Automaticity

Automaticity refers to the emergence of ectopic pacemaker activity and may result from enhanced normal automaticity or from the development of abnormal automaticity.

Enhanced normal automaticity occurs when cells whose pacemaker potentials are normally under overdrive suppression (e.g., cells from the AV node or His-Purkinje system) fire at rates that escape the overdrive suppression of the SA node. This phenomenon may result from effects on phase 4 pre-potentials favoring earlier development of action potentials (i.e., less maximal polarization, faster depolarization, or lower threshold potential) or from shortening of the action potential duration, with an earlier return to phase 4. Enhanced normal automaticity is usually the result of adrenergic stimulation.

Abnormal automaticity refers to the generation of impulses in cells that normally do not exhibit pacemaker potential. This phenomenon can occur in cells that are partially depolarized as a result of a pathologic process (e.g., ischemia). Under these conditions, the reduction in the resting membrane potential (less negative; to −70 or even −50 mV) shifts the balance during phase 4 toward depolarizing currents.²⁹ Through this mechanism, automaticity can developed in atrial and ventricular muscle cells and in specialized tissues other than the SA in which the firing conditions can be altered. Examples of abnormal automaticity include accelerated idioventricular rhythms and some VTs that develop 24 to 72 hours after an acute myocardial infarction.^30,31

Triggered Activity

Triggered activity refers to arrhythmias that arise from afterdepolarizations. Afterdepolarizations are alterations in membrane potential that occur during the repolarization phase without intervening external triggers or cell-to-cell interactions.³² Afterdepolarizations can develop in different phases of the action potential. Those that develop during phase 2, phase 3, or early phase 4 and are called early afterdepolarizations and are characterized by transient retardations in repolarization with or without upturn of the membrane potential (Figure 79-3). An upturn of sufficient magnitude may trigger an “extra” action potential before the cycle is over. Early afterdepolarizations are typically associated with conditions that prolong the action potential duration, such as decreased inactivation of fast I_Na (e.g., long QT3 syndrome) or decreased outward K⁺ currents (e.g., I_Ks in long QT1 and I_Kr in long QT2 syndromes) prolonging Ca²⁺ entry through I_Ca-L.³³ The development of early afterdepolarizations in this setting is thought to trigger torsades de pointes. Early afterdepolarizations are also associated with increased sympathetic tone, use of catecholamines, hypoxia, acidosis, and bradycardia.

Figure 79-3 Afterdepolarizations (dotted lines). Early afterdepolarizations are retardations in repolarization with prolongation in action potential duration (upper figure). Delayed afterdepolarizations represent spontaneous depolarizations that occur after repolarization is over (lower figure). Afterdepolarizations that reach threshold trigger an action potential.

Afterdepolarizations that occur in late phase 4 are called delayed afterdepolarizations and are characterized by low-amplitude depolarizations that may reach threshold and trigger an action potential (see Figure 79-3). The main underlying abnormality in delayed afterdepolarizations is intracellular Ca²⁺ overload, promoting Ca²⁺ release from the sarcoplasmic reticulum³³ and depolarizing currents (i.e., inward I_Na/Ca currents). Delayed afterdepolarizations are classically associated with digitalis toxicity; however, many other conditions favoring cytosolic Ca²⁺ overload can also produce delayed afterdepolarizations such as myocardial stretch, hypertrophy, catecholamines, ischemia, and reperfusion. In the setting of heart failure, increased expression of Na⁺-Ca²⁺ exchanger along with abnormalities in the ryanodine receptor has been shown to predispose to delayed afterdepolarizations.

Circus Movement

Circus movement is the most widely studied mechanism and encompasses four distinct models: ring, leading circle, figure of eight, and spiral wave.

The ring model is the simplest of all³⁵ and can be used to illustrate the basic mechanism of reentry (Figure 79-4). The ring model requires two anatomically contiguous paths in specialized tissue or in muscle fibers separated by a central area of unexcitable tissue. One of these paths (b in Figure 79-4) must exhibit a zone of unidirectional block allowing the impulse to propagate in only one direction. The alternative path (a in Figure 79-4) allows the impulse to circumvent the unidirectional block. Conduction through this alternative path should be slow or refractoriness proximal to the path should be brief to allow recovery of excitability. Once the impulse reaches the distal end of the alternative path, it propagates in a retrograde manner through the path of unidirectional block to reenter the proximal end of the alternative path. For the cycle to repeat (and establish a reentry circuit causing tachyarrhythmia), the wavelength of the circling impulse must be shorter than or at least equal to the length of the reentry circuit (or path length), thus enabling the leading edge of the circling impulse to find the tissue in an excitable state. The wavelength of the circling impulse is defined as the product of conduction velocity and duration of the refractory period.

Figure 79-4 Ring model of reentry.

Reentry is usually triggered by the arrival of a premature beat that finds the path of unidirectional block in a refractory period. Unidirectional block may result from increased refractoriness associated with either anatomic abnormalities (e.g., fibrosis, accessory pathway, bundle branch) or functional defects (e.g., ischemia, action of drugs). The ring model best applies to tachyarrhythmias that involve AV accessory pathways and the AV node.

The leading circle model is similar to the ring model but does not require anatomic obstacles and can develop in structurally uniform myocardium by a properly timed premature impulse.^36,37 The figure-of-eight model was first described in experimental myocardial infarction. It refers to two reentry circuits moving alongside a functional conduction block (ischemia or infarct) in opposite directions, forming a pretzel-like configuration.³⁸ The spiral wave model is considered a more complex version of the leading circle model. It involves a core and filaments and is usually described as reentry in two dimensions.^39,40 The spiral wave model has been used to explain the electrocardiographic patterns associated with monomorphic and polymorphic VTs and also VF. In monomorphic VTs, the spiral wave is thought to be anchored and unable to drift within the myocardium, whereas in polymorphic VTs, such as torsades de pointes, the spiral is thought to drift. In the case of VF, the spiral wave is believed to break up into multiple rotating spiral waves that are continuously extinguishing and recreating. However, some authors have proposed a single rapidly shifting spiral, and others have postulated a stationary rotor whose frequency of excitation is exceedingly high, resulting in multiple areas of intermittent block.⁴¹

Phase 2

Phase 2 reentry refers to the generation of local reexcitation as a result of increased heterogeneity of repolarization. This phenomenon occurs when repolarization is markedly shortened in certain regions of the myocardium—essentially obliterating phase 2 of the action potential (plateau phase)—but is maintained in others. This creates conditions conducive to local reexcitation, which may precipitate ventricular tachyarrhythmias during myocardial ischemia.⁴² During ischemia, action potentials of normal duration alternate with ones of shorter duration, yielding beat-to-beat alternans (temporal dispersion) and site-to-site alternans (spatial dispersion) and promoting regions with conduction block and regions with injury current, leading to reentry and ventricular tachyarrhythmias. The degree of spatial and temporal dispersion progresses along with the duration of ischemia, suggesting that this mechanism may be an important trigger of VT and VF during acute myocardial ischemia.^43,44 In the surface ECG, dispersion of the action potential duration manifests as T-wave alternans, which is a predictor of VF.⁴⁵

Reflection

Reflection refers to a back-and-forth propagation of the impulse over the same functionally unexcitable tissue, with recurrent activation of the proximal region as a result of electrotonic currents.^46,47 The area of unexcitable tissue could result from ischemia and lead to extrasystolic activity. Reflection differs from classic reentry in that the impulse travels along the same pathway in both directions.

Long QT Syndrome

The vast majority of hereditary channelopathies result from mutations in genes that encode for Na⁺ and K⁺ channels, with the most representative being the long QT syndrome.^50–52 The long QT syndrome was first described in 1957 by Jervell and Lange-Nielsen in a group of patients with long QT intervals, episodes of torsades de pointes, and deafness.⁵³ This syndrome is transmitted by autosomal recessive inheritance and is known as the Jervell and Lange-Nielsen syndrome. In 1963 and 1964, Romano and colleagues⁵⁴ and Ward⁵⁵ independently reported patients with an almost identical disorder but without deafness. This syndrome is transmitted by autosomal dominant inheritance and is known as the Romano-Ward syndrome.

It is now recognized that long QT syndrome results from mutations in at least 12 genes, leading to distinct types designated long QT1 through long QT12 (Table 79-1). Long QT1 is the principal genetic type responsible for both Jervell and Lange-Nielsen and Romano-Ward syndromes and accounts for nearly 50% of all genotyped families. Long QT2 accounts for nearly 40% and long QT3 for about 5%. The remaining types are much less frequent.⁵⁶

Long QT1, QT2, QT5, QT6, QT7, and QT11 result from mutations in the genes KCNQ1, HERG, KCNE1, KCNE2, KCNJ2, and AKAP9, respectively, which encode various components of K⁺ channels, leading to loss-of-function mutations and consequent decrease in the main repolarizing K⁺ current, I_k, and thus prolongation of the QT interval.

Long QT3 stems from a mutation in SCN5A, the gene that encodes the α-subunit of the fast cardiac Na⁺ channel. SCN5A mutation causes a gain of function leading to incomplete channel inactivation and persistence of I_Na during the plateau phase of the action potential.^57,58

Long QT4 has been linked to a loss-of-function mutation in the ANKB gene.⁵⁹ This gene encodes ankyrin-B, which is a member of a family of versatile membrane adapters. Ankyrin-B, among other functions, coordinates the opening and closing of calcium, potassium, sodium, and chloride channels. The failure to properly coordinate the opening and closing of ion channels leading to long QT syndrome and arrhythmias illustrates a novel mechanism of arrhythmias.

Long QT8 stems from a mutation on the gene CACNA1C, which encodes the α_1c-subunit of I_Ca-L. The mutation causes a gain of function that leads to increased Ca⁺ influx into cardiac cells. Long QT8 presents with an exaggerated QT interval prolongation and is associated with neurocognitive impairment, congenital structural heart disease, developmental abnormalities, and immunodeficiencies.

In long QT9, QT10, and QT12, the mutations affect the genes CAV3, SCN4β, and SNTA1, leading to a gain of function in I_Na, resulting in increased Na⁺ influx within the cardiac cell.^60,61

Accordingly, the common mechanistic thread among long QT syndromes is perturbation of the balance between I_Na and I_K during the plateau phase of the action potential, yielding prolongation of repolarization, a reduced rate of I_Ca-L inactivation, late Ca²⁺ influx, and early afterdepolarizations predisposing to torsades de pointes.⁶²

The diagnosis is suspected in young individuals who present with syncope or episodes of sudden death typically during exercise, emotional distress, or exposure to factors that cause prolongation of the QT interval. A family history of unexplained syncope or sudden cardiac death, especially in young kindred, should raise suspicion. Sudden cardiac death occurs in approximately 4% of affected individuals. The diagnosis should be suspected when the corrected QT interval () exceeds 470 milliseconds in males (normal <422 milliseconds) and 480 milliseconds in females (normal <432 milliseconds) in the absence of other conditions that may lengthen the QT interval. In addition, there may be sinus bradycardia with sinus pauses in about one-third of individuals (especially in long QT3), QT dispersion, and various T-wave abnormalities (e.g., notched, bifid, biphasic). Factors predisposing to sudden cardiac death include recurrent syncope, survival from cardiac arrest, congenital deafness, female sex, relative bradycardia, corrected QT interval greater than 600 milliseconds, and kinship with a symptomatic patient.⁵⁰ Genetic testing for identifying the various long QT subtypes is becoming readily available, with its impact on risk stratification and guidance for placement of an implantable cardioverter-defibrillator (ICD) to be determined by future research.^56,60

In addition to long QT syndromes, recent population studies⁶³ have shown that even milder prolongation of the QTc in adults (>450 milliseconds in men and > 470 milliseconds in women) increases the risk of sudden cardiac death by threefold after adjustment for age, gender, body mass index, hypertension, cholesterol/high-density lipoprotein ratio, diabetes mellitus, myocardial infarction, heart failure, and heart rate. In the same population, QTc prolongation was strongly associated with variant rs10494366 T>G and rs10918594 C>G of the nitric oxide synthase 1 adaptor protein (NOS1AP) gene.⁶⁴ More recent studies show that use of the calcium channel blocker, verapamil, in patients with these variants prompts a greater QTc prolongation than in patients with the wild genotype.⁶⁵

Accordingly, this is an evolving concept showing the importance prolongation in repolarization has in the genesis of arrhythmias, not only in individuals with defined genetic abnormalities but also in individuals who appear to be phenotypically normal.

Short QT Syndrome

Short QT is a more recently described syndrome⁶⁶ characterized by tall and peaked T waves with QT interval ≤ 300 milliseconds, insensitive to changes in heart rate, and a structurally normal heart. Individuals are at risk of developing VF and also atrial fibrillation and may complain of palpitations and episodes of syncope. They may also have family members with a similar history or a history of unexplained or sudden death at a young age.

The underlying mechanism is increased outward potassium currents during phase 2 and phase 3 of the action potential, shortening its plateau phase. Mutations in the KCNH2, KCNJ2, and KCNQ1 gene products with an autosomal dominant pattern of inheritance have been associated with the short QT syndrome. A few affected families have been identified.

Current treatment is implantation of an ICD. A recent study suggests that quinidine could be beneficial by prolonging the action potential duration through action on I_K channels, which may benefit patients with ICDs and reduce the number of arrhythmic events, or become a useful treatment in affected individuals who are at risk of sudden cardiac death from birth.

Brugada Syndrome

Another important hereditary channelopathy is Brugada syndrome, described in 1992 by the Brugada brothers,^67–70 who noticed an association between sudden cardiac death and ST-segment elevation in V₁ to V₃, with a pattern resembling right bundle branch block in individuals with structurally normal hearts.

Brugada syndrome results in part from mutations in the SCN5A gene (encoding for the I_Na α-subunit). In contrast to long QT3—which also affects the SCN5A gene—the mutations in Brugada syndrome lead to a loss of function resulting in accelerated inactivation of I_Na during phase 1, leaving the repolarizing I_To current unopposed and consequently prompting rapid repolarization and shortening of the action potential duration (refer to Figure 79-2 for the I_Na and I_To contributions to the action potential). Because I_To is expressed predominantly in the epicardium, the normally depolarized endocardium can re-excite the prematurely repolarized epicardium, leading to phase 2 reentry and generation of a phase 2 reentrant premature beat that could capture a vulnerable window and precipitate VT (which is typically polymorphic) and/or VF.

Brugada syndrome exhibits predominantly an autosomal dominant pattern of inheritance, with an average worldwide prevalence of 5 : 10,000. More than 100 mutations in seven genes have been identified. Loss-of-function mutations in the SCN5A gene cause approximately 20% of cases. A few mutations have been described in the GPD1L gene, which encodes the glycerol-3-phosphate dehydrogenase-1 like protein; the CACNA1C gene, which encodes the α-subunit of the Ca(v)1.2 ion channel conducting the inward current (I_Ca-L); the CACNB2 gene, which encodes the β₂-subunit of the Ca(v)1.2 ion channel; the SCN1B and SCN3B genes, which in the heart encode the β-subunits of the Na(v)1.5 sodium ion channel; and the KCNE3 gene, which encodes the ancillary inhibitory β-subunit of several potassium channels including the Kv4.3 ion channel conducting the repolarizing potassium current I_Tos.⁷¹

The ST-segment elevation can adopt various shapes that have been related to the severity of the I_Na/I_To imbalance, including—in order of increasing severity—saddleback, coved, and triangular shapes.⁶² These changes are dynamic and can change in the same affected individual as shown in Figure 79-5.

Figure 79-5 Representative tracings in a patient with Brugada syndrome, demonstrating dynamic changes in V₁ to V₂ after resuscitation from cardiac arrest. Type 1 refers to the coved-type ST-T configuration, whereas type 2 and type 3 refer to the saddleback ST-T configuration.

(From Wilde AA, Antzelevitch C, Borggrefe M, Brugada J, Brugada R, Corrado D et al. Study Group on the Molecular Basis of Arrhythmias of the European Society of Cardiology. Proposed diagnostic criteria for the Brugada syndrome: consensus report. Circulation 2002;106:2514-9.)

Brugada syndrome is the major but not the only cause of sudden unexpected death syndrome (SUDS)^72,73 and is the most common cause of sudden death in young men without known underlying cardiac disease in Thailand and Laos.⁷⁴ However, Brugada syndrome exhibits variable expressivity, reduced penetrance, and “mixed phenotypes” where families may contain members with Brugada syndrome as well as members with short QT syndrome, long QT syndrome, atrial fibrillation, disease of the conduction system, and even structural heart disease.⁷¹

Patient with Brugada syndrome may have concealed or intermittent forms that can be unmasked (or precipitated) by febrile states, vagotonic agents, α-adrenergic agonists, β-adrenergic blockers, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin and hypokalemia, and alcohol and cocaine toxicity.⁷⁵

A useful clinical test to identify concealed Brugada syndrome is the administration of class IC antiarrhythmic drugs: Na⁺