Specialized conducting cells in the heart are found in the sinoatrial (SA) node, atrioventricular (AV) node, and the His-Purkinje system and exhibit automaticity to self-generate spontaneous, rhythmic action potentials. A cardinal attribute of these pacemaking cells is the spontaneous diastolic depolarization during phase 4 that follows an action potential, originally attributed to the “funny” current (I_f) identified in the late 1970s.¹ This current is now known to be mediated by sarcolemmal potassium (K⁺)/sodium (Na⁺) hyperpolarization-activated cyclic nucleotide-gated channels (HCN4 in the heart), distinct among voltage-sensitive ion channels in their activation upon hyperpolarization rather than depolarization (Figure 50.1).²,³ Permeable to both Na⁺ and K⁺ ions, I_f is an inward current that depolarizes the diastolic resting potential. Assisted by a host of other sarcolemmal ion channels constituting the membrane clock, I_f brings the cell to the threshold for voltage-gated L-type calcium Ca²⁺ channels to generate the action potential upstroke. In the early 2000s, improved confocal microscopic imaging demonstrated that the membrane clock is integrally coupled to a Ca²⁺ clock that plays an essential shared role in automaticity.⁴ The Ca²⁺ clock, driven by progressive Ca²⁺ release from the sarcoplasmic reticulum (SR) into the cytoplasm during diastole, activates inward current via electrogenic Na⁺-Ca²⁺ exchange (ie, three Na⁺ in, one Ca²⁺ out) to assist in depolarizing diastolic membrane potential sufficiently to activate voltage-gated L-type Ca²⁺ channels and generate the upstroke of the action potential.⁵ Overall, the heart rate is regulated by phosphorylation of key proteins in both clocks in response to changes in autonomic tone and other factors.

In tissues with pacemaking ability, the SA node normally has the fastest intrinsic rate and serves as the primary pacemaker. Impairment of SA nodal function results in latent or subsidiary pacemakers in atria or ventricles taking over, albeit at slower rates, with atrial and AV junctional subsidiary pacemakers also responsive to autonomic tone. Normally, quiescent cardiac tissue can also develop automaticity or triggered activity under pathophysiologic conditions or due to a host of genetic abnormalities, as discussed in a later chapter.

The SA node is densely innervated and under neural control that regulates the heart rate. The enhanced automaticity mediates physiologic responses to stress such as exercise, anxiety, or hypovolemia. Autonomic modulation of heart rate occurs through affecting both the Ca²⁺ and membrane clocks (Figure 50.1). The sympathetic nervous system provides adrenergic input to increase the heart rate through multiple ionic currents, including I_f, to increase the rate of diastolic depolarization and shorten diastole.⁴ For example, β-adrenergic stimulation increases intracellular cyclic adenosine monophosphate (cAMP), which then directly binds HCN4 channels to augment I_f.⁶ The Ca²⁺ clock is also modulated by phosphorylation of Ca²⁺ cycling proteins (eg, phospholamban, L-type Ca²⁺ channels, and ryanodine receptors) that regulate [Ca²⁺]_i balance and spontaneous SR Ca²⁺ cycling.⁷ The resultant changes in rate may be accompanied by shifts in the dominant pacemaking site within the SA node or to a subsidiary pacemaker site. Enhanced automaticity in other foci may cause ectopic beats or rhythms to emerge. For example, insults to the AV node such as acute myocardial infarction, digitalis toxicity, isoproterenol, or cardiac surgery may result in enhanced automaticity. In such instances, the firing rate of the AV junction may supersede that of the SA node and result in an accelerated junctional rhythm.

Conversely, the parasympathetic nervous system activates muscarinic K⁺ channels and decreases I_f to decrease the rate of diastolic depolarization and reduce heart rate. Acetylcholine (ACh) binds muscarinic receptors to inhibit adenylate cyclase and reduce cAMP levels at low-moderate vagal stimulation.⁴ Decreased automaticity of the SA node may further result in escape rhythms to become the dominant rhythm. In short, in each SA nodal pacemaking cycle, the membrane and calcium clocks are continuously coupled and are modulated by the autonomic nervous system to maintain spontaneous, rhythmic action potentials across a wide physiologic range.

Abnormal automaticity may also develop in normally non-pacemaking cells. A high resting K⁺ conductance together with a high intracellular-to-extracellular ratio of K⁺ maintained by Na⁺-K⁺ adenosine triphosphatase (ATPase) generate a negative resting membrane potential that approaches the K⁺ equilibrium potential (˜-95 mV by the Nernst equation), rendering working atrial and ventricular cardiomyocytes quiescent during diastole. However, multiple different mechanisms can cause abnormal automaticity in such normally quiescent cells, such as membrane depolarization.⁸ Some factors, such as hypokalemia, can also induce automaticity in association with membrane hyperpolarization. At normally polarized resting
membrane potentials, Na⁺ channels are activated and contribute to a rapid upstroke. At depolarized resting membrane potentials, Ca²⁺ currents mediate a slow upstroke.

Automaticity of most pacemakers, including the sinus node, is inhibited by overdrive suppression and remains latent unless their intrinsic rate exceeds that of the sinus node.⁹ Overdrive suppression of automaticity can result from the faster pacing rate, causing intracellular Na⁺ accumulation that increases outward current via electrogenic Na⁺-K⁺ ATPase activity. The resulting hyperpolarizing current opposes phase 4 depolarization to slow spontaneous diastolic depolarization. Even after overdrive pacing terminates, continued Na⁺-K⁺ ATPase activity suppresses the rate of diastolic depolarization and heart rate until the elevated intracellular Na⁺ levels normalize. The faster the rate or longer the duration of overdrive suppression, the greater the intracellular Na⁺ accumulation and duration of increased Na⁺-K⁺ ATPase activity, resulting in a longer period of quiescence after cessation of stimulation.

Latent pacemakers are typically suppressed because of resetting by the faster dominant pacemaker, whereas a latent pacemaker site can also exhibit entrance block that insulates it either fully or partially from being reset by the dominant pacemaker. The result is a parasystole or modulated parasystole, an ectopic rhythm that marches independently or quasi-independently through the dominant rhythm. This situation can arise when the dominant pacemaker is surrounded by ischemic, infarcted, or otherwise electrically compromised tissues that inhibit resetting of the latent pacemaker. This activity is typically characterized by premature ventricular contractions that march through the sinus rate and rarely result in a life-threatening ventricular arrhythmia.

Afterdepolarizations are abnormal impulses that are classified as early afterdepolarization (EAD) or delayed afterdepolarization (DAD) depending on whether they arise during or following an action potential, respectively. Unlike automaticity, they require an antecedent action potential, whether spontaneous, triggered, or artificially paced. If an EAD or DAD depolarizes the membrane potential to threshold, an action potential results, and is referred to as triggered activity (Figure 50.2). In cardiac tissue, such triggered beats can propagate from regions with EADs into regions without EADs, generating tachycardias and initiating reentry when dispersion of refractoriness is sufficient.¹⁰ Unfortunately, EADs and DADs cannot be directly detected clinically from an electrocardiogram.

EADs occur during phase 2 or phase 3 of the cardiac action potential before repolarization is complete. They typically occur in the setting of a prolonged action potential such as in long QT syndromes. Multiple conditions may result in QT prolongation including myocardial injury, electrolyte disturbances (hypokalemia, hypomagnesemia), acidosis, hypoxia, catecholamines, QT prolonging drugs (antiarrhythmic and noncardiac drugs), left ventricular hypertrophy, heart failure, and congenital ion channels defects. Clinically, EADs can cause polymorphic ventricular tachycardias and torsades de pointes when QT prolongation concomitantly increases dispersion of refractoriness and makes tissue vulnerable to reentry.

Action potential duration (APD) prolongation occurs when net outward current during the action potential plateau is reduced so that repolarization reserve becomes impaired. The imbalance can be caused by uncompensated increases in inward currents such as the late sodium (I_Na) or Ca²⁺ currents (I_Ca or I_NCX) or decreases in outward repolarizing potassium currents (I_Kr, I_KS, I_K1). If sufficiently severe, reactivation of the L-type Ca²⁺ channels during phase 2 or 3 can reverse repolarization altogether and cause the upstroke of EAD¹¹ to trigger a new action potential that propagates into surrounding tissue that has already repolarized.