Lilly Chapter 11: Mechanisms of Cardiac Arrhythmias

B. Unidirectional Block and Reentry REENTRY: electrical impulse circulates repeatedly around a reentry path, recurrently depolarizing a region of cardiac tissue. If normal, originate at SA node, in sequential fashion through rest of heart, ultimately depolarizing all of them. If a branch exists, current splits equally and ends up cancelling out its counterpart on other side of split. REFRACTORY PERIODS prevents immediate reexcitation from adjacent depolarized cells, so that impulse stops when all the heart tissue has been excited. In CONDUCTION BLOCKS: prevent rapid depolarization of parts of myocardium- can create environment conducive to CONTINUED IMPULSE PROPAGATION and reentry. In a unidirectional block: one side of the branch is blocked, so when the first impulse spreads, it can spread backward to the other side of the block. While the second branch is just stopped. The first impulse can keep going in circles, re-entering areas it has already stimulated (especially if it is slower than normal, and it arrives at old tissue when it has already repolarized.) FIG 11-9 circulation can continue indefinitely, and each pass through the loop excites distal conduction tissue, propagating through the myocardium at an abnormally high rate- tachyarrhythmia normal conduction velocity in ventricular muscle is approximately 50 cm/s and the average effective refractory period is about 0.2 seconds, a reentry path circuit would need to be at least 10 cm long for reentry to occur in a normal ventricle. If it is slower, than a shorter reentry circuit is possible. WHEN DOES REENTRY HAPPEN: 1. unidirectional block 2. slowed conduction through re-entry path ie. scarring/infarction fibrosis. over an anatomically fixed circuit or path, such as AV reentry using accessory pathway (following section) ECG: 1.Reentry around FIXED DISTINCT anatomic pathways usually appears as MONOMORPHIC TACHYCARDIA. i.e. in Ventricular Tachycardia, each QRS has same appearance as preceding and subsequent QRS complexes.... because reentry path is same from beat to beat, producing a STABLE, REGULAR tachycardia. Common pattern with prior MI (ventricular scar) 2.OTHER TYPES of reentry do not require a stable, fixed path.....ie could be an electrically heterogenous myocardium, in which waves of reentrant excitation spiral through the tissue, continually changing direction. "spiral waves" initiated when wave front encounters a BROAD REGION of block, could be refractory from previous wave, poorly excitable due to mmi, or under influence of arntiarrythmatic drug. ----Asymmetrically blocks forward propagation!!! as the remainder of the front moves around the block. As the region repolarizes, parts of the wave spread retrograde through it and continue in a spiral path following in the wake of the depolarization that has just passed. UNLIKE IN AN ANATOMICALLY FIXED REENTRANT TRACT, center of the spiral wave moves through myocardium, even split into two or more reentry waves..... ECG: if this happens in ventricles, resulting tachycardia has a CONTINUALLY CHANGING QRS, producing POLYMORPHIC VENTRICULAR TACHYCARDIA. If it is rapid and disorganized, no distinct QRS will be discernable- this is called VENTRICULAR FIBRILLATION HOW IS THIS DIFFERENT FROM FIGURE D above?

A common mechanism by which altered impulse conduction leads to tachyarrhythmias is termed reentry. During such a rhythm, an electric impulse circulates repeatedly around a reentry path, recurrently depolarizing a region of cardiac tissue. During normal cardiac conduction, each electric impulse that originates in the SA node travels in an orderly, sequential fashion through the rest of the heart, ultimately depolarizing all the myocardial fibers. The refractory period of each cell prevents immediate reexcitation from adjacent depolarized cells, so that the impulse stops when all of the heart muscle has been excited. However, conduction blocks that prevent rapid depolarization of parts of the myocardium can create an environment conducive to continued impulse propagation and reentry, as illustrated in Figure 11-9. The figure depicts electric activity as it flows through a branch point anywhere within the conduction pathways. Panel A shows propagation of a normal action potential. At point x, the impulse branches into two pathways (α and β) and travels down each into the more distal conduction tissue. In the normal heart, the α and β pathways have similar conduction velocities and refractory periods such that portions of the wave fronts that pass through them may collide in the distal conduction tissue and extinguish each other, as shown by the red line. Panel B shows what happens if conduction is blocked in one limb of the pathways. In this example, the action potential is obstructed when it encounters the β pathway from above and therefore propagates only down the α tract into the distal tissue. As the impulse continues to spread, it encounters the distal end of the β pathway (at point y). If the tissue in the distal β tract is also unable to conduct, the impulse simply continues to propagate into the deeper tissues and reentry does not occur. However, if the impulse at point y is able to propagate retrogradely (backward) into pathway β, one of the necessary conditions for reentry is met. When an action potential can conduct in a retrograde direction in a conduction pathway, whereas it had been prevented from doing so in the forward direction, unidirectional block is said to be present. Unidirectional block tends to occur in regions where the refractory periods of adjacent cells are heterogeneous, such that some cells recover before others. In addition, unidirectional block may occur in states of cellular dysfunction and in regions where fibrosis has altered the myocardial structure. As shown in panel C of Figure 11-9, if the impulse is able to propagate retrogradely up the β pathway, it will again arrive at point x. At that time, if the α pathway has not yet repolarized from the previous action potential that had occurred moments earlier, that limb is refractory to repeat stimulation and the returning impulse simply stops there. However, panel D illustrates what happens if the velocity of retrograde conduction in the diseased β path is not normal but slower than normal. In that case, sufficient time may elapse for the α pathway to repolarize before the returning impulse reaches point x from the β limb. Then, the invading impulse is able to stimulate the α pathway once again, and the cycle repeats itself. This circular stimulation can continue indefinitely, and each pass of the impulse through the loop excites cells of the distal conduction tissue, which propagates to the rest of the myocardium, at an abnormally high rate, resulting in a tachyarrhythmia. For the mechanism of reentry to occur, the propagating impulse must continuously encounter excitable tissue. Thus, the time it takes for the impulse to travel around the reentrant loop must be greater than the time required for recovery (the refractory period) of the tissue, and this must be true for each point in the circuit. If the conduction time is shorter than the recovery time, the impulse will encounter refractory tissue and stop. Because normal conduction velocity in ventricular muscle is approximately 50 cm/s and the average effective refractory period is about 0.2 seconds, a reentry path circuit would need to be at least 10 cm long for reentry to occur in a normal ventricle. However, with slower conduction velocities, a shorter reentry circuit is possible. Most clinical cases of reentry occur within small regions of tissue because the conduction velocity within the reentrant loop is, in fact, abnormally slow. In summary, the two critical conditions for reentry are (1) unidirectional block and (2) slowed conduction through the reentry path. These conditions commonly occur in regions where fibrosis has developed, such as infarction scars. In some cases, reentry occurs over an anatomically fixed circuit or path, such as AV reentry using an accessory pathway (as discussed in the following section). Reentry around distinct anatomic pathways usually appears as a monomorphic tachycardia on the electrocardiogram (ECG); that is, in the case of ventricular tachycardia, each QRS has the same appearance as the preceding and subsequent QRS complexes. This is because the reentry path is the same from beat to beat, producing a stable, regular tachycardia. This is the most common mechanism of ventricular tachycardia associated with areas of ventricular scar, as may result from a prior myocardial infarction. Other types of reentry do not require a stable, fixed path. For example, one form can occur in electrically heterogeneous myocardium, in which waves of reentrant excitation spiral through the tissue, continually changing direction. These so-called "spiral waves" can be initiated when a wave front of depolarization encounters a broad region of functional block, which could be refractory from a preceding wave front, be poorly excitable tissue due to myocardial ischemia, or be under the influence of certain antiarrhythmic medications. Forward propagation of the wave front is asymmetrically blocked by this region, as the remainder of the front proceeds around the block. As the region repolarizes and becomes excitable again, parts of the wave front then spread retrogradely through it and continue in a spiral path following in the wake of the depolarization that had just passed. Unlike an anatomically fixed reentrant tract, the center of the spiral wave can move through the myocardium and even split into two or more reentry waves. In the ventricles, the resulting tachycardia has a continually changing QRS appearance, producing polymorphic ventricular tachycardia. If such activation is rapid and very disorganized, no distinct QRS complexes will be discernable and the rhythm is ventricular fibrillation (as described in Chapter 12).

A. Conduction Block Blocked because the impulse encounters un-excitable tissue. Transient or permanent, and unidirectional or in both directions. "functional" block means that the block is due to encountering cardiac cells that are still refractory from a previous depolarization.ie with certain antiarrhythmics that prolong AP duration. "fixed" when due to fibrosis/scarring AV block: Block within AV node or His-Purkinje system -removes normal overdrive suppression that keeps latent pacemakers of the His-Purkinje system in check, so escape beats or rhythms are common as the more distal sites assume pacemaker function. can implant a permanent pacemaker to help.

A propagating impulse is blocked when it encounters a region of the heart that is electrically unexcitable. Conduction block can be either transient or permanent and may be unidirectional (i.e., conduction proceeds when the involved region is stimulated from one direction but not when stimulated from the opposite direction) or bidirectional (conduction is blocked in both directions). Various conditions may cause conduction block, including ischemia, fibrosis, inflammation, and certain drugs. When conduction block occurs because a propagating impulse encounters cardiac cells that are still refractory from a previous depolarization, the block is said to be functional. A propagating impulse that arrives a short time later, when the tissue is no longer refractory, may be conducted appropriately. For example, antiarrhythmic drugs that prolong the action potential duration (described in Chapter 17) tend to produce functional conduction blocks. Conversely, when conduction block is caused by a barrier imposed by fibrosis or scarring that replaces myocytes, the block is said to be fixed. Conduction block within the specialized conducting system of the AV node or the His-Purkinje system prevents normal propagation of the cardiac impulse from the sinus node to more distal sites. This atrioventricular block (AV block) removes the normal overdrive suppression that keeps latent pacemakers in the His-Purkinje system in check. Thus, conduction block usually results in emergence of escape beats or escape rhythms, as the more distal sites assume the pacemaker function. AV block is common and a major reason for implantation of a permanent pacemaker, as discussed in Chapter 12.

III. Altered Impulse Formation Main abnormalities: (1) altered automaticity (of the sinus node or latent pacemakers within the specialized conduction pathway), (2) abnormal automaticity in atrial or ventricular myocytes, and (3) triggered activity.

Arrhythmias may arise from altered impulse formation at the SA node or from other sites, including the specialized conduction pathways or regions of cardiac muscle. The main abnormalities of impulse initiation that lead to arrhythmias are (1) altered automaticity (of the sinus node or latent pacemakers within the specialized conduction pathway), (2) abnormal automaticity in atrial or ventricular myocytes, and (3) triggered activity.

1. Early afterdepolarizations /most liKELY DUE TO PROLONGED QT INTERVALS (AP): drugs or congenital long QT syndromes. Depolarizations that INTERRUPT NORMAL REPOLARIZATION During Phase 2 (plateau) or phase 3 (rapid repol) 2(in which case the depolarization relies on Ca inward current, while most fast Na channels are still inactivated) or 3 (in which case it relies on Na inward current as well, as membrane voltage is more negative, and partial recovery of these fast Na channels). EARLY AFTERDEPOLARIZATIONS CAUSE polymorphic ventricular tachycardia known as torsades de pointes

Early afterdepolarizations are changes of the membrane potential in the positive direction that interrupt normal repolarization (see Fig. 11-7). They can occur either during the plateau of the action potential (phase 2) or during rapid repolarization (phase 3). Early afterdepolarizations are more likely to develop in conditions that prolong the action potential duration (and therefore the electrocardiographic QT interval), as may occur during therapy with certain drugs (see Chapter 17) and in the inherited long QT syndromes (see Chapter 12). The ionic current responsible for an early afterdepolarization depends on the membrane voltage at which the triggered event occurs. If the early afterdepolarization occurs during phase 2 of the action potential, when most of the Na+ channels are still in an inactivated state, the upstroke of the triggered beat relies mostly on an inward Ca++ current. If, however, the afterdepolarization occurs during phase 3 (when the membrane voltage is more negative), there is partial recovery of the inactivated Na+ channels, which then contribute more to the current underlying the triggered beat. An early afterdepolarization-triggered action potential can be self-perpetuating and lead to a series of depolarizations and therefore a tachyarrhythmia (see Fig. 11-7). Early afterdepolarizations appear to be the initiating mechanism of the polymorphic ventricular tachycardia known as torsades de pointes, which is described in Chapter 12.

4. Implantable Cardioverter-Defibrillators AUTOMATICALLY terminate ventricular arrhythmias via a special artificial pacing. Implanted like a permanent pacemakers. For those at risk of sudden cardiac death from ventricular arrhythmias Continuously monitors cardiac activity. Exceeds a certain programmable threshold, ICD delivers intervention shock. cardioversion/defibrillation from an INTERNAL electrode requires much less force. but is still PAINFUL. ATP: antitachyardia pacing- rapid burst of MULTIPLE electric impulses, effective for most monomorphic ventricular tachycardias... artificially pace the heart rate faster than tachycardia to prematurely depolarize areas of REENTRANT CIRCUITS,putting them in refractory period to prevent further propagation. NOT EFFECTIVE FOR V FIB....... so ICD gives full electric shock for VFIB.

ICDs automatically terminate dangerous ventricular arrhythmias using internal cardioversion/defibrillation or by way of a special type of artificial pacing. These devices are implanted, in a manner similar to that of permanent pacemakers, in patients at high risk of sudden cardiac death from ventricular arrhythmias. The device continuously monitors cardiac activity, and if the heart rate exceeds a certain programmable threshold for a specified time, the ICD delivers an appropriate intervention, such as an electric shock. Internal cardioversion or defibrillation requires substantially less energy than does external defibrillation but is still painful if the patient is conscious. The majority of monomorphic ventricular tachycardias can be terminated by an ICD with a rapid burst of electric impulses, termed antitachycardia pacing (ATP), rather than a shock. The goal is to artificially pace the heart at a rate faster than the tachycardia to prematurely depolarize a portion of a reentrant circuit, thereby rendering it refractory to further immediate stimulation. Consequently, when a reentrant impulse returns to the zone that has already been depolarized by the device, it encounters unexcitable tissue, it cannot propagate further, and the circuit is broken. An advantage of the ATP technique is that, unlike internal cardioversion, it is painless. However, ATP is not effective for terminating ventricular fibrillation, a situation in which the device is programmed to deliver an electric shock instead.

5. Catheter Ablation distinct anatomical reentry circuit or automatic focus. map it and ablate via catheter with radio frequency current--heat and destroy tissue. permanent therapy. reducing frequency of ICD shocks due to ventricular tachycardias.

If an arrhythmia originates from a distinct anatomical reentry circuit or an automatic focus, electrophysiologic mapping techniques can be used to localize the region of myocardium or conduction tissue responsible for the disturbance. It is then often possible to ablate the site via a catheter that applies radiofrequency current to heat and destroy the tissue. Such procedures have revolutionized the management of patients with many types of tachycardias, because they often offer a permanent therapeutic solution that spares patients from prolonged antiarrhythmic drug therapy. Additionally, for patients with ICDs and recurrent ventricular tachycardias causing defibrillator shocks, ablation is often effective in reducing the frequency of episodes.

D. Electronic Interactions (adjacent cells electrically couple, depolarizing (seeding up) the more negative RMP, and Hyperpolarizing slowing down), the more positive RMP) ANATOMIC CONNECTIONS between pacemaker and non pacemaker cells are ALSO important in determining how adjacent cells SUPPRESS latent pacemaker foci. Ventricular cells, Purkinje system pacemaker cells repolarize to -90mV AV/SAnodes re polarize to -60mV. If these two cells are next to each other, the purkinje cell will HYPERPOLARIZE the AV/SA Node cell slightly (making slower) And the SA/AV Node cell will DEPOLARIZE the Purkinje cell slightly (making faster) Important in suppression of AV node by atrial cells. and suppression of distal Purkinje fibers by ventricular cells. SA node is less electrically coupled to any cells, with looser connections. Loss of suppression i.e. at AV node from ischemia, reduces inhibitory influence, enhance automaticity, producing ectopic rhythms.

In addition to overdrive suppression, anatomic connections between pacemaker and nonpacemaker cells are important in determining how adjacent cells suppress latent pacemaker foci. Myocardial cells in the ventricle and Purkinje system repolarize to a resting potential of approximately −90 mV, whereas pacemaker cells in the sinus and AV nodes repolarize to a maximum diastolic potential of about −60 mV. When these two cell types are adjacent to one another, they are electrically coupled through low-resistance gap junctions concentrated in their intercalated discs. This coupling results in a compromise of electric potentials owing to electrotonic current flow between the cells, causing relative hyperpolarization of the pacemaker cell and relative depolarization of the nonpacemaker cell (Fig. 11-5). Hyperpolarization moves the diastolic potential further from threshold and thus slows the heart rate (as shown in Fig. 11-3A). Electrotonic effects may be particularly important in suppressing automaticity in the AV node (via connections between atrial myocytes and AV nodal cells) and in the distal Purkinje fibers (which are coupled to ventricular myocardial cells). In contrast, cells in the center of the SA node are less tightly coupled to atrial myocytes; thus, their automaticity is less subject to electrotonic interactions. Decoupling of normally suppressed cells, such as those in the AV node (e.g., by ischemic damage), may reduce the inhibitory electrotonic influence and enhance automaticity, producing ectopic rhythms by the latent pacemaker tissue.

A. Bradyarrhythmias acute: drugs chronic: electronic pacemaker

Not all slow heart rhythms require specific treatment. For those that do, pharmacologic therapy can increase the heart rate acutely, but the effect is transient. Electronic pacemakers are used when more sustained therapy is needed.

C. Overdrive Suppression The fastest intrinsic rhythm cell population preempts other automatic cells from spontaneous firing, and also suppresses their automaticity. 3Na(OUT)/2K(IN) ATPase is responsible for transsarcrolemmal ion distributions. Thus, it creates a net HYPERPOLARIZING CURRENT (outside positive relative to negative inside, we say the cell potential is negative) AS cell is MORE HYPERPOLARIZED (i.e. cell potential is more negative), it takes longer for spontaneous phase 4 depolarization to reach threshold. !!!depolarizing If is always sufficiently large to overcome the hyper polarization current's making the cell potential more negative in pacemakers. OVERDRIVE SUPPRESSION: HYPER POLARIZING CURRENT is INCREASED though when a cell fires more frequently than its intrinsic pacemaker rate. More often firing, more Na+ enters cell, Na/K ATPase more active, more dramatic restoration membrane ----becomes even larger hyper polarizing current. !!!!!!!

Not only does the cell population with the fastest intrinsic rhythm preempt all other automatic cells from spontaneously firing but it also directly suppresses their automaticity. This phenomenon is called overdrive suppression. Cells maintain their transsarcolemmal ion distributions because of the continuously active Na+K+-ATPase that extrudes three Na+ ions from the cell in exchange for two K+ ions transported in (Fig. 11-4). Because its net transport effect is one positive charge in the outward direction, Na+K+-ATPase creates a hyperpolarizing current (i.e., it tends to make the inside of the cell more negative). As the cell potential becomes increasingly negative, additional time is required for spontaneous phase 4 depolarization to reach the threshold voltage (see Fig. 11-3A), and therefore, the rate of spontaneous firing is decreased. Although the hyperpolarizing current moves the membrane voltage away from threshold, pacemaker cells firing at their own intrinsic rate have an If current sufficiently large to overcome this hyperpolarizing influence (see Fig. 11-4). The hyperpolarizing current increases when a cell is caused to fire more frequently than its intrinsic pacemaker rate. The more often the cell is depolarized, the greater the quantity of Na+ ions that enter the cell per unit time. As a result of the increased intracellular Na+ content, Na+K+-ATPase becomes more active, thereby tending to restore the normal transmembrane Na+ gradient. This increased pump activity provides a larger hyperpolarizing current, opposing the depolarizing current If, and further decreases the rate of spontaneous depolarization. Thus, overdrive suppression decreases a cell's automaticity when that cell is driven to depolarize faster than its intrinsic discharge rate.

1. Accessory Pathways and the Wolff-Parkinson-White Syndrome An illustration of reentry mechanism. !!!!Accessory pathway/bypass tract: an additional connection between atria and ventricles, that bypasses AV node. Stimulation through bypass tract goes faster than AV-His-Purkinje system (shorter PR interval, meaning QRS occurs EARLIER). However, the bypass tract goes to regular myocardial cells, not purkinje system, so the spread through ventricles is SLOWER, and occurs concurrently with His-Purkinje QRS.... so (QRS is WIDER, and there is a SLURRING UPSTROKE at the beginning, termed a DELTA WAVE) No real symptoms. Ideal condition for reentry, however. Refractory period of pathway is usually different from AV node. An appropriate premature beat may encounter block in accessory pathway but conduct through AV node or vice versa. If propagating impulse then finds initially blocked pathway has recovered (unidirectional), it can go retrograde up to the atrium, down the other pathway, back to ventricles. LARGE ANATOMIC LOOP established.

The mechanism of reentry is dramatically illustrated by the Wolff-Parkinson-White (WPW) syndrome. In the normal heart, an impulse generated by the SA node propagates through atrial tissue to the AV node, where expected slower conduction causes a short delay before continuing on to the ventricles. However, approximately 1 in 1,500 people has the WPW syndrome and is born with an additional connection between an atrium and ventricle. Termed an accessory pathway (or bypass tract), this connection allows conduction between the atria and ventricles to bypass the AV node. The most common type of accessory pathway consists of microscopic fibers (known as a bundle of Kent) that span the AV groove somewhere along the mitral or tricuspid annuli, as shown in Figure 11-10. Because accessory pathway tissue conducts impulses faster than the AV node, stimulation of the ventricles during sinus rhythm begins earlier than normal and the PR interval of the ECG is therefore shortened (usually <0.12 seconds, or <3 small boxes). In this situation, the ventricles are said to be "preexcited." However, the accessory pathway connects to ventricular myocardium rather than to the Purkinje system, such that the subsequent spread of the impulse through the ventricles from that site is slower than usual. In addition, because normal conduction over the AV node proceeds concurrently, ventricular depolarization represents a combination of the electric impulse traveling via the accessory tract and that conducted through the normal Purkinje system. As a result, the QRS complex in patients with WPW is wider than normal and demonstrates an abnormally slurred initial upstroke, known as a delta wave (Fig. 11-10). During sinus rhythm, simultaneous conduction through the accessory pathway and AV node results in this interesting ECG appearance but causes no symptoms. The presence of the abnormal pathway, however, creates an ideal condition for reentry because the refractory period of the pathway is usually different from that of the AV node. An appropriately timed abnormal impulse (e.g., a premature beat) may encounter block in the accessory pathway but conduct through the AV node or vice versa. If the propagating impulse then finds that the initially blocked pathway has recovered (unidirectional block), it can conduct in a retrograde direction up to the atrium and then down the other pathway back to the ventricles. Thus, a large anatomic loop is established, with the accessory pathway serving as one limb and the normal conduction pathway through the AV node as the other. The clinical characteristics of the WPW syndrome, including the types of reentrant tachycardia associated with it, are described in Chapter 12. The mechanisms of altered impulse formation and conduction form the basis of all common arrhythmias, both abnormally slow rhythms (bradyarrhythmias) and abnormally fast ones (tachyarrhythmias). Table 11-1 lists the underlying mechanisms and examples of their commonly associated rhythm disturbances.

A. Alterations in Sinus Node Automaticity NEUROHORMONES regulate it.

The rate of impulse initiation by the sinus node, as well as by the latent pacemakers of the specialized conducting system, is regulated primarily by neurohumoral factors.

B. Tachyarrhythmias Goals 1. protection from consequences of arrhythmia 2. specific mechanism responsible for original abnormal rhythm.

The treatment of tachyarrhythmias is directed at (1) protection of the patient from the consequences of the arrhythmia and (2) the specific mechanism responsible for the abnormal rhythm. Pharmacologic agents and cardioversion/defibrillation are commonly used approaches, but innovative electronic devices and transvenous catheter-based techniques to intentionally damage (ablate) arrhythmia-causing tissue have revolutionized treatment of these disorders.

E. Triggered Activity AP can TRIGGER abnormal depolarizations=results in extra heart beats or tachyarrhythmias. First AP leads to oscillations of membrane voltage called afterdepolarizations, and these may reach threshold to form abnormal APs. 2 types: early (DURING repolarization) and delayed (shortly after REPOLARIZATION)

Under certain conditions, an action potential can "trigger" abnormal depolarizations that result in extra heart beats or tachyarrhythmias. This process may occur when the first action potential leads to oscillations of the membrane voltage known as afterdepolarizations. Unlike the spontaneous activity seen when enhanced automaticity occurs, this type of automaticity is stimulated by a preceding action potential. As illustrated in Figures 11-7 and 11-8, there are two types of afterdepolarizations depending on their timing after the inciting action potential: early afterdepolarizations occur during the repolarization phase of the inciting beat, whereas delayed afterdepolarizations occur shortly after repolarization has been completed. In either case, abnormal action potentials are triggered if the afterdepolarization reaches a threshold voltage.

IV. Altered Impulse Conduction USUALLY cause Bradyarrhythmias but RE-ENTRY can cause TACHYARRHYTHMIAS

Alterations in impulse conduction also lead to arrhythmias. Conduction blocks generally slow the heart rate (bradyarrhythmias); however, under certain circumstances, the process of reentry (described later) can ensue and produce abnormal fast rhythms (tachyarrhythmias).

C. Enhanced Automaticity of Latent Pacemakers ECTOPIC beat: A latent pacemaker can also become the primary driver of impulse formation if it develops a faster intrinsic rate of depolarization than the SA node. Early, where an escape beat is late. Ectopic rhythm: series of them. Caused by SNS: high catecholamines enhance automaticity of latent pacemakers. DITITALIS TOXICITY hypoxemia, ischemia, electrolyte disturbances.

Another means by which a latent pacemaker can assume control of impulse formation is if it develops an intrinsic rate of depolarization faster than that of the sinus node. Termed an ectopic beat, such an impulse is premature relative to the normal rhythm, whereas an escape beat is late and terminates a pause caused by a slowed sinus rhythm. A sequence of similar ectopic beats is called an ectopic rhythm. Ectopic beats may arise in several circumstances. For example, high catecholamine concentrations can enhance the automaticity of latent pacemakers, and if the resulting rate of depolarization exceeds that of the sinus node, then an ectopic rhythm will develop. Ectopic beats are also commonly induced by hypoxemia, ischemia, electrolyte disturbances, and certain drug toxicities (such as digitalis, as described in Chapter 17).

V. Physiological Basis of Antiarrhythmic Therapy Why do we treat them? Severe HOTN or Cardiac Arrest. tachycardias: shock, internal cardioverter-defibrillator (ICD) to automatically terminate malignant tachyarrhythmias. bradycardia: electric pacing or meds, Permanet pacemaker CORRECT: ischemia and electrolyte abnormalities. Meds that alter automaticity, conduction, refractoriness Catheter/surgical ablation of conduction pathways to physically disrupt the region responsible for arrhythmia.

Appropriate treatment of a rhythm disorder depends on its severity and its likely mechanism. When an arrhythmia produces severe hypotension or cardiac arrest, it must be immediately terminated to restore effective cardiac function. Therapy for termination may include electrical cardioversion (an electric "shock") for tachycardias, cardiac pacing for bradycardias, or administration of medications. Additional therapy to prevent recurrences is guided by the etiology of the rhythm disturbance. Correctable factors that contribute to abnormal impulse formation and conduction (such as ischemia or electrolyte abnormalities) should be corrected. If there is a risk of recurrent arrhythmia, medications that alter automaticity, conduction, and/or refractoriness may be administered, or catheter or surgical ablation of conduction pathways is undertaken to physically disrupt the region responsible for the arrhythmia. Other advanced options include implantation of a permanent pacemaker for serious bradyarrhythmias or an internal cardioverter-defibrillator (ICD) to automatically terminate malignant tachyarrhythmias should they recur. The following sections summarize the common therapeutic modalities, and Chapter 12 describes how they are used to address specific rhythm disorders.

Summary

Arrhythmias result from disorders of impulse formation, impulse conduction, or both. Bradyarrhythmias (abnormally slow heart rhythms) develop because of decreased impulse formation (e.g., sinus bradycardia) or decreased impulse conduction (e.g., AV nodal conduction blocks). Tachyarrhythmias (abnormally fast rhythms) result from increased automaticity (of the SA node, latent pacemakers, or abnormal myocardial sites), triggered activity, or reentry. The two critical conditions for reentry are (1) unidirectional block and (2) slowed conduction through the reentry path; these conditions commonly occur in regions where fibrosis has developed, such as infarction scars. Bradyarrhythmias are usually treated acutely with drugs that accelerate the rate of sinus node discharge and enhance AV nodal conduction (atropine, isoproterenol) or with temporary electronic pacemakers. Permanent electronic pacemakers are implanted when more sustained therapy for bradyarrhythmias is needed. Pharmacologic therapy for tachyarrhythmias is directed at the mechanism responsible for the rhythm disturbance. For refractory tachyarrhythmias, or in emergency situations, electrical cardioversion or defibrillation is utilized. Catheter-based ablative techniques are useful for long-term control of certain tachyarrhythmias. ICDs are lifesaving devices implanted in patients at high risk of sudden cardiac death. For patients with ICDs and recurrent ventricular tachycardias causing defibrillator shocks, ablation techniques are often effective in reducing the frequency of episodes. Chapter 12 describes the diagnosis and management of the most common arrhythmias. Chapter 17 describes commonly used antiarrhythmic drugs.

II. Normal Impulse Formation Automaticity: cell's ability to SPONTANEOUSLY depolarize to a threshold voltage to generate an AP Pacemaker cells are the cells of specialized conducting system (SA, AV nodes, Ventricular conduction system: His, bundle branches, Purkinje fibers), who have this property. Atrial and ventricular myocytes do not have this property.

As described in Chapter 1, electric impulse formation in the heart arises from the intrinsic automaticity of specialized cardiac cells. Automaticity refers to a cell's ability to spontaneously depolarize to a threshold voltage to generate an action potential. Although atrial and ventricular myocytes do not have this property under normal conditions, the cells of the specialized conducting system do possess natural automaticity and are therefore termed pacemaker cells. The specialized conducting system includes the sinoatrial (SA) node, the AV nodal region, and the ventricular conducting system. The latter is composed of the bundle of His, the bundle branches, and the Purkinje fibers. In pathologic situations, myocardial cells outside the conducting system may also acquire automaticity.

D. Abnormal automaticity Ectopic beats arising from cells that do not normally possess automaticity. Such cells do not normally carry If, but in injury, they may become leaky, and when a RMP is reduced to LESS THAN -60mV, gradual Phase 4 depolarization can be demonstrated. DUE TO -very slowly inactivating calcium current -a decrease in outward Potassium current (that normally repolarizes the cell, -and loss of inward rectifier K+ current that normally HOLDS CELL at a MORE NEGATIVE RMP.

Cardiac tissue injury may lead to pathologic changes in impulse formation whereby myocardial cells outside the specialized conduction system acquire automaticity and spontaneously depolarize. Although such activity may appear similar to impulses originating from latent pacemakers within the specialized conduction pathways, these ectopic beats arise from cells that do not usually possess automaticity. If the rate of depolarization of such cells exceeds that of the sinus node, they transiently take over the pacemaker function and become the source of an abnormal ectopic rhythm. Because these myocardial cells have few or no activated pacemaker channels, they do not normally carry If. How injury allows such cells to spontaneously depolarize has not been fully elucidated. However, when cardiac tissue becomes injured, its cellular membranes become "leaky." As such, they are unable to maintain the concentration gradients of ions, and the resting potential becomes less negative (i.e., the cell partially depolarizes). When a cell's membrane potential is reduced to a value less negative than −60 mV, gradual phase 4 depolarization can be demonstrated even among nonpacemaker cells. This spontaneous depolarization probably results from a very slowly inactivating calcium current, a decrease in the outward potassium current that normally acts to repolarize the cell, and less effect of the inward rectifier K+ current that normally holds cells at a more negative potential range.

3. Electric Cardioversion and Defibrillation Electric shock to TERMINATE A TACHYCARDIA depolarizes bulk of excitable tissue interrupts reentrant circuits establishes electric homogeneity allows sinus node (fastest) to regain control. REENTRY ARRHYTHMIAS CAN USUALLY BE TERMINATED WITH THIS, but those due to abnormal automaticity cannot. EXTERNAL CARDIOVERSION: supraventricular tachycardias or organized ventricular tachycardias. Sedation, paddles, shock occurs at time of QRS complex(ventricular depolarization) Prevents possibility of discharge during T wave, when a shock could INDUCE REENTRY (ventricular defibrillation would result) because regions of myocardium are in DIFFERENT PHASES OF DEPOLARIZATION AND RECOVERY. EXTERNAL DEFIBRILLATION: same equipment. USED TO TERMINATE VENTRICULAR FIBRILLATION. No organized QRS complex on which to synchronize electric discharge, delivered using asynchronous mode of device.

Cardioversion and defibrillation involve the application of an electric shock to terminate a tachycardia. A shock with sufficient energy depolarizes the bulk of excitable myocardial tissue, interrupts reentrant circuits, establishes electric homogeneity, and allows the sinus node (the site of fastest spontaneous discharge) to regain pacemaker control. Tachyarrhythmias that are caused by reentry can usually be terminated by this procedure, whereas arrhythmias due to abnormal automaticity may simply persist. External cardioversion is used to terminate supraventricular tachycardias or organized ventricular tachycardias. It is performed by briefly sedating the patient and then placing two large electrode paddles (or adhesive electrodes) against the chest on either side of the heart. The electric discharge is electronically synchronized to occur at the time of a QRS complex (i.e., when ventricular depolarization occurs). This prevents the possibility of discharge during the T wave, when a shock could induce reentry (leading to ventricular fibrillation) because regions of myocardium are in different phases of depolarization and recovery. External defibrillation is performed to terminate ventricular fibrillation, employing the same equipment as that used for cardioversion. However, during fibrillation, there is no organized QRS complex on which to synchronize the electric discharge, so it is delivered using the "asynchronous" mode of the device.

A. Ionic Basis of Automaticity Phase 4: spontaneous inherent gradual depolarization: due to pacemaker current (If) These channels are ACTIVATED BY HYPERPOLARIZATION (increasingly NEGATIVE VOLTAGES, starting around -50mV) and allow SODIUM IONS INTO the cell. These are DIFFERENT channels than the FAST SODIUM channels responsible for RAPID PHASE 0 Depolarization in atrial and ventricular myocytes. In pacemaker cells of the SA Node Specifically: THREE OTHER IONIC CURRENTS contribute to Phase 4 gradual depolarization: 1. Slowly increasing inward Ca2+ current through L-type Ca2+ channels. BECOME ACTIVATED at voltages reached NEAR END OF PHASE 4. 2. Progressively DECLINING OUTWARD POTASSIUM CURRENT 3. Additional INWARD SODIUM CURRENT mediated by activation of ELECTROGENIC Na/Ca exchanger by Calcium release from SR! IF these all contribute, and it reaches threshold, AP is generated. The Phase 0 upstroke of the AP in SA/AV Nodes is MUCH SLOWER than the Phase 0 of Purkinje system. Because SA/AV Node cells RMP = -50- -60mV and Purkinje system cells RMP = -90mV!!!!!!!!!!!!!!! BECAUSE membrane potential determines proportion of fast Na+ channels in the resting state who are CAPABLE OF DEPOLARIZATION, compared with in an INACTIVATED state. The # of resting, capable fast Na+ channels DECREASES as resting membrane potential becomes more and more positive. (Higher membrane potential means less fast Na+ channels are accessible), so depolarization goes slower, slope is less extreme. REPOLARIZATION: Inactivation of open Ca2+ channels opening voltage-gated K+ channels, efflux of K+

Cells with natural automaticity do not have a static resting voltage. Rather, they inherently display gradual depolarization during phase 4 of the action potential (Fig. 11-2). If this spontaneous diastolic depolarization reaches the threshold condition, an action potential upstroke is generated. An important ionic current largely responsible for phase 4 spontaneous depolarization is known as the pacemaker current (If). The channels that carry this current are activated by hyperpolarization (increasingly negative voltages) and mainly conduct sodium ions. If channels begin to open when the membrane voltage becomes more negative than approximately −50 mV and are different entities than the fast sodium channels responsible for rapid phase 0 depolarization in ventricular and atrial myocytes. The inward flow of Na+ through these slow channels, driven by its concentration gradient and the negative intracellular potential, depolarizes the membrane toward threshold. In the pacemaker cells of the SA node, three other ionic currents also contribute to phase 4 gradual depolarization: (1) a slowly increasing inward calcium current, carried mostly by L-type Ca++ channels that become activated at voltages reached near the end of phase 4; (2) a progressively declining outward potassium current; and (3) an additional inward sodium current mediated by activation of the electrogenic sodium-calcium exchanger by calcium release from the sarcoplasmic reticulum. When the membrane potential of a pacemaker cell reaches the threshold condition, the upstroke of the action potential is generated. In contrast to the phase 0 upstroke of cells in the Purkinje system, that of cells in the sinus and AV nodes is much slower (see Fig. 11-2). The reason for the difference is that the membrane potential determines the proportion of fast sodium channels that are in a resting state capable of depolarization, compared with an inactivated state. The number of available (or resting-state) fast sodium channels decreases as the resting (diastolic) membrane potential becomes less negative. Because sinus and AV nodal cells have less negative maximum diastolic membrane voltages (−50 to −60 mV) than do Purkinje cells (−90 mV), the large majority of fast sodium channels is inactivated in these pacemaker cells. Thus, the action potential upstroke relies to a great extent on a smaller calcium current (through the relatively slower opening of L-type Ca++ channels) and has a less rapid rate of rise than do cells of the Purkinje system or ventricular myocardium. The repolarization phase of pacemaker cells results from both the inactivation of the open calcium channels and the opening of voltage-gated potassium channels that permit efflux of potassium from the cells (see Fig. 11-2).

2. Delayed afterdepolarizations shortly after repolarization Most often in STATES OF HIGH CALCIUM, i.e. DIGITALIS toxicity or HIGH CATECHOLAMINES Extracellular Ca2+ accumulates, activating Chloride Currents or the Na/Ca exchanger- result in inward currents that generate delayed after depolarization. lead to tachyarrhythmias, including idiopathic ventricular tachyarrhythmias, and atrial/ventricular tachycardias associated with DIGITALIS TOXICITY

Delayed afterdepolarizations may appear shortly after repolarization is complete (see Fig. 11-8). They most commonly develop in states of high intracellular calcium, as may be present with digitalis intoxication (see Chapter 17), or during marked catecholamine stimulation. It is thought that intracellular Ca++ accumulation causes the activation of chloride currents, or of the Na+-Ca++ exchanger, that results in brief inward currents that generate the delayed afterdepolarization. As with early afterdepolarizations, if the amplitude of the delayed afterdepolarization reaches a threshold voltage, an action potential will be generated. Such action potentials can be self-perpetuating and lead to tachyarrhythmias. Some idiopathic ventricular tachycardias that occur in otherwise structurally normal hearts are likely due to this mechanism, as are atrial and ventricular tachycardias associated with digitalis toxicity (see Chapter 17).

2. Electronic Pacemakers for BRADYARRHYTHMIAS or specific HF cases. apply repeated electric stimulation to the heart to initiate depolarizations at a desired rate, thereby assuming control of the rhythm. TEMPORARY waiting implantation or treating transient bradyarrhythmias from drug toxicity. 2 types: external transthoracic pacemakers: large adhesive electrodes on skin-fast but uncomfortable (requires large impulse-stimulates thoracic nerves/skeletal muscle. ER only transvensous temporary pacemakers- electrode tipped catheter inserted percutaneously into venous system, passed into heart(RV or RA), connected to external power source. Risk of infection and thrombosis. But effective for days. PERMANENT 1+ wires with pacing electrodes from venous side into RV or RA. or through coronary sinus into cardiac vein (for LV). Pulse generator connected to leads, implanted in infraclavicular skin. 10 yr battery. Sense cardiac activity and pace when needed. Also record data, whether fast rates have been sensed (tachyarrhythmias), amount of pacemaker function used, etc. External radio frequency device used to obtain info. IN HF: LV pacing lead pacemakers also used.

Electronic pacemakers apply repeated electric stimulation to the heart to initiate depolarizations at a desired rate, thereby assuming control of the rhythm. Pacemakers may be installed on a temporary or a permanent basis. Temporary units are used to stabilize patients who are awaiting implantation of a permanent pacemaker or to treat transient bradyarrhythmias, such as those caused by reversible drug toxicities. There are two types of temporary pacemakers. External transthoracic pacemakers deliver electric pulses to the patient's chest through large adhesive electrodes placed on the skin. The advantage of this technique is that it can be applied rapidly. Unfortunately, because the current used must be sufficient to initiate a cardiac depolarization, it stimulates thoracic nerves and skeletal muscle, which can be quite uncomfortable. Therefore, this form of pacing is usually used only on an emergency basis until another means of treating the arrhythmia can be implemented. The other option for temporary pacing is a transvenous unit. In this case, an electrode-tipped catheter is inserted percutaneously into the venous system, passed into the heart, and connected to an external power source (termed a pulse generator). Electric pulses are applied directly to the heart through the electrode catheter, which is typically placed in the right ventricle or right atrium. This type of pacing is not painful and can be effective for days. There is, however, a risk of infection and/or thrombosis associated with the catheter. Permanent pacemakers are more sophisticated than the temporary variety. Various configurations can sense and capture the electric activity of the atria and/or ventricles. One or more wires (known as leads) with pacing electrodes are passed through an axillary or subclavian vein into the right ventricle or right atrium, or through the coronary sinus into a cardiac vein (to stimulate the left ventricle). The pulse generator, similar in size to two silver dollars stacked on top of one another, is connected to the leads and then implanted under the skin, typically in the infraclavicular region. The pacemaker battery typically lasts about 10 years. Modern permanent pacemakers sense cardiac activity and pace only when needed. They incorporate complex functions to track the patient's normal heart rate and can stimulate beats automatically in response to activity. They can also record useful data, such as whether fast rates have been sensed (that might indicate a tachyarrhythmia), the amount of pacing that has been required, and other parameters of pacemaker function. An external radio frequency programming device is used to "interrogate" the pacemaker to obtain the recorded information and to adjust the pacing functions. Although the most common indications for permanent pacemakers are bradyarrhythmias, pacemakers that incorporate a left ventricular pacing lead are also used to improve cardiac performance in some patients with heart failure (cardiac resynchronization therapy—see Chapter 9).

B. Escape Rhythms Called an Escape beat: shift to a latent pacemaker when SA node is suppressed and fires too slow. Escape rhythm: persistent impairment of SA node firing leads to continued series of escape beats, protects heart from pathologically slow when SA is impaired. Suppressed SA node: PNS stimulation. SA/AV nodes are most sensitive within the heart to vagal tone. Atria are more sensitive than ventricles. So escape beasts usually come from AV node, but with increasing PNS stimulation, may have to come from ventricular escape pacemaker.

If the sinus node becomes suppressed and fires much less frequently than normal, the site of impulse formation may shift to a latent pacemaker within the specialized conduction pathway. An impulse initiated by a latent pacemaker because the SA node rate has slowed is called an escape beat. Persistent impairment of the SA node will allow a continued series of escape beats, termed an escape rhythm. Escape rhythms are protective in that they prevent the heart rate from becoming pathologically slow when SA node firing is impaired. As discussed in the previous section, suppression of sinus node activity may occur because of increased parasympathetic tone. Different regions of the heart have varied sensitivities to parasympathetic (vagal) stimulation. The SA node and the AV node are most sensitive to such an influence, followed by atrial tissue. The ventricular conducting system is the least sensitive. Therefore, moderate parasympathetic stimulation slows the sinus rate and allows the pacemaker to shift to the AV node. However, very strong parasympathetic stimulation suppresses excitability at both the SA node and AV node and may therefore result in the emergence of a ventricular escape pacemaker.

2. Vagotonia Maneuvers AV node is sensitive to Vagal stimulation. VAGAL tone INCREASED at bedside: SLOWING CONDUCTION, terminating re-entrant tachyarrhythmias. CAROTID SINUS MASSAGE stimulates baroreceptor reflex, increases vagal tone, withdraws SNS tone. Only on one at a time (avoid brain perfusion inhibition), and not in those with known carotid atherosclerosis (stroke risk)

Many tachycardias involve transmission of impulses through the AV node, a structure that is sensitive to vagal modulation. Vagal tone can be transiently increased by a number of bedside maneuvers, and performing these may slow conduction, which terminates some reentrant tachyarrhythmias. For example, carotid sinus massage is performed by rubbing firmly for a few seconds over the carotid sinus, located at the bifurcation of the internal and external carotid arteries on either side of the neck. This maneuver stimulates the baroreceptor reflex (see Chapter 13), which elicits the desired increase in vagal tone and withdrawal of sympathetic tone. This maneuver should be performed on only one carotid sinus at a time (to prevent interference with brain perfusion) and is best avoided in patients with known advanced atherosclerosis involving the carotid arteries.

Introduction Bradyarrhythmias: slow rhythms Tachyarrhythmias: fast rhythms Supraventricular-atria or AV node Ventricular-His-Purkinje or ventricular origin Arrhythmias result from impulse formation impulse conduction or both Fig 11-1 shows flow chart of arrhythmias Remember myocytes are all connected =operate as a syncytium. Rapidly propagates with minimal resistance. Leading edge of a depolarization may be several centimeters ahead of its trailing edge.......

Normal cardiac function relies on the flow of electric impulses through the heart in an exquisitely coordinated fashion. Abnormalities of the electric rhythm are known as arrhythmias (also termed dysrhythmias) and are among the most common clinical problems encountered. The presentations of arrhythmias range from common benign palpitations to severe symptoms of low cardiac output and death. Therefore, a thorough understanding of these disorders is important to the daily practice of medicine. Abnormally slow heart rhythms are termed bradycardias (or bradyarrhythmias). Fast rhythms are known as tachycardias (or tachyarrhythmias). Tachycardias are further characterized as supraventricular when they involve the atrium or atrioventricular (AV) node and designated ventricular when they originate from the His-Purkinje system or ventricles. This chapter extends the description of basic cardiac electrophysiology presented in Chapter 1 and explains the mechanisms by which arrhythmias develop, followed by a general approach to their management. Chapter 12 describes specific rhythm disorders, including how to recognize and treat them. Disorders of heart rhythm result from alterations of impulse formation, impulse conduction, or both. The chapter first addresses how abnormalities of impulse formation and conduction occur and under what circumstances they cause arrhythmias. Figure 11-1 provides an organizational schema for this presentation. While studying the concepts in this chapter, it is important to recall that cardiac tissue is composed of cells that are electrically coupled and operate as a syncytium. As myocytes depolarize and ionic currents result in individual action potentials, the electrical activity rapidly propagates from one cell to the next with minimal resistance, spreading through a large mass of tissue. As a result, the leading edge of a depolarization may be located several centimeters ahead of its trailing edge, and this property plays an important role in the genesis of certain arrhythmias, as will be described.

2. Decreased Sinus Node Automaticity [PNS reduced If(pacemaker Na+ channels), a less negative threshold level (voltage gated Ca2+ channels), a more negative maximum diastolic potential (inward rectifier K+ channels)] PNS mediates control of heart rate at rest. Vagus nerve stimulation upon SA NODE -REDUCES THE PROBABILITY of pacemaker channels being open (less If into cell, slower depolarization Phase 4) -and REDUCES THE PROBABILITY of Ca2+ channels being open, INCREASING THRESHOLD VALUE to a less negative value(making it harder to reach, slowing Phase 4 depolarization) -and INCREASES THE PROBABILITY of ACh-sensitive K+ channels (INWARD RECTIFIER CHANNELS, through which K+ exits) being open at rest. These producing an outward current that drives DIASTOLIC POTENTIAL more negative (farther from, and harder to reach threshold) These differ from K+ channels who are active in phase 3 repolarization. Altogether: slowed automaticity and slowed HR. Drugs: B blockers: antagonize adrenergic sympathetic effect: decrease rate of phase 4 depolarization, slow HR. Atropine: antimuscarinic-block PNS: increase rate of Phase 4 depolarization, increase HR.

Normal decreases in SA node automaticity are mediated by reduced sympathetic stimulation and by increased activity of the parasympathetic nervous system. Whereas activation of the sympathetic nervous system has a major role in increasing the heart rate during times of stress, the parasympathetic nervous system is the major controller of the heart rate at rest. Cholinergic (i.e., parasympathetic) stimulation via the vagus nerve acts at the SA node to reduce the probability of pacemaker channels being open (see Fig. 11-6). Thus, If and the slope of phase 4 depolarization are reduced, and the intrinsic firing rate of the cell is slowed. In addition, the probability of the Ca++ channels being open is decreased, such that the action potential threshold increases to a less negative potential. Furthermore, cholinergic stimulation increases the probability of acetylcholine-sensitive K+ channels being open at rest. Positively charged K+ ions exit through these "inward rectifier" channels, which differ from the K+ channels that are active in phase 3 repolarization (see Chapter 1), producing an outward current that drives the diastolic potential more negative. The overall effect of reduced If, a more negative maximum diastolic potential, and a less negative threshold level is a slowing of the intrinsic firing rate and therefore a reduced heart rate. It follows that the use of pharmacologic agents that modify these effects of the autonomic nervous system will also affect the firing rate of the SA node. For example, β-receptor blocking drugs ("β-blockers") antagonize the β-adrenergic sympathetic effect; therefore, they decrease the rate of phase 4 depolarization of the SA node and slow the heart rate. Conversely, atropine, an anticholinergic (antimuscarinic) drug, has the opposite effect: by blocking parasympathetic activity, the rate of phase 4 depolarization increases and the heart rate accelerates.

1. Pharmacologic Therapy Directed against original mechanisms: 1. abnormal automaticity 2. reentrant circuits 3. triggered activity 1. decrease automaticity: -reduce slope of Phase 4 -Hyper polarize -Raise threshold potential 2. Interrupt reentrant circuits: -inhibit conduction in reentry circuit to the point that conduction fails-stopping reentry impulse. -Increase refractory period within reentrant circuit so that a propagating impulse finds tissue within the loop unexcitable and impulse stops -Suppress premature beats that initiate reentry. 3. Eliminate Triggered Activity: -Shorten AP (prevent early afterdepolarizations) -Correct calcium overload conditions (prevent delayed afterdepolarizations) through interactions with ion channels, surface receptors, and transport pumps. SERIOUS PROaarrhythmia side-effects. ie. antiarrhythmic agents that act therapeutically to prolong the action potential duration can, as an undesired effect, cause early afterdepolarizations, the mechanism underlying the polymorphic ventricular tachycardia torsades de points ie. most agents used to treat tachyarrhythmias have the potential to aggravate bradyarrhythmias, and all antiarrhythmics have potentially toxic noncardiac side effects. So.. not great.

Pharmacologic management of tachyarrhythmias is directed against the underlying mechanism (abnormal automaticity, reentrant circuits, or triggered activity). Many antiarrhythmic drugs are available, and the choice of which to use relies on the cause of the specific arrhythmia. From consideration of the arrhythmia mechanisms presented in this chapter, the following strategies emerge: Desired Drug Effects to Eliminate Rhythms Caused by Increased Automaticity: Reduce the slope of phase 4 spontaneous depolarization of the automatic cells Make the diastolic potential more negative (hyperpolarize) Make the threshold potential less negative Desired Antiarrhythmic Effects to Interrupt Reentrant Circuits: Inhibit conduction in the reentry circuit to the point that conduction fails, thus stopping the reentry impulse Increase the refractory period within the reentrant circuit so that a propagating impulse finds tissue within the loop unexcitable and the impulse stops Suppress premature beats that can initiate reentry Desired Drug Effects to Eliminate Triggered Activity: Shorten the action potential duration (to prevent early afterdepolarizations) Correct conditions of calcium overload (to prevent delayed afterdepolarizations) Drugs used to achieve these goals modulate the action potential through interactions with ion channels, surface receptors, and transport pumps. Many drugs have multiple effects and may attack arrhythmias through more than one mechanism. The commonly used antiarrhythmic drugs and their actions are described in Chapter 17. It is important to recognize that although these drugs suppress arrhythmias, they also have the potential to aggravate or provoke certain rhythm disturbances. This undesired consequence is referred to as proarrhythmia and is a major limitation of contemporary antiarrhythmic drug therapy. For example, antiarrhythmic agents that act therapeutically to prolong the action potential duration can, as an undesired effect, cause early afterdepolarizations, the mechanism underlying the polymorphic ventricular tachycardia torsades de pointes (see Chapter 12). In addition, most agents used to treat tachyarrhythmias have the potential to aggravate bradyarrhythmias, and all antiarrhythmics have potentially toxic noncardiac side effects. These shortcomings have led to an increased reliance on nonpharmacologic treatment options, as described in the following sections.

1. Pharmacologic Therapy for Bradyarrhythmias modify autonomic input to heart by 1. Anticholinergic drugs ATROPINE antagonize ACh muscarinic receptors responding to Vagus nerve to SA. -Increase HR, Enhance AV conduction 2. b1 receptor agonists ISOPROTERENOL mimic endogenous catecholamines Increase HR and AV node conduction. not for prophylaxis long term.

Pharmacologic therapy of bradyarrhythmias modifies the autonomic input to the heart in one of two ways: Anticholinergic drugs (i.e., antimuscarinic agents such as atropine). Vagal stimulation reduces the rate of sinus node depolarization (which slows the heart rate) and decreases conduction through the AV node, through the release of acetylcholine onto muscarinic receptors. Anticholinergic drugs competitively bind to muscarinic receptors and thereby reduce the vagal effect. This results in an increased heart rate and enhanced AV nodal conduction. β1-Receptor agonists (e.g., isoproterenol). Mimicking the effect of endogenous catecholamines, these drugs increase heart rate and speed AV nodal conduction. Atropine and isoproterenol are administered intravenously. Although these drugs are useful in managing certain slow heart rhythms emergently, it is not practical to continue them over the long term to treat persistent bradyarrhythmias.

B. Native and Latent Pacemakers Distinct populations of cells in specialized conduction pathway have different intrinsic RATES OF FIRING! RATES of FIRING determined by: 1. RATE of Phase 4 -If current (steeper is faster)-determined by opening kinetics and individual pacemaker channels. 2. Maximum NEGATIVE DIASTOLIC POTENTIAL (Less negative is faster) 3. THRESHOLD POTENTIAL (more negative is faster) SA Node determines HR in normal: Through gap junctions, a depolarized cell threshold will bring adjacent cells membrane potential up to threshold, and it will fire (regardless of how close its intrinsic If has brought it to threshold)..... SO, it is really just the FASTEST ones to threshold who start off the current, and thus determine the HR. Normally, this is the SA node, who fires at a faster frequency than other cells with automaticity, prevent spontaneous discharge of other potential pacemaker sites. latent/ectopic pacemakers: slower HR intrinsic firing rates. AV node, bundle of His: 50-60 Bpm Purkinje system: 30-40 BPM They may take over when SA node slows or fails or if a conduction block occurs.

The distinct populations of automatic cells in the specialized conduction pathway have different intrinsic rates of firing. These rates are determined by three variables that influence how fast the membrane potential reaches the threshold condition: (1) the rate (i.e., the slope) of phase 4 spontaneous depolarization, (2) the maximum negative diastolic potential, and (3) the threshold potential. A more negative maximum diastolic potential, or a less negative threshold potential, slows the rate of impulse initiation because it takes longer to reach the threshold value (Fig. 11-3). Conversely, the greater the If, the steeper the slope of phase 4 and the faster the cell depolarizes. The size of If depends on the number and opening kinetics of the individual pacemaker channels through which this current flows. Since all healthy myocardial cells are electrically connected by gap junctions, an action potential generated in one part of the myocardium will ultimately spread to all other regions. When an impulse arrives at a cell that is not yet close to threshold, current from the depolarized cell will bring the adjacent cell's membrane potential to the threshold level so that it will fire (regardless of how close its intrinsic If has brought it to threshold). Thus, the pacemaker cells with the fastest rate of depolarization set the heart rate. In the normal heart, the dominant pacemaker is the sinoatrial node, which at rest initiates impulses at a rate of 60 to 100 bpm. Because the sinus node rate is faster than that of the other tissues that possess automaticity, its repeated discharges prevent spontaneous firing of other potential pacemaker sites. The SA node is known as the native pacemaker because it normally sets the heart rate. Other cells within the specialized conduction system harbor the potential to act as pacemakers if necessary and are therefore called latent pacemakers (or ectopic pacemakers). In contrast to the SA node, the AV node and the bundle of His have intrinsic firing rates of 50 to 60 bpm, and cells of the Purkinje system have rates of approximately 30 to 40 bpm. These latent sites may initiate impulses and take over the pacemaker function if the SA node slows or fails to fire or if conduction abnormalities block the normal wave of depolarization from reaching them.

1. Increased Sinus Node Automaticity [!SNS: increase probability of open Na channels (If into cell faster) and increase probability of Ca2+ channels available to open] -β1-adrenergic receptors increase OPEN PROBABILITY OF PACEMAKER CHANNELS (through which If can enter the cell), STEEPER Phase 4. SA Node reaches threshold earlier, and HEART RATE INCREASES. -SNS also shifts AP threshold to MORE NEGATIVE voltages(easier to reach) by INCREASING PROBABILITY THAT VOLTAGE-SENSITIVE Ca++ channels are capable of opening (who are responsible for Phase 0 depol). Thus, Phase 4 depolarization reaches threshold potential EARLIER.

The most important modulator of normal sinus node automaticity is the autonomic nervous system. Sympathetic stimulation, acting through β1-adrenergic receptors, increases the open probability of the pacemaker channels (Fig. 11-6), through which If can flow. The increase in If leads to a steeper slope of phase 4 depolarization, causing the SA node to reach threshold and fire earlier than normal and the heart rate to increase. In addition, sympathetic stimulation shifts the action potential threshold to more negative voltages by increasing the probability that voltage-sensitive Ca++ channels are capable of opening (recall that calcium carries the current of phase 0 depolarization in pacemaker cells). Therefore, phase 4 depolarization reaches the threshold potential earlier. Sympathetic activity thus increases sinus node automaticity both by increasing the rate of pacemaker depolarization via If and by causing the action potential threshold to become more negative. Examples of this normal physiologic effect occur during physical exercise or emotional stress, when sympathetic stimulation appropriately increases the heart rate.