Which term refers to the ability to rhythmically beat without nervous stimulation?

Abnormal Automaticity

In the normal heart, automaticity is confined to the sinus node and other specialized conducting tissues. Working atrial and ventricular myocardial cells do not normally exhibit spontaneous diastolic depolarization and do not initiate spontaneous impulses, even when they are not excited for long periods of time by propagating impulses. Although these cells do have an If, the range of activation of this current in these cells is much more negative (−120 to −170 mV) than in Purkinje fibers or in the sinus node. As a result, during physiological Em (−85 to −95 mV), the If is not activated and ventricular cells do not depolarize spontaneously. However, when the resting potentials of these cells are depolarized sufficiently, to approximately −70 to −30 mV, spontaneous diastolic depolarization can occur and cause repetitive impulse initiation, a phenomenon called depolarization-induced automaticity or abnormal automaticity (see eFig. 3.1). Similarly, cells in the Purkinje system, which are normally automatic at high levels of membrane potential, show abnormal automaticity when the membrane potential is reduced to approximately −60 mV or less, as can occur in ischemic regions of the heart. When the steady-state membrane potential of Purkinje fibers is reduced to levels more positive to −60 mV, the If channels that participate in normal pacemaker activity in Purkinje fibers are closed and nonfunctional, and automaticity is therefore not caused by the normal pacemaker mechanism. However, it can be caused by an “abnormal” mechanism. In contrast, enhanced automaticity of the sinus node, subsidiary atrial pacemakers, or the AVN caused by a mechanism other than acceleration of normal automaticity has not been demonstrated clinically.1,9

A low level of membrane potential is not the only criterion for defining abnormal automaticity. If this were so, the automaticity of the sinus node would have to be considered abnormal. Therefore an important distinction between abnormal and normal automaticity is that the membrane potentials of fibers showing the abnormal type of activity are reduced from their own normal level. For this reason, automaticity in the AVN (e.g., where the membrane potential is normally low) is not classified as abnormal automaticity.

Several different mechanisms probably cause abnormal pacemaker activity at low membrane potentials, including activation and deactivation of the delayed rectifier IK, intracellular Ca2+ release from the sarcoplasmic reticulum that causes activation of inward Ca2+ current as well as INa (through the Na+-Ca2+ exchanger), and a potential contribution by If. It has not been determined which of these mechanisms are operative in the different pathological conditions in which abnormal automaticity can occur.

The upstroke of the spontaneously occurring action potentials generated by abnormal automaticity can be caused by Na+ or Ca2+ inward currents or possibly a combination of the two. In the range of diastolic potentials between approximately −70 and −50 mV, repetitive activity is dependent on extracellular Na+ concentration and can be decreased or abolished by Na+ channel blockers. In a diastolic potential range of approximately −50 to −30 mV, Na+ channels are predominantly inactivated; repetitive activity depends on extracellular Ca2+ concentration and is reduced by L-type Ca2+ channel blockers.

The intrinsic rate of a focus with abnormal automaticity is a function of the membrane potential. The more positive the membrane potential, the faster the automatic rate (see eFig. 3.1). Abnormal automaticity is less vulnerable to suppression by overdrive pacing (see later). Therefore even occasional slowing of the sinus node rate can allow an ectopic focus with abnormal automaticity to fire without a preceding long period of quiescence. Catecholamines can increase the rate of discharge caused by abnormal automaticity and therefore can contribute to a shift in the pacemaker site from the sinus node to a region with abnormal automaticity.

The decrease in the membrane potential of cardiac cells required for abnormal automaticity to occur can be induced by a variety of factors related to cardiac disease, such as ischemia and infarction. However, the circumstance under which membrane depolarization occurs can influence the development of abnormal automaticity. For example, an increase in extracellular K+ concentration, as occurs in acutely ischemic myocardium, can reduce membrane potential; however, normal or abnormal automaticity in working atrial, ventricular, and Purkinje fibers usually does not occur because of an increase in K+ conductance (and hence net outward current) that results from the increase in extracellular K+ concentration.

14 How does hypocalcemia affect cardiac function?

Calcium is involved in cardiac automaticity and is required for muscle contraction. Hypocalcemia can therefore result in arrhythmias and reduced myocardial contractility. This decrease in the force of contraction may be refractory to pressor agents, especially those that involve calcium in their mechanism of action. Through this process, beta-blockers and calcium channel blockers can exacerbate cardiac failure. With low serum calcium, the Q-T interval is prolonged, and ST changes may mimic myocardial infarction. Although the relationship is variable, the calcium level correlates moderately well with the interval from the Q-wave onset to the peak of the T-wave.

Disopyramide

Disopyramide is a sodium channel blocking drug that decreases cardiac automaticity, increases refractory periods and slows conduction. Anticholinergic properties are largely responsible for its adverse effects (Morady et al., 1982; Teichman, 1985). These include constipation, urinary retention, mouth dryness, and blurred vision. In an amiodarone comparison trial, 41 patients received disopyramide, of which 4 stopped taking the drug due to anticholinergic side effects (Villani et al., 1992). Case reports describe a sensory and a sensorimotor polyneuropathy (Dawkins and Gibson, 1978; Briani et al., 2002). Several reports describe altered mentation and psychosis thought to be related to the drug's anticholinergic properties (Falk et al., 1977; Padfield et al., 1977; Ahmad et al., 1979). Myasthenia gravis can be exacerbated by disopyramide (Hirose et al., 2008).

Sarcoplasmic reticulum Ca2 + release and Na+–Ca2 + exchange

Evidence of a role for sarcoplasmic reticulum (SR) Ca2 + release in cardiac automaticity was first shown in latent pacemaker cells in the atria and in the SAN, whereby application of ryanodine was found to slow spontaneous pacemaker activity (Rubenstein and Lipsius, 1989; Rigg and Terrar, 1996; Li et al., 1997). Since then, this phenomenon has been explored in great detail in the mammalian SAN (Lakatta et al., 2010). The central tenet of this hypothesis is that localized subsarcolemmal Ca2 + release (LCR) events from the SR occur during the late DD. These LCRs occur rhythmically and lead to the activation of NCX, which extrudes this Ca2 + from the SAN myocytes, thereby generating an inward current (INCX) during the DD. This SR Ca2 + release/INCX mechanism appears to depend on a high level of basal PKA activity in the SAN and is controlled by phosphodiesterases, which are responsible for hydrolyzing cAMP (Vinogradova et al., 2006, 2008). It has been proposed that the LCR events present during the DD occur spontaneously and do not depend on membrane depolarization (Lakatta et al., 2010). On the other hand, more recent evidence has demonstrated that CaV1.3 Ca2 + channels are colocalized with ryanodine receptors in the SAN (Christel et al., 2012) and it has been suggested that Ca2 + influx via CaV1.3 channels during the DD may lead to the opening of ryanodine receptors by Ca2 +-induced Ca2 + release (Torrente et al., 2016). There has been considerable debate on the relative importance of this Ca2 + clock mechanism in SAN automaticity with some studies ascribing it a dominant or even essential role and others concluding that the Ca2 + clock is an important contributor, but that spontaneous activity in the SAN can continue without it, albeit with reduced rates and/or stability (Lakatta and DiFrancesco, 2009; Honjo et al., 2003; Lakatta et al., 2010). Nevertheless, the evidence is overwhelming that SR Ca2 + release occurs during the late DD and this leads to the activation of INCX, which increases the rate of depolarization during diastole and thus enhances spontaneous AP firing in the SAN.

Further evidence of a role for SR Ca2 + release in automaticity comes from studies of IP3 receptors (IP3Rs) in the SAN. All three IP3R subtypes (IP3R1, IP3R2, and IP3R3) are expressed in the heart and IP3R1 and IP3R2 have both been detected in the SAN (Ju et al., 2011, 2012). Activation of IP3Rs with either membrane-permeable IP3 or indirectly via application of endothelin-1 (which increases endogenous IP3 levels via the phospholipase C signaling pathway) caused a significant increase in Ca2 + spark frequency near the cell membrane, indicating SR Ca2 + release. Furthermore, these IP3R agonists also increased spontaneous AP generation in the SAN (Ju et al., 2011). Consistent with these findings, IP3R2 knockout mice as well as pharmacological inhibition of IP3Rs result in a reduction in spontaneous Ca2 + spark frequency and SAN AP firing rate (Ju et al., 2011; Kapoor et al., 2015). Combined, these data indicate IP3R2-mediated SR Ca2 + release can contribute to pacemaker activity in the SAN.

Digoxin

Digoxin is a member of a group of glycosides derived from the foxglove plant and increases cardiac contractility and automaticity. Digoxin and digitoxin are the sole agents currently in use. Therefore, they are still widely used in the management of congestive heart failure and arrhythmias in both children and adults. They have a narrow therapeutic index, and poisoning is common both in the setting of clinical use and in accidental ingestion. Cardiac glycosides are found in many common decorative plants such as yellow oleander, and accidental ingestion presents with symptoms similar to digitalis poisoning. Because of its prolonged kinetics, digoxin therapy is frequently initiated by a loading dose, commonly 35 to 50 mcg/kg, given in divided doses over several days, followed by maintenance therapy of 7 to 10 mcg/kg/dose every 12 hours. The dose is adjusted in the face of renal insufficiency.

Digoxin has a large volume of distribution, being concentrated in the muscle mass. Bioavailability after oral ingestion is variable, depending substantially on the manufacturer. For that reason Lanoxin is the most widely prescribed agent, in which nearly 90% of an oral dose is absorbed. Onset of effect is between 1.5 and 6 hours. It is slowly excreted intact by the kidneys. A decrease in renal function or significant dehydration may provoke digoxin intoxication in the patient who has previously been safely taking a given dose. In this setting, peritoneal dialysis may be useful in addition to the other measures undertaken to treat digitalis intoxication.67 Digoxin impairs the Na+/K+ membrane pump, increasing intracellular sodium and impairing Na+-Ca2+-dependent egress of calcium from the cell, thereby enhancing contractility. The transmembrane potential is raised, increasing automaticity. Digoxin also increases cardiac vagal tone, slowing the heart rate and delaying atrioventricular nodal conduction. As digoxin's effect is dependent on its membrane-bound fraction, serum digoxin levels, although widely available, are poor prognostic indicators for the development of digitoxicity.68 Intracellular electrolytes, although not widely available, may be a sensitive indicator of the risk for digitoxicity.69 Therapeutic drug monitoring may be more useful in specific settings, such as the management of congestive heart failure in a patient with renal impairment. Elevated digoxin levels in the correct clinical setting may be of assistance in establishing the diagnosis of digitoxi-city, but too great an overlap exists between therapeutic and toxic levels to use the digoxin level as a sole index of toxicity.70

Acute digoxin poisoning presents with vomiting, bradycardia, and arrhythmias, frequently heart block and bradycardia, although virtually any cardiac rhythm disturbance may be attributed to digitalis poisoning. Hyperkalemia is frequently observed and may be life threatening. Chronic digoxin poisoning may present with an array of bizarre complaints, including vomiting, anorexia, weakness, altered mental status, and visual disturbances such as altered color perception. Cardiac manifestations of poisoning include ventricular arrhythmias, heart block, and nodal escape rhythms. Rhythm disturbances commonly manifest some form of myocardial irritability with delayed conduction. Bidirectional ventricular tachycardia is thought to be particularly characteristic of digitalis poisoning71 (Fig. 137-2).

Emesis is not recommended in digoxin poisoning, as it may increase vagal tone, exacerbating bradycardia. Activated charcoal binds digoxin well, and should be given. Multiple-dose activated charcoal is not clearly beneficial.72 There are no data on the efficacy of catharsis. Dialysis is of no benefit.

The development of digoxin-specific antibody fragments (Fab) has significantly altered the management of digoxin poisoning. Administration rapidly reverses bradycardia, arrhythmias, and hyperkalemia associated with digoxin poisoning and related, naturally occurring, cardiac glycosides.73,74 It is effective in the treatment of poisoning due to digoxin, digitoxin, and congeners, as well as the naturally occurring glycosides.75 Fab should be given to patients with any dysrrhythmia causing hemodynamic compromise or with a serum potassium level greater than 10 mEq/L.76 It should be given after ingestion of more than 4 mg in a child without underlying disease, and may be given intravenously or by the intraosseous route. The amount administered may be determined by the following formula if the dose taken is known77:

Number of Fab vials (38 mg/vial) = amount ingested (mg) × 0.48 (mg neutralized/vial)

If the dose is unknown, the amount given may be determined by the steady state serum digoxin concentration 6 hours after the ingestion:

Number of Fab vials = serum digoxin level (ng/ml) × body weight (kg)/100

Fab is also useful in the treatment of chronic digoxin intoxication. The previous equation may be used, obtaining the steady state concentration. If the dose ingested is unknown, 5 vials may be given to a child, 10 to 20 vials to an acutely intoxicated adult, or 10 vials to an adult with chronic toxicity.

Atropine is useful as an antidote and is indicated for severe bradycardia. Phenytoin and lidocaine were both previously considered primary therapy for the treatment of ventricular dysrrhythmias, and may still be useful in the absence of Fab, or as adjunctive therapy.78 Amiodarone has been reported to be of assistance in the conversion of ventricular fibrillation.79 Magnesium has occasionally been reported to be of assistance in the conversion of ventricular arrhythmias attendant to chronic digitalis poisoning.

10 Describe the hemodynamic profiles of isoproterenol and dobutamine

Isoproterenol is an extremely potent β1- and β2- agonist that possesses no α-stimulating properties. Therefore isoproterenol increases heart rate, automaticity, and contractility and dilates both venous capacitance and arterial vessels. It may be a good choice for heart-rate maintenance in a denervated nonpaced transplanted heart. Dobutamine acts principally on β-adrenergic receptors, impacting β1-receptors in a relatively selective fashion. In addition, it has a mild indirect β1-stimulating effect that is secondary to prevention of norepinephrine reuptake but is offset by slightly more potent β2-stimulation. Generally at clinical doses minimal increases in heart rate, positive inotropy, increased cardiac output, and minimal or modest decreases in systemic and pulmonary vascular resistance occur. Because of the indirect β1-stimulating effect, patients concurrently receiving β-blockers can exhibit marked increases in systemic vascular resistance without improvement in cardiac output. In addition, an occasional patient will display dose-related increases in heart rate.

Automatic Versus Re-entrant Tachycardia

The rhythm disturbances referred to earlier are classified as automatic rhythm disturbances. If properly diagnosed, they can be classified as disorders of cardiac automaticity. The warmup phenomenon (gradual, nonabrupt increase in heart rate) is a hallmark of automatic tachycardia. Usually, an automatic tachycardia requires a search for its cause, which is then treated. For example, multifocal atrial tachycardia is typically seen in patients with lung disease, and improvement of hypoxemia often results in the return of the cardiac rhythm to normal. Sinus tachycardia frequently indicates a metabolic disturbance such as fever, thyrotoxicosis, or hypovolemia. Again, therapy of the cause is the proper approach rather than addressing the mechanism of the rhythm disturbance itself.12,13 Conversely, a group of tachycardias referred to as re-entrant are treated by addressing the mechanism of re-entry. When this is corrected, the rhythm is restored to normal.

Key Points

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Action potentials vary within the heart and can be classified as fast or slow in nature. Characteristics of action potentials determine or contribute to cardiac automaticity, bathmotropy (cellular excitability), and dromotropy (impulse conduction).

The normal heartbeat begins with spontaneous depolarization of cells within the sinoatrial node and is the result of both a slow, inward Na+ current (also known as a “funny” current) and spontaneous, rhythmic release of Ca2+ from the sarcoplasmic reticulum.

Within the myocardium proper, fast action potentials occur and are initiated by rapid entry of Na+ into the cell via voltage-gated Na+ channels. These channels represent an important site for pharmacologic intervention.

During phase 2 of the action potential, voltage-gated Ca2+ channels open and Ca2+ enters the cardiomyocyte. This small amount of activator Ca2+ induces release of a larger amount from the sarcoplasmic reticulum in what has been termed calcium-stimulated calcium release. As intracellular Ca2+ rises, binding to troponin C occurs, allowing interaction between actin and myosin and resulting in cardiomyocyte contraction. The amount of Ca2+ released during each beat along with the sensitivity of contractile proteins dictates myocardial inotropy (active relaxation).

Relaxation ensues when Ca2+ is taken back into the sarcoplasmic reticulum or extruded from the cell. The rate at which Ca2+ is removed from the cytoplasm, in addition to how quickly it dissociates from the contractile proteins, dictates myocardial lusitropy.

When the myocardium is stimulated more frequently, adaptations occur within the cardiomyocyte, causing Ca2+ to be cleared more quickly during diastole and released in larger amounts during systole. As a result, the myocardium exhibits increased inotropy (contractility) and lusitropy in what has been termed the force-frequency relationship.

When the myocardium is stretched, the number of actin-myosin cross-bridges increases and the overall force of contraction increases. This represents the length-tension relationship, or Frank-Starling mechanism. Importantly, this effect initially does not involve an increase in Ca2+ release from the sarcoplasmic reticulum or a change in Ca2+ sensitivity of the contractile proteins, so although the force of contraction increases, myocardial inotropy does not. By definition, increased inotropy means an augmented ability to do work independent of muscle stretch.

In contrast to the myocardium, Ca2+ entering vascular smooth muscle binds with calmodulin rather than troponin. The Ca2+-calmodulin complex then activates myosin light chain kinase, which phosphorylates the 20-kDa regulatory myosin light chain, releasing inhibition of the actin-myosin interaction. Relaxation then ensues when the regulatory myosin light chain is dephosphorylated by myosin light chain phosphatase.

Vascular smooth muscle tone is critical for maintaining blood pressure and proper distribution of tissue blood flow, and multiple levels of regulation exist. These encompass autonomic, humoral, and local processes as well as intrinsic myogenic responses to stretch that affect either the phosphorylation state of the regulatory myosin light chain or the sensitivity of contractile proteins.

1.5 Basic mechanism of automaticity and its modulation

The cyclic release of stored Ca2 + from the SR produces the tone of the muscle and was thought to be the basic source of rhythmic cardiac automaticity. Pale oval P cells are located centrally in the SA and AV nodes and so named as they are pale, primitive, and pacemaker cells. These cells are oval or rounded in contrast to the elongated shape of other myocardial cells. They are low-conductive cells with a shorter refractory period and have slower depolarization rate. The P cells in the SA node initiate rhythmical impulses automatically at a regular speed, that is, 60–80 beats per minute. Additionally, the P cells in the AV node are called latent pacemakers, which take over rhythmic impulse activities at the slightly slower pace, i.e., 40–60 beats per minute if the SA node stops initiating beats.

The sinoatrial (SA) and atrioventricular (AV) node of the heart have innervation of postganglionic parasympathetic and sympathetic nerves. Nerve impulses cannot initiate rhythmic contraction of cardiac muscle, but they can modulate the contraction rate and its intensity. The membranes of adjacent cardiac muscle fibers interlock each other. The impulse can pass directly from cell to cell through gap junctions. Thus, heart muscle fibers can do rhythmic coordinate contractions without the necessity of an individual innervation. However, its automaticity is under the control of the autonomic nerve innervation. The sympathetic nervous system mediates the excitability of the pacemaker cells by means of the second messenger of cAMP, which acts on HCN channels and activates cyclic AMP-dependent protein kinase (that phosphorylates the Ca2 + channels to open), and excite the pacemaker cells by another second messenger, i.e., Ca2 + by enhancing Ca2+ leak out of the SR in the heart. Cyclic AMP and Ca2 + by stimulation of sympathetic nerve is implicated in making cardiac muscles to be excitable (see Sections 7.4 and 7.9). On the other hand, activation of the IKACh channels begins with the release of ACh from the vagus nerve supplying the specialized myocardial tissue of the SA and AV nodes. ACh binds to the M2 muscarinic acetylcholine receptors on pacemaker cells, which promotes the dissociation of the βγ-complex from α subunit of Gi protein [2] (see Section 7.3). Once the plug of IKACh channel is removed by binding to the βγ-complex, more K+ ions flow out of the pacemaker cells causing hyperpolarization in a resting state during diastole [3]. In its hyperpolarized state, action potentials cannot be generated as quickly, which slows the heart rate (see Section 7.9).

The outstanding characteristic of the small intestinal muscle is its rhythmicity, which is alternate contraction and relaxation at a regular frequency. The basic source of pacemaker activity is thought to be rhythmic Ca2 + diffusion through IP3-gated Ca2 + channels from the ER, which produces the tone of smooth muscle. However, the pacemaker activity can be modified by parasympathetic stimulation which causes an increase in cytosolic Ca2 + via opening of IP3-gated Ca2 + channels and voltage-gated Ca2+ channels, thereby activating myosin ATPase and by sympathetic stimulation which causes a decrease in affinity between the light-chain kinase and Ca2 +-calmodulin, thereby inactivating myosin ATPase. A spike on each small rhythmic depolarization occurs when the circular muscle contracts. Each sharp spike may correspond to Na+ influx and the circular muscle contraction, and the small sinusoidal wave activity may relate to the oscillatory release of stored Ca2 + from the ER and correspond to the tone, but there is no indication of influx of extracellular Ca2 + during relaxation while the contractile stimulus such as parasympathetic stimulation and stretch are absent. ACh raised not only “the base membrane potential” that probably results from an increase in cytosolic Ca2 + but also “the sharp spike frequency,” which results in large increases in the tonic tension and the rate of the circular muscle contractions. The raised base membrane potential probably due to high cytosolic Ca2 + is considered a result of opening of L-type Ca2 + channels by the activated protein kinase C (see Section 8.6). The second messenger in this case is triphosphate, diacylglycerol and Ca2 + instead of cyclic AMP and Ca2 + in the heart. The cyclic increase in cytosolic Ca2 + leads to the phosphorylation of the myosin light chain at serine, which induces the activation of myosin ATPase on the actin binding site. Energy released from the hydrolysis of ATP by the activated ATPase enables recocking of the myosin head to be ready for binding to actin and cyclic muscle contractions (see Section 8.5).