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Home , Cardiac action potential, Cardiac cycle, Chronotropic, Diastole, Membrane potential, Resting potential

Electrical Activity of the : , Automaticity, and Conduction 1 & 2 Clive M. Baumgarten, Ph.D.

OBJECTIVES:

1. Describe the basic characteristics of cardiac electrical activity and the spread of the action potential through the heart 2. Compare the characteristics of action potentials in different parts of the heart 3. Describe how serum K modulates 4. Describe the ionic basis for the and changes in currents during each phase of the action potential 5. Identify differences in electrical activity across the tissues of the heart 6. Describe the basis for normal automaticity 7. Describe the basis for excitability 8. Describe the basis for conduction of the cardiac action potential 9. Describe how the responsiveness relationship and the Na+ channel cycle modulate cardiac electrical activity

I. BASIC ELECTROPHYSIOLOGIC CHARACTERISTICS OF

A. Electrical activity is myogenic, i.e., it originates in the heart. The heart is an electrical syncitium (i.e., behaves as if one ). The action potential spreads from cell-to-cell initiating contraction. Cardiac electrical activity is modulated by the autonomic . B. Cardiac cells are electrically coupled by low resistance conducting pathways gap junctions located at the , at the ends of cells, and at nexus, points of side-to-side contact. The low resistance pathways (wide channels) are formed by connexins. Connexins permit the flow of current and the spread of the action potential from cell-to-cell. C. Action potentials are much longer in duration in cardiac muscle (up to 400 msec) than in or (~5 msec). Action potential characteristics vary in different portions of the heart. II. ELECTRICAL ANATOMY OF THE HEART

A. The pacemaker of the heart is the sino-atrial node (SAN). The SAN is located under the endocardium in the right at the superior vena cava. Action potentials arise in the SAN spontaneously and propagate to the rest of the heart with a specific sequence and specific timing.

B. The rate of spontaneous firing of the SAN determines normal . Parasympathetic (vagus n.; ) and sympathetic () enervate the SAN and modulate heart rate. Slowing of the HR (parasympathetic) is termed a negative effect, and increasing HR (sympathetic) is termed a positive chronotropic effect.

C. The SAN action potential spreads into atria in all directions. The atrial internodal tracts are preferential conduction pathways from SAN to AVN and LA (of little physiological significance). Internodal tracts are also called the atrial specialized conducting system. Conduction velocity is ~1 m/sec.

D. The AV node is the electrical link between the atria and ventricles. It is located under the endocardium in the floor of the right atrium at the septum. The speed of conduction of the action potential slows dramatically (~20 to l00-fold) in the AV node. Normally, AV node conduction velocity is 0.01 to 0.05 m/sec. This gives rise to the AV delay. The AV delay allows for the time needed to complete filling of the before ventricular contraction begins.

Conduction velocity in AVN is modulated by autonomic tone. Sympathetics speed conduction velocity, termed a positive effect, and parasympathetics slow conduction velocity, a negative dromotropic effect. E. After passing through AV node, excitation enters the ventricular specialized conducting system (His-Purkinje system) at the (Common Bundle), proceeds through right and left , their divisions, and terminal to ventricular muscle. Conduction velocity is 2-4 m/sec in the His-Purkinje system, the fastest conduction velocity in the heart. The His- Purkinje system rapidly distributes the cardiac impulse; this allows contraction to proceed from apex to base, as needed for efficient ejection of . F. In the ventricular muscle, the action potential spreads at ~1 m/sec. (Details of sequence of ventricular activation are covered in the ECG lecture.) G. Normal (NSR) is the normal rhythm of the heart. Normal sinus rhythm requires that: 1. the impulse that initiates the beat must arise in the SAN; 2. the rate must be 60 to 100 bpm and regular; 3. excitation must occur in a normal sequence (given above) with appropriate timing of excitation of various portions of the heart.

III. THE ACTION POTENTIAL

A. Phases of the Action Potential Phase 0 – upstroke Phase 1 − initial Phase 2 – plateau Phase 3 – repolarization Phase 4 − electrical B. Resting Potential

In atria, ventricle and Purkinje fibers, the is normally constant during phase 4 and is termed the resting potential (Em). Em is largely + + determined by the transmembrane K gradient and approaches EK, the K equilibrium potential. Changes in serum K+ over the clinically observed range significantly alter Em. Em of SA and AV nodes is essentially insensitive to serum K+ (below ~20 mM). In SAN and AVN, where phase 4 is not constant, the most negative potential attained is termed the maximum diastolic potential (MDP) rather than Em.

(Note: Alterations in serum K+ must be electroneutral, e.g., opposite changes in K+ and Na+ or matching changes in K+ and Cl-; effects of + altered serum K on Em are due to changes in EK. Students sometimes erroneously assume that the altered serum K+ changes simply increases the number of positive charges outside the cell.)

C. Action Potential Duration

Action potential duration (APD) varies inversely with rate. As heart rate increases, the APD shortens. D. Characteristics of the action potential vary in different portions of the heart.

1. Em is about −85 mV (inside neg.), except at SAN and AVN, Em is −60 mV. 2. APD: 150 to 400 msec PKJ > Vent > Atria > AVN ≈ SAN 3. Upstroke is rapid except in SA and AV nodes. 4. Some tissues can spontaneously initiate action potentials. They are said to exhibit automaticity. 5. Phases 2 and 3 run together in SAN and AVN and phase 1 is absent.

IV. IONIC BASIS FOR THE CARDIAC ACTION POTENTIAL

A. The movement of charge across the membrane (current flow) causes changes in membrane potential. Inward movement of positive charge (inward current; e.g., influx of Na+ and Ca2+) causes . Outward movement of positive charge (outward current; e.g., efflux of K+ or influx of Cl-) causes hyperpolarization. A constant membrane potential means inward and outward currents are equal. B. The magnitude of current carried by an ion (I) is equal to the product of the conductance (g) of the membrane for that ion and the driving force (i.e., how far from electrochemical equilibrium is the distribution of the ion). + For K : IK = gK (Em − EK) + For Na : INa = gNa (Em − ENa) 1. Conductance is the reciprocal of electrical resistance; it is related to but not identical to permeability and reflects the ability of to cross the membrane. High conductance implies that it is easy for ions to cross the membrane.

2. Driving force is the difference between Em and the Nernst equilibrium potential for the ion. Driving force is the , the sum of the electrical and concentration (chemical) gradients, expressed in terms of . The electrochemical gradient drives of ions across the membrane. 3. Direction of current. By definition: (1) the direction of current flow is the direction of flow of cations (K+ efflux = outward current; Cl– efflux = inward current); (2) positive current is outward current (repolarizing or hyperpolarizing) and negative current is inward current (depolarizing). • The sign and direction of current are set by the sign of the driving force. + • K : Em always is positive to EK. This means driving force (Em − EK) is + + positive, and K current (IK) is positive (outward), corresponding to K efflux. + • Na : Em always is negative to ENa. This means the driving force + (Em − ENa) is negative, and Na current (INa) is negative (inward), corresponding to Na+ influx.

4. Nernst equilibrium potential represents the membrane potential at which the electrical and chemical gradients are equal and opposite. At that potential, influx and efflux of an ion are equal, i.e., there is no net flux and no current. + If Em were positive to EK, the electrical gradient drawing K in would be less than the concentration gradient pushing K+ out, and a net K+ efflux (positive current) would be observed. The is:

Equilibrium Potential = −2.303 RT/zF log [C]i/[C]o = −61/z log [C]i/[C]o where R is the , T the temperature (°K), F Faraday's constant, and z the valance (e.g., Na+ = +1, K+ = +1, Cl- = −1, Ca2+ = +2). The approximate values of the equilibrium potentials for K+, Na+ and Ca2+ and how changes in intra or extracellular concentrations affects the equilibrium potentials are important. + + EK = −61 log [K ]i/[K ]o = −61 log (150 mM / 4 mM) ≈ −100 mV + + ENa = −61 log [Na ]i/[Na ]o = −61 log (15 mM / 150 mM) ≈ +60 mV 2+ 2+ -7 -3 ECa = −61/2 log [Ca ]i/[Ca ]o = −61/2 log (10 M / 2×10 M) ≈ +110 mV C. Membrane Conductances. Electrical activity is controlled by the and time- dependence of membrane conductance. Several types of channels with differing selective ionic permeabilities have been identified; each channel type is a different molecule. Each channel type has its own conductance term.

Current Effect on Em Current Conductance Ion Equilib. Pot. During AP During AP + INa gNa Na +60 mV Inward Depolarizing + IK gK K −100 mV Outward Repolarizing 2+ ICa gCa Ca +100 mV Inward Depolarizing + IK1 gK1 K −100 mV Outward Repolarizing + Ito gto K −100 mV Outward Repolarizing ______

+ K Current Nomenclature. Some texts use 'IK' to include IK and IK1, but + separate membrane are responsible. IK is similar to K current (delayed ) in nerve. Rapid (IKr), slow (IKs), and ultra-rapid (IKur, atria only) activating components of delayed rectifier with distinct sensitivity are present. IK1 behaves differently than IK in nerve and also is termed the inward- going rectifier. Electrogenic ion transport. Na+-K+ pump and Na+-Ca2+ exchange maintain the ionic gradients. Both processes are electrogenic, meaning they produce a net + + current. At Em, the Na -K pump produces an outward (hyperpolarizing) current (3 Na+ out/2 K+ in) and Na+-Ca2+ exchange an inward (depolarizing) current (1 Ca2+ out/3 Na+ in). The contribution of these currents to the action potential configuration is relatively modest, but over the long term, maintenance of the ionic gradients is critical. D. Ionic Basis for Phases of Ventricular Action Potential. (See next Figure)

$ Phase 4 − Em is constant. Thus inward currents and outward currents are equal. The conductance (gK1) is high; other conductances are low. (To see quantitatively why inward and outward currents are equal, remember that the driving force for K+ is small and those for Na+ and Ca2+ are large.)

$ Phase 0 − Depolarization causes an increase (activation) of gNa. Because + driving force on Na is large and inwardly directed (Em − ENa = −85 − 60 = + −145 mV), Na rushes into the cell. This large INa causes further depolarization. In turn, depolarization increases gNa even more, leading to a further increase in INa. A rapid, regenerative (self-sustained) depolarization results, and Em approaches ENa.

By late in phase 0, INa begins to decrease because: (1) depolarization causes + inactivation (decrease) of gNa, and (2) driving force on Na is reduced. At the action potential peak, Em ≈ +40 mV, and (Em − ENa) = +50 − 60 = −10, less than 10% of its value during phase 4. $ Phase 1 − A rapid repolarization results when outward currents exceed inward currents. INa continues to decrease because of inactivation (reduced + gNa). IK1 is slightly increased because of the large increase in K driving force and despite the voltage-dependent decrease in gK1. At the peak of the action potential, (Em− EK) is +140 mV, while during phase 4, (Em − EK) is +15 mV.

An additional outward current, Ito, contributes to phase 1 repolarization in some parts of the heart including epicardial ventricular muscle and Purkinje fibers. These tissues have a prominent phase 1 and a distinct notch between phase 1 and 2. Ito is a K+ current. There also is evidence for a repolarizing Cl- current (Cl- influx) during phase 1. . $ Phase 2 − Inward and outward currents are nearly equal. Depolarization causes:

1. activation (increase) followed by inactivation (decrease) of gCa; ICa is 2+ much smaller than INa, about 1/50 of the amplitude. L-type Ca channels are mainly responsible for the main plateau Ca2+ current.

2. slow activation (increase) in gK; IK is outward current.

During the plateau, total current becomes more outward (ICa decreases, IK increases) and membrane potential slowly repolarizes. $ Phase 3 − Outward K+ currents are significantly greater than inward current (primarily ICa). gK1 increases rapidly giving the maximum outward current observed. By the end of phase 3, gK1 has increased to its resting level and gK slowly deactivates (decreases) to its resting level. As phase 3 progresses, the outward K+ currents tend to decrease in magnitude because of decreases in driving force and conductance.

E. Important Tissue Differences in the Ionic Basis of the Action Potential.

1. SA and AV Nodes

a. INa is NOT responsible for phase 0. Instead, depolarization is caused by regenerative activation of ICa (L- and T-type). Because the amplitude of the current is smaller, the rate of depolarization is slower. T-type Ca2+ channels are more prominent in SAN than in other parts of the heart. b. Automaticity is due to the sum of the currents becoming inward during diastole. An increasing inward current carried primarily by Na+ is responsible. This current is the , If. If is turned off by depolarization during AP and is turned on by hyperpolarization (phase 4). + Depolarization initiated by If reduces a background K current and begins to activate ICa as is approached. If is prominent in both SA and AV nodes. 2. His-Purkinje System

Em is normally constant during diastole in the His-Purkinje system. In the absence of a sinus beat, however, Em can spontaneously depolarize causing automaticity. If is responsible for normal automaticity in the His-Purkinje system. F. Role of currents in action potential

1. INa − Responsible for upstroke; Turns on during phase 0 and off during phases 0 & 1.

2. ICa − Responsible for inward current during plateau. Turns on early in phase 2 and slowly turns off in phase 2. Inactivation of ICa helps set action potential duration. Note that ICa reflects the activity of 2 distinct channel types, T (transient) and L (longer lasting). Most effects ascribed to Ca2+ channels are due to L channels. L-type Ca2+ channels are modulated by classical Ca2+ channel agonists (norepinephrine) and antagonists (, acetylcholine). T-type Ca2+ channels are more important in SAN than in other parts of the heart.

3. IK1 − Responsible for resting potential. Decrease in gK1 upon depolarization + limits increase in IK1 otherwise caused by increased K driving force during plateau.

4. IK− Slowly turns on during phase 2. Slow increase in IK helps set action potential duration. There are several types of IK channels in heart. IKr activates more rapidly than slowly activating IKs, and ultra-rapid IKur speeds atrial repolarization. Some distinguish between types.

5. Ito − Contributes to phase 1 repolarization, especially in epicardial ventricular muscle and Purkinje fiber. Also contributes to heart rate-dependence of APD in these tissues. Expression of Ito varies in different parts of the heart. At least two different channels with different kinetics contribute to Ito. – 6. ICl - At least 3 distinct, Cl currents have been identified in heart. A Ca- - dependent Cl current contributes to Ito (Ito2). These currents can modulate action potential configuration.

Action potential duration, primarily the length of phase 2, is set by the slow turn on (activation) of IK and slow turn off (inactivation) of ICa. These events occur during phase 2 and initiate the rapid repolarization of phase 3. The outward K+ currents are greatest during phase 3 when the rate of repolarization is greatest. APD decrease as HR increases because of slow changes in several currents including IKr, IKs, and ICa-L.

Why is there a plateau in heart but not in nerve? (1) ICa provides the inward current to maintain the depolarization. ICa is absent or insignificant in nerve; and (2) the decrease in gK1 on depolarization limits outward current and makes it easier to maintain a plateau. In nerve, gK1 does not decrease. Thus, outward IK1 is much larger and repolarization occurs within msec. V. IMPULSE FORMATION

A. Normal automaticity is the intrinsic ability of specialized cells of the heart to spontaneously depolarize during diastole (also termed phase 4 depolarization) and to initiate an action potential.

B. Cells exhibiting normal automaticity are found in: 1. SAN 2. Certain specialized peri-nodal atrial fibers. 3. AVN (N-H region, i.e., that portion adjacent to His Bundle) 4. Bundle of His 5. Bundle Branches 6. Purkinje fibers. C. The pacemaker with the fastest rate will control heart rate. Normally, the hierarchy is: SAN (fastest), AVN, Bundle of His, Bundle Branches, Purkinje fibers (slowest). That is, as one moves distally in the sequence of activation, the intrinsic rate of automaticity slows. However, disease processes and/or autonomic tone can modify this order. Upon blocking or abolishing the SAN impulse, the AVN usually takes over. D. Cells that do not normally exhibit normal automaticity are termed latent pacemakers (B(2) to B(6), above). Their automaticity is suppressed by the normal heart beat or by electrical stimulation. This suppression of latent pacemakers is termed overdrive suppression. Latent pacemakers are also referred to as ectopic pacemakers because the site of initiation of the heart beat is outside SAN. E. To initiate a spontaneous beat, a pacemaker cell must depolarize from the maximum diastolic potential to the threshold potential. That means that the rate of firing of pacemakers is dependent on three factors that control 1. Maximum diastolic potential. 2. Threshold potential. 3. Rate of diastolic (phase 4) depolarization.

The rate of firing reflects diastolic events and threshold potential. Because APD is much shorter than phase 4 (diastole), changes in APD do not significantly alter automaticity. Threshold potential. Potential at which membrane generates a net inward current (i.e., the inward current becomes larger than the outward current), and the depolarization becomes self-sustained and gives rise to the upstroke. Some characteristics of threshold potential. Threshold potential is NOT the voltage at which Na+ (or Ca2+ in SAN or AVN) channels suddenly switch on. Rather, Na+ (and Ca2+) channels begin to open at far negative to the threshold potential. The fraction of resting channels that open increases gradually as the membrane is depolarized. This implies that interventions that alter the number of Na+ channels in the resting state also alter threshold potential. For example, if an intervention reduced the number of Na+ channels in the resting state, a greater fraction of the remaining Na+ channels must open to overcome the outward current; a greater depolarization would be required, and threshold potential would shift to a more positive potential. Because Em controls the number of resting Na+ (e.g., in Purkinje fibers) and Ca2+ channels (in SAN and AVN), threshold potential usually moves in the same direction as Em. VI. EXCITABILITY

A. Excitability reflects the ability of heart muscle to initiate an action potential in response to depolarizing current. Threshold is the amount of current needed to depolarize from Em to the threshold potential.

B. Excitability changes during the action potential.

1. Absolute Refractory Period (ARP): Stimulation is not possible. 2. Relative Refractory Period (RRP): Begins after ARP. An action potential can be elicited, but a larger current is needed than at rest. During the first part of the RRP, within the ERP, action potentials generate a local response but fail to conduct. 3. Effective Refractory Period (ERP): Longer than ARP. A conducted action potential cannot be elicited. 4. Supranormal Period (SNP): Current required for excitation is less than required at rest. Threshold potential returns to control value just before repolarization is complete. The SNP is most prominent in Purkinje fibers.

C. Recovery of the ability to generate an inward current is essential to recovery of excitability. Recovery of the Na+ channel (or Ca2+ channel in SAN or AVN) from the Inactivated (I) to the Closed but Available (C) state requires repolarization. During the , changes in membrane potential, threshold potential, and membrane resistance contribute to the time-dependence of excitability. Except for SAN and AVN, recovery of excitability closely follows repolarization. In SAN and AVN recovery of excitability lags further behind repolarization because the slow kinetics of Ca2+ channels. VII. IMPULSE CONDUCTION

A. Conduction in heart occurs via local circuit currents as in unmyelinated nerves.

rm = membrane resistance ri = intracellular resistance for cell-to-cell current flow

1. Inward current generated by INa (or ICa in SAN or AVN) depolarizes the membrane. 2. Depolarizing current spreads down the fiber from cell-to-cell causing distant membrane to depolarize Depolarization alters the charge stored by membrane capacitance. 3. Current loop is completed in the extracellular space. 4. When a distant patch of membrane is sufficiently depolarized, it also generates inward current, and conduction continues. This requires depolarization to threshold potential. 5. Conduction velocity is NOT related to action potential duration (APD). Conduction velocity reflects the time it takes for excitation to spread. APD reflects the time depolarization persists once a cell is excited.

B. Determinants of Conduction Velocity

1. Amplitude of inward current that generates local circuit current flow. Smaller inward currents will depolarize distant membrane more slowly and, thereby, slow conduction velocity. 2. Passive properties - the resistive and capacitive properties of the membrane and cell-to-cell junctions determine the spread of current. Increased resistance (Ri), referred to as electrical uncoupling, makes it more difficult to depolarize distant membrane and, thereby, slows conduction velocity.

Rm = membrane resistance Cm = membrane capacitance Ri = intracellular (cell-to-cell) resistance 3. Excitability − the amount of current required to reach threshold potential. Decreased excitability means a larger amplitude current (or the same current for a longer time) is required to depolarize to threshold potential; decreased excitability slows conduction velocity. VI. RESPONSIVENESS

• A. The maximum rate of rise of phase 0 of the action potential (dV/dt or V max) is dependent on the membrane potential at the moment of excitation.

B. dV/dt is a rough measure of the amplitude of the inward current during phase 0 (INa in atria, ventricle and Purkinje fibers or ICa in SA and AV node). C. After depolarization, recovery to a more negative potential is necessary to reprime Na+ (or Ca2+) channels. Depolarization can again elicit an increase in conductance only after recovery.

D. All other things being equal, dV/dt is roughly directly proportional to both conduction velocity and excitability.

E. The voltage-dependence inactivation also explains why changes in Em cause threshold potential to shift in the same direction. IX. REFERENCES

A. Koeppen, B.M. and Stanton, B.A. Berne & Levy Physiology, 6th Ed., 2008. pp 292-300. B. Costanzo, L.S. Physiology, 3rd, Saunders, 2006. Chapter 4, pp. 125-136.

5-electrical activity of the heart-2009.doc 8/28/2008