywhere but at the ST segment—which makes the ST segment appear elevated. This is also the ECG change that one views with an acute myocardial infarction.
FIGURE 21-13 Two-cell model of a myocardial infarction. A, The damaged cell B (blue record) has a lower resting potential, but the plateau of its action potential is at the same level as that of the normal cell A (green record). B, After the records in A are subtracted, the apparent elevation of the ST segment is the same as the difference in resting potentials; the TP and PR regions are actually depressed.
Brief periods of coronary artery spasm can also produce ST elevation, presumably by the same mechanism. Rapid reperfusion of coronary arteries after acute blockage may lead to rapid and complete recovery of the myocardial cells, as indicated by the evanescent nature of the ECG changes.
Ischemia without cell death due to a fixed degree of occlusion (e.g., that caused by a thrombus or atherosclerosis) is often associated with changes in the ECG, typically ST-segment and T-wave changes. However, these changes are quite variable, presumably brought about by altered action potential duration in the affected regions. Patients experiencing exertional chest pain (angina) due to diminished coronary blood flow frequently have ECG changes during the anginal episode that include ST-segment depression and T-wave inversion.
With irreversible cell death, the ECG typically shows the evolution of deep Q waves (a large negative deflection at the beginning of the QRS complex). Q waves develop only in those leads overlying or near the region of the infarction. The Q waves indicate an area of myocardium that has become electrically silent. Because action potentials cannot propagate into the infarcted area, the net vector of the remaining areas of ventricular depolarization—by default—points away from this area. The result is a deep negative deflection on the ECG in the appropriate leads. Thus, an inferior wall infarction inscribes deep Q waves in leads II, III, and aVF. An infarction affecting the large muscular anterior wall of the heart will inscribe deep Q waves in some of the precordial leads (V1 through V6).
Not all infarctions create deep Q waves; the only visible changes may be T-wave inversion and ST-segment depression. Clinically, these infarctions behave like incomplete infarctions, and patients are at risk of a second, completing event. Therefore, these patients are investigated and treated aggressively to prevent further infarction.
Conduction abnormalities are a major cause of arrhythmias
Disturbances of conduction make up the first major category of cardiac arrhythmias. Conduction disturbances can have multiple causes and can occur at any point in the conduction pathway. Conduction disturbances can be partial or complete. The two major causes of conduction disturbances are depolarization and abnormal anatomy.
If a tissue is injured (e.g., by stretch or anoxia), an altered balance of ionic currents can lead to a depolarization. The depolarization, in turn, partially inactivates INa and ICa, slowing the spread of current (i.e., slowing conduction). As a result, the tissue may become less excitable (partial conduction block) or completely inexcitable (complete conduction block).
Another type of conduction disturbance is the presence of an aberrant conduction pathway, reflecting abnormal anatomy. One such example is an accessory conduction pathway that rapidly transmits the action potential from the atria to the ventricles, bypassing the AV node, which normally imposes a conduction delay. Patients with the common Wolff-Parkinson-White syndrome have a bypass pathway called the bundle of Kent. The existence of a second pathway between the atria and ventricles predisposes affected individuals to supraventricular arrhythmias (see pp. 504–505).
Partial (or Incomplete) Conduction Block
Three major types of partial conduction block exist: slowed conduction, intermittent block, and unidirectional block. We defer the discussion of unidirectional block until we consider re-entry phenomena.
In slowed conduction, the tissue conducts all the impulses, but more slowly than normal. First-degree AV block reflects a slowing of conduction through the AV node. On an ECG, first-degree AV block appears as an unusually long PR interval (compare A and B in Fig. 21-14).
FIGURE 21-14 Pathological ECGs. In E, right bundle branch block is visible in the V1 or V2 precordial leads; left bundle branch block is visible in the V5 or V6 leads. (Modified from Chernoff HM: Workbook in Clinical Electrocardiography. New York, Medcom, 1972.)
A second example of partial conduction block is intermittent block, in which the tissue conducts some impulses but not others. In the AV node, intermittent block leads to second-degree AV block, of which there are two types. Both reflect incomplete (i.e., intermittent) coupling of the atria to the ventricles. In a Mobitz type I block (or Wenckebach block), the PR interval gradually lengthens from one cycle to the next until the AV node fails completely, skipping a ventricular depolarization (see Fig. 21-14C). With Mobitz type I block, it is most common to see every third or fourth atrial beat fail to conduct to the ventricles. In a Mobitz type II block, the PR interval is constant from beat to beat, but every nth ventricular depolarization is missing. In Figure 21-14D, the first cardiac cycle is normal. However, the second P wave is not followed by a QRS or T. Instead, the ECG record is flat until the third P wave arrives at the expected time, followed by a QRS and a T. Thus, we say that every second QRS is dropped (2:1 block).
Another form of intermittent conduction block, called rate-dependent block, reflects disease often seen in the large branches of the His-Purkinje fiber system (i.e., the bundle branches). When the heart rate exceeds a critical level, the ventricular conduction system fails, presumably because a part of the conducting system lacks sufficient time to repolarize. With intermittent failure of the His-Purkinje fiber system, the impulse is left to spread slowly and inefficiently through the ventricles by conducting from one myocyte to the next. Such a failure, whether intermittent or continuous, is known as a bundle branch block and appears on the ECG as an intermittently wide QRS complex (see Fig. 21-14E). Because this block impairs the coordinated spread of the action potential throughout the ventricles, the resulting contraction loses some efficiency.
Complete Conduction Block
In complete block, or third-degree AV block, no impulses conduct through the affected area, in either direction. For example, complete block at the AV node stops any supraventricular electrical impulse from triggering a ventricular contraction. Thus, AV nodal block electrically severs the atria and ventricles, each of which beats under control of its own pacemakers. This situation is called AV dissociation. The only ventricular pacemakers that are available to initiate cardiac contraction are the Purkinje fiber cells, which are notoriously unreliable and slow. Thus, cardiac output may fall, and blood pressure along with it. AV dissociation can therefore constitute a medical emergency, and placement of an artificial ventricular pacemaker can prove lifesaving. On an ECG, complete block appears as regularly spaced P waves (i.e., the SA node properly triggers the atria) and as irregularly spaced QRS and T waves that have a low frequency and no fixed relationship to the P waves (see Fig. 21-14F).
An independent focus of pacemaker activity can develop as a consequence of a conduction disturbance. This class of conduction disturbance is called re-entry (or re-entrant excitation or circus movement). It is one of the major causes of clinical arrhythmias. It occurs when a wave of depolarization travels in an apparently endless circle. Re-entry has three requirements: (1) a closed conduction loop, (2) a region of unidirectional block (at least briefly), and (3) a sufficiently slow conduction of action potentials around the loop.
Before further considering re-entry, we need to discuss a conduction defect that is essential for re-entry—unidirectional block. Unidirectional block is a type of partial conduction block in which impulses travel in one direction but not in the opposite one. Unidirectional block may arise as a result of a local depolarization or may be due to pathological changes in functional anatomy. Normal cardiac tissue can conduct impulses in both directions (Fig. 21-15A). However, after an asymmetric anatomical lesion develops, many more healthy cells may remain on one side of the lesion than on the other. When conduction proceeds in the direction from the many healthy cells to the few healthy cells, the current from the many may be sufficient to excite the few (right to left in Fig. 21-15B). On the other hand, when conduction proceeds in the opposite direction, the few healthy cells cannot generate enough current to excite the region of many healthy cells (left to right in Fig. 21-15B). The result is a unidirectional block.
FIGURE 21-15 Abnormal conduction.
We return now to the problem of re-entry. Imagine that an impulse is traveling down a bifurcating Purkinje fiber and is about to reach a group of ventricular myocytes—a closed conduction loop (see Fig. 21-15C). However, the refractory zones prevent the re-entry of impulses from the right to the left, and vice versa. We now introduce a lesion that causes a unidirectional conduction block in the left branch of the Purkinje fiber. When the impulse reaches the fork in the road, it spreads in both directions (see Fig. 21-15D, step 1). However, the impulse cannot continue past the unidirectional block in the left branch. The impulse traveling down the right branch stimulates the distal conducting cells (see Fig. 21-15D, step 2), leaving them in an effective refractory period (see p. 491). When the impulse reaches the ventricular muscle, it begins to travel back toward the damaged left branch (step 3). At this point, the cells in the normal right branch may still be refractory to excitation. The impulse finally reaches the damaged left branch and travels in a retrograde fashion up this branch, reaching and passing through the region of the unidirectional conduction block (step 4). Finally, the impulse again reaches the bifurcation (step 5). Because enough time has elapsed for the cells at the bifurcation as well as in the right branch to recover from their refractory period, the impulse can now travel retrograde up the main part of the Purkinje fiber as well as orthograde down the right branch—for a second time.
If this re-entrant movement (steps 2 → 5 → 2, and so on) continues, the frequency of re-entry will generally outpace the SA nodal pacemaker (frequency of step 1) and is often responsible for diverse tachyarrhythmias because the fastest pacemaker sets the heart rate. Re-entry excitation may be responsible for atrial and ventricular tachycardia, atrial and ventricular fibrillation, and many other arrhythmias. Re-entry can occur in big loops (see Fig. 21-15D) or in small loops consisting entirely of myocardial cells.
Accessory Conduction Pathways
Wolff-Parkinson-White (WPW) syndrome, briefly mentioned above (see pp. 501–502), is a common example of an accessory conduction pathway, which in this case provides a short circuit (i.e., bundle of Kent) around the delay in the AV node. The fast accessory pathway is composed not of Purkinje fibers but instead of muscle cells. It conducts the action potential directly from the atria to the ventricular septum, depolarizing some of the septal muscle earlier than if the depolarization had reached it via the normal, slower AV nodal pathway. As a result, ventricular depolarization is more spread out in time than is normal, giving rise to a broader-than-normal QRS complex. The general direction of ventricular depolarization is reversed, so that the events normally underlying the Q wave of the QRS complex have an axis opposite to that normally seen. This early depolarization, or pre-excitation, appears as a small, positive delta wave at the beginning of the QRS complex (see Fig. 21-14G). In addition, because the time between atrial depolarization and ventricular depolarization (i.e., beginning of delta wave) is shortened, the interval between the P wave and the QRS complex is shortened.
The aberrant conduction pathway in WPW syndrome also establishes a loop that may meet the requirements for re-entry and may therefore be associated with a supraventricular tachycardia. Although in general a benign condition, WPW syndrome is associated with at least one attack of supraventricular tachycardia in at least 50% of affected individuals. The two most common supraventricular tachycardias seen in this population are paroxysmal supraventricular tachycardia and atrial fibrillation (described below). Paroxysmal supraventricular tachycardia (PSVT) is a regular tachycardia with a ventricular rate usually exceeding 150 beats/min. Because ventricular depolarization still occurs via the normal conducting pathways, the QRS complex appears normal.
If, during an episode of PSVT, the conduction direction for re-entry is in the reverse direction (i.e., down the accessory pathway and back up through the AV node), the QRS shape may be unusual. This arrangement may produce a PSVT with wide and bizarre QRS complexes because ventricular depolarization does not occur along the normal bundle branches. A small number of people with WPW syndrome have more than one accessory pathway, so that multiple re-entry loops are possible.
In fibrillation, many regions of re-entrant electrical activity are present, creating electrical chaos that is not associated with useful contraction. Atrial fibrillation N21-15 (see Fig. 21-14H) is commonly found in elderly patients, sometimes with mitral valve or coronary artery disease, but often without any evidence of underlying cardiac disease. The re-entry loop within the atria moves wildly and rapidly, generating a rapid succession of action potentials—as many as 500 per minute. This wandering re-entry circuit easily becomes the fastest pacemaker in the heart, outpacing the SA node and bombarding the AV node. Fortunately, the AV node cannot repolarize fast enough to pass along all of these impulses. Only some make it through to the ventricles, resulting in the irregular appearance of QRS complexes without any detectable P waves. The baseline between QRS complexes may appear straight or may show small, rapid fluctuations. Although only some atrial impulses reach the ventricles, the ventricular rate can still be quite high.
Contributed by W. Jonathan Lederer
Atrial fibrillation (AF) is the most common cardiac arrhythmia. It frequently presents with modest or no symptoms and may be diagnosed on a routine ECG when no clear P wave can be identified on the ECG and the QRS complex occurs at “irregularly irregular” intervals. Compared to ventricular fibrillation with its extreme and rapid lethality, AF has more modest pathology. It is an arrhythmia that depends on altered cellular electrical properties, on tissue organization problems (e.g., fibrosis), and on diverse background issues (e.g., increased blood pressure, increased vascular volume, duration of the fibrillation). Cardioversion works best only when applied early in the course of the disease and often yields only a short-term improvement. Because AF is frequently found in the context of much atrial fibrosis and widespread electrical re-entry sites in both atria, invasive structural changes in the atrial conduction pathways may be beneficial. Conceptually these procedures seek to prevent the electrical activity from multiple re-entry sites from impinging on the AV node. Introducing atrial scars to block conduction out of re-entry regions can help. These are frequently referred to as “maze” ablations and involve procedures such as controlled freezing or radiofrequency destruction in a complex maze pattern in the affected regions of the atria. There is often a Ca2+-dependent component of AF, and therapeutic drugs are often used to mitigate this Ca2+-dependent component.
Because the atria function mainly as a booster pump (see p. 508), many patients tolerate atrial fibrillation without harm and may even be unaware that they have it. Others may suffer greatly from the loss of a coordinated atrial contraction, particularly the elderly or those with coexisting cardiac disease. In most individuals, attempts should be made to convert the rhythm back to normal sinus rhythm if possible, by either electrical or chemical means. If this is not possible, then attempts can be made to at least slow conduction through the AV node. For example, digitalis compounds increase parasympathetic and decrease sympathetic stimulation to the AV node, decreasing the speed of AV conduction and thus reducing the ventricular rate (see p. 493). β-adrenergic blockers or Ca2+ channel blockers are also used to control ventricular rate.
Ventricular fibrillation (see Fig. 21-14I) is a life-threatening medical emergency. The heart cannot generate cardiac output because the ventricles are not able to pump blood without a coordinated ventricular depolarization.
Altered automaticity can originate from the sinus node or from an ectopic locus
The automaticity of any cardiac tissue can change. Pacemaker cells can experience an alteration in or even a complete absence of automaticity. Conversely, other cells that normally have no automaticity (e.g., ventricular muscle) can become “ectopic” pacemakers. These disturbances of automaticity make up the second major category of cardiac arrhythmias.
Depolarization-Dependent Triggered Activity
A positive shift in the maximum diastolic potential brings Vm closer to the threshold for an action potential and can induce automaticity in cardiac tissue that otherwise has no pacemaker activity. The development of depolarization-induced triggered activity depends on the interaction of the Ca2+ current (ICa) and the repolarizing K+ current (IK). This mechanism can produce a more rapid pacemaker depolarization in the SA or AV nodal cells, causing them to accelerate their pacemakers. It can also increase the intrinsic pacemaker rate in Purkinje fiber cells, which normally have a very slow pacemaker.
Depolarization-induced triggered activity is particularly dramatic in nonpacemaker tissues (e.g., ventricular muscle), which normally exhibit no diastolic depolarization. Factors that significantly prolong action potential duration can cause depolarization-dependent triggered activity. During the repolarization phase, INa remains inactivated because the cell is so depolarized (Fig. 21-16A). On the other hand, ICa has had enough time to recover from inactivation and—because the cell is still depolarized—triggers a slow, positive deflection in Vm known as an early afterdepolarization (EAD). N21-16 Eventually, IK increases and returns Vm toward the resting potential. Such EADs, if they are larger than the one shown in Figure 21-16A, may trigger an extrasystole. Isolated ventricular extrasystoles (known by many names, including premature ventricular contractions, or PVCs) may occur in normal individuals. Alterations in cellular Ca2+ metabolism (discussed in the next section) may increase the tendency of a prolonged action potential to produce an extrasystole. Ironically, a class of drugs used to treat arrhythmias can become arrhythmogenic by producing EADs. For example, quinidine can produce this dangerous adverse effect, presumably by inhibiting Na+ channels and some K+ channels and thus prolonging the ventricular muscle action potential.
FIGURE 21-16 Abnormal automaticity in ventricular muscle. The records in this figure are idealized. A, The prolonged action potential keeps INa inactivated but permits ICa and IK to interact and thereby produce a spontaneous depolarization—the early afterdepolarization. B, The afterdepolarization reaches threshold, triggering a sequence of several slow pacemaker-like action potentials that generate extrasystoles.
Contributed by W. Jonathan Lederer
Both the early afterdepolarizations (EADs; see p. 505) and the delayed afterdepolarizations (DAD; see p. 506) are the impetus for a form of arrhythmia called triggered activity, which is a spontaneous abnormal beat or series of beats.
The natural automaticity generated by pacemaker cells (e.g., in the SA node) can occur without any preceding action potentials. In contrast, triggered activity requires at least one preceding action potential. Thus, if an afterdepolarization occurs but does not reach threshold, the cell will eventually return to its resting potential and no triggered activity will occur. If, however, an afterdepolarization reaches threshold, it can generate an unusual action potential from which another afterdepolarization may or may not arise. Thus, it is possible to generate a train of spontaneous depolarizations before the cell finally returns to its resting potential. In the case of a single unusual action potential, the electrical activity can generate an extrasystole. In the case of a train of depolarizations, the electrical activity can generate a run of extrasystoles.
The difference between EADs and DADs is that the additional depolarization in an early afterdepolarization occurs during phase 2 or 3. On the other hand, with a delayed afterdepolarization, the additional depolarization takes place during phase 4. The ventricular tachyarrhythmias seen in long QT syndrome (LQTS) are an example of arrhythmias caused by early afterdepolarizations. Some digitalis-induced arrhythmias are examples of arrhythmias caused by delayed afterdepolarizations.
More than one extrasystole—a run of extrasystoles (see Fig. 21-16B)—is pathological. A run of three or more ventricular extrasystoles is the minimal requirement for diagnosis of ventricular tachycardia. This arrhythmia is life-threatening, because it can degenerate into ventricular fibrillation (see Fig. 21-14I), which is associated with no meaningful cardiac output. The heart rate in ventricular tachycardia is much faster than normal, usually between 120 and 150 beats/min (or faster), and the pacemaker driving the heartbeat is located in the ventricle itself. The heart rate in ventricular tachycardia may be so fast that the heart cannot pump blood effectively.
Long QT Syndrome
Patients with long QT syndrome (LQTS) have a prolonged ventricular action potential and are prone to ventricular arrhythmias. In particular, these patients are susceptible to a form of ventricular tachycardia called torsades de pointes, or “twisting of the points,” in which the QRS complexes appear to spiral around the baseline, constantly changing their axes and amplitude. LQTS can be congenital or acquired. The congenital form can involve mutations of cardiac Na+ channels (see pp. 188–189) or K+ channels (see p. 195). The acquired form of LQTS, which is much more common, can result from various electrolyte disturbances (especially hypokalemia and hypocalcemia) or from prescribed or over-the-counter medications (e.g., several antiarrhythmic drugs, tricyclic antidepressants, and some nonsedating antihistamines when they are taken together with certain antibiotics, notably erythromycin).
Ca2+ overload and metabolic changes can also cause arrhythmias
Ca2+ overload in the heart has many potential causes. One frequent factor is digitalis intoxication. Another is injury-related cellular depolarization. Ca2+ overload occurs when [Ca2+]i increases, causing the SR to sequester too much Ca2+. Thus overloaded, the SR begins to cyclically—and spontaneously—dump Ca2+ and then take it back up. The Ca2+ release may be large enough to stimulate a Ca2+-activated nonselective cation channel and the Na-Ca exchanger (see pp. 123–124). N21-2 These current sources combine to produce Iti, a transient inward current that produces a delayed afterdepolarization (DAD). N21-16 When it is large enough, Iti can depolarize the cell beyond threshold and produce a spontaneous action potential.
Metabolism-Dependent Conduction Changes
During ischemia and anoxia, many cellular events take place, including a fall in intracellular ATP levels. This fall in [ATP]i activates the ATP-sensitive K+ channel (KATP), which is plentiful in cardiac myocytes. Thus, when [ATP]i falls sufficiently, KATP is less inhibited and the cells tend to become less excitable (i.e., KATP helps keep Vm close to EK). The activation of this channel may explain, in part, the slowing or blocking of conduction that may occur during ischemia or in the peri-infarction period.
Rarely, patients being resuscitated from cardiac arrest exhibit a phenomenon called electromechanical dissociation in which the heart's ECG activity is not accompanied by the pumping of blood. In many cases, the basis of electromechanical dissociation is not understood. However, in other cases, the cause is obvious. For example, the heart of a patient with a large pericardial effusion may manifest normal electrical activity, but the fluid between the heart and the pericardium may press in on the heart (cardiac tamponade) and prevent effective pumping.